NZ615557B2 - Pyrrolo [2,3-d] pyrimidine derivatives as inhibitors of tropomyosin- related kinases - Google Patents

Abstract

Disclosed are pyrrolo[2,3-d]pyrimidine compounds of Formula (I) wherein the substituents are as described in the specification, which includes the compound N-(5-{[2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-dlpyrimidin-5-yllcarbonyl}pyridin-3-yl)-2-[4-(trifluoromethyl)phenyllacetamide. Also disclosed are processes for the preparation of the compounds, compositions containing the compounds, and the uses of such compounds and salts in treating diseases or conditions associated with tropomyosin-related kinase (Trk), and activity. More specifically the invention relates to the compounds and their salts useful as inhibitors of Trk for the treatment of diseases or conditions such as pain and cancer. so disclosed are processes for the preparation of the compounds, compositions containing the compounds, and the uses of such compounds and salts in treating diseases or conditions associated with tropomyosin-related kinase (Trk), and activity. More specifically the invention relates to the compounds and their salts useful as inhibitors of Trk for the treatment of diseases or conditions such as pain and cancer.

Description

PYRROLO [2,3-D] PYRIMIDINE DERIVATIVES AS INHIBITORS OF TROPOMYSIN-RELATED KINASES The invention described herein relates to n o[2,3-d}pyrimidine compounds and the pharmaceutically acceptable salts of such nds. The invention also relates to the processes for the preparation of the compounds, itions 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 or tyrosine kinases activated by neurotrophins.

Trks play important roles in pain sensation as well as tumour cell growth and survival signaling. Thus, inhibitors of Trk receptor kinases might provide targeted treatments for conditions such as pain and cancer. Recent developments in this field have been reviewed by Wang et al in Expert Opin. Ther.

Patents (2009) 19(3): 305-319 and an extract is reproduced below. “1.1 Trk receptors As one of the largest family of proteins encoded by the human genome, protein kinases are the central regulators of signal transduction as well as control of various complex cell processes. Receptor ne kinases (RTKs) are a ily of protein kinases (up to 100 members) bound to the cell membrane that ically 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. All three isoforms are activated by high affinity growth factors named neurotrophins (NT): i) nerve growth factor (NGF), which activates TrkA; ii) derived neurotrophic factor (BDNF) and NT-4/5, which te TrkB; and iii) NT-3, which activates TrkC. The binding of neurotrophins to the extracellular domain of Trks causes the Trk kinase to autophosphorylate at several intracellular tyrosine sites and rs 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 nance and survival of neuronal cells. However, in the past 20 years, increasing ce has suggested that Trks play key roles in malignant transformation, chemotaxis, metastasis, and survival signaling in human tumors. The association n Trks and cancer focused on prostate cancer in r years and the topic has been reviewed. For example, it was reported that malignant prostate epithelial cells secrete a series of neurotrophins and at least one Trks. In pancreatic cancer, it was proposed that paracrine and/or autocrine rophin-Trk interactions may influence the invasive behavior of the cancer. TrkB was also reported to be overexpressed in metastatic human atic cancer cells. Recently, there have been a number of new findings in other cancer settings. For example, a translocation leads to expression of a fusion protein derived from the N-terminus of the ETV6 ription factor and the C-terminal kinase domain of TrkC. 40 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 sis, and TrkB overexpression was also associated with increased resistance to chemotherapy in neuroblastoma tumor cells in vitro. One report showed that a novel splice variant of TrkA called l signaled in the e of neurotrophins through the inositol phosphate—AKT y in a subset of neuroblastoma. Also, mutational analysis of the tyrosine kinome revealed that Trk mutations occurred in colorectal and lung cancers. In summary, Trks have been linked to a y of human cancers, and discovering a Trk inhibitor and testing it clinically might provide further insight to the biological and l hypothesis of treating cancer with targeted therapies. 1.3 Trks and pain Besides the newly developed ation with cancer, Trks are also being recognized as an important mediator of pain sensation. Congenital insensitivity to pain with anhidrosis (CIPA) is a disorder of the peripheral nerves (and normally innervated sweat glands) that prevents the patient from either being able to adequately perceive painful stimuli or to sweat. TrkA s have been shown to cause CIPA in various ethnic groups.

Currently, eroidal anti-inflammatory drugs (NSAIDs) and opiates have low efficacy and/or side effects (e.g., gastrointestinal/renal and psychotropic side s, respectively) against neuropathic pain and therefore development of novel pain treatments is highly desired. It has been recognized that NGF levels are elevated in response to chronic pain, injury and inflammation and the administration of ous NGF increases pain hypersensitivity. In addition, inhibition of NGF function with either anti- NGF antibodies or non-selective small molecule Trk inhibitors has been shown to have effects on pain in animal models. It appears that a selective Trk inhibitor (inhibiting at least NGF’s target, the TrkA receptor) might provide clinical benefit for the treatment of pain. ent earlier reviews have covered targeting NGF/BDNF for the treatment of pain so this review will only focus on small le 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 ation 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 /143024 and W02009/143018 refer to various pyrrolo[2,3-d]pyrimidines substituted as Trk inhibitors; International Patent Application publication s W02004/056830 and W02005/116035 describe various 4-amino-pyrrolo[2,3- d]pyrimidines as Trk inhibitors. International Patent Application publication number W02011/133637 bes various pyrrolo[2,3-d]pyrimidines and pyrrolo[2,3-b]pyridines as inhibitors of various kinases.

US ional application U861/471758 was filed 5th April 2012 and the whole contents of that application in it’s entirety are herewith included by reference thereto.

Thus Trk tors have a wide variety of potential medical uses. There is a need to provide new Trk 40 inhibitors that are good drug ates. In particular, compounds should preferably bind potently to the Trk receptors in a ive manner compared to other receptors, whilst showing little affinity for other receptors, including other kinase and / or GPC receptors, and show functional ty as Trk receptor antagonists. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will exist in a physical form that is stable, groscopic 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 nces, particularly Trk antagonists, i.e. that block the intracellular kinase activity of the Trk, e.g. TrkA (NGF) receptor. Other desirable features include good HLM/hepatocyte stability, oral bioavailability, metabolic stability, absorption, selectivity over other types of kinase, dofetilide selectivity. Preferable nds and salts will show a lack of CYP inhibition/induction, and be CNS- spanng.

W The present invention provides compounds of Formula I: and pharmaceutically acceptable salts thereof wherein the subsituents are defined below.

The ion also comprises pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt f, and a pharmaceutically able carrier.

The invention is also directed to a method of treating a disease or condition indicated for ent with a Trk antagonist, in a subject, by administering to a subject in need thereof a therapeutically effective amount of one or more of the compounds herein, or a pharmaceutically acceptable salt thereof.

Other aspects of the invention will be nt from the remaining description and claims.

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

The compounds of the present invention are potentially useful in the treatment of a range of disorders where a Trk antagonist is indicated, particularly pain indications. Depending on the disease and ion of the t, 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 t invention may be useful to treat any physiological pain such as inflammatory pain, nociceptive pain, neuropathic pain, acute pain, chronic pain, musculo- skeletal pain, on-going pain, central pain, heart and vascular pain, head pain, orofacial pain. Other pain conditions which may be treated include intense acute pain and chronic pain conditions which may involve the same pain pathways driven by pathophysiological processes and as such cease to provide a protective mechanism and instead contribute to debilitating symptoms associated with a wide range of e states.

Pain is a feature of many trauma and e 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 ensitivity far outlasts the healing process and is normally due to s system injury due to maladaptation of the afferent fibres (Woolf & Salter 2000 Science 288: 1765-1768). Clinical pain is present when discomfort and abnormal sensitivity feature among the patient’s symptoms. There are a number of typical pain subtypes: 1) spontaneous pain which may be dull, burning, or stabbing; 2) pain responses to noxious stimuli are exaggerated (hyperalgesia); 3) pain is ed by normally innocuous stimuli (allodynia) (Meyer et al., 1994 Textbook of Pain . Pain can be d into a number of different areas because of differing hysiology, these include nociceptive, inflammatory, neuropathic pain among others. It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. Back pain, Cancer pain have both nociceptive and neuropathic components.

NOCICEPTIVE PAIN Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are ted 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 d up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994 Textbook of Pain 13-44). The activation of nociceptors activates two types of nt nerve fibres. Myelinated A—delta fibres transmit rapidly and are responsible for the sharp and stabbing pain ions, 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 40 pain from strains/sprains, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, burns, myocardial infarction, acute pancreatitis, and renal colic. Also cancer related acute pain syndromes commonly due to therapeutic interactions such as chemotherapy toxicity, immunotherapy, hormonal therapy and radiotherapy. Moderate to severe acute nociceptive pain is a prominent feature of, but is not limited to, cancer pain which may be tumour related pain, (e.g. bone pain, headache and facial pain, viscera pain) or associated with cancer therapy (e.g. postchemotherapy syndromes, chronic postsurgical pain syndromes, post radiation syndromes), back pain which may be due to herniated or ruptured intervertabral discs or abnormalities of the lumbar facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament.

NEUROPATHIC PAIN According to the invention a compound of the present invention can potentially be used to treat neuropathic pain and the symptoms of neuropathic pain including hyperalgesia, allodynia and ongoing pain. Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (IASP definition). Nerve damage can be caused by trauma and disease and thus the term ‘neuropathic pain’ encompasses many disorders with diverse aetiologies. These include but are not limited to, Diabetic neuropathy, Post herpetic neuralgia, Back pain, Cancer neuropathy, HIV athy, Phantom limb pain, Carpal Tunnel Syndrome, c alcoholism, hypothyroidism, trigeminal gia, uremia, or vitamin deficiencies. Neuropathic pain is pathological as it has no protective role. It is often t well after the original cause has ated, commonly lasting for years, significantly decreasing a patients y of life (Woolf and Mannion 1999 Lancet 353: 1959-1964). The ms of neuropathic pain are difficult to treat, as they are often heterogeneous even n patients with the same disease (Woolf & Decosterd 1999 Pain Supp. 6: 8141-8147; 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 tivity to a normally ous stimulus).

E ACUTE PAIN AND CHRONIC PAIN Intense acute pain and chronic pain may involve the same pathways driven by hysiological processes and as such cease to provide a tive mechanism and instead contribute to debilitating symptoms associated with a wide range of disease states. Pain is a feature of many trauma and disease . When a substantial injury, via disease or , to body tissue occurs the characteristics of nociceptor activation are altered. There is isation 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 ses to take place and the hypersensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is normally due to nervous system injury. This injury often leads to maladaptation of the afferent fibres (Woolf & Salter 2000 Science 288: 1765-1768). Clinical pain is present when discomfort and abnormal sensitivity feature among the t’s symptoms. Patients tend to be quite heterogeneous and may present with s pain 40 symptoms. There are a number of typical pain subtypes: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain ses to noxious stimuli (hyperalgesia); 3) pain is produced by normally innocuous stimuli (allodynia) (Meyer et al., 1994 Textbook of Pain 13-44). Although patients with back pain, arthritis pain, CNS trauma, or athic pain may have r 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 athic pain, chronic inflammatory pain, breakthrough pain, persistent pain hyperalgesia, allodynia, central isation, 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, oma in epithelial , leukemia in tissues that form blood cells, lymphoma in lymphatic tissue, a in bone marrow, sarcoma in connective or supportive tissue, adrenal cancer, AIDS-related lymphoma, anemia, bladder cancer, bone , brain cancer, breast cancer, carcinoid tumour s, cervical cancer, chemotherapy, colon cancer, cytopenia, , endometrial cancer, esophageal cancer, gastric cancer, head cancer, neck cancer, hepatobiliary cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, Hodgkin's disease, lymphoma, non- Hodgkin's, nervous system tumours, oral cancer, n cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, ular cancer, thyroid cancer, urethral cancer, bone cancer, sarcomas cancer of the connective tissue, cancer of bone tissue, cancer of blood-forming cells, cancer of bone marrow, multiple a, leukaemia, primary or secondary bone cancer, tumours that metastasize to the bone, tumours infiltrating the nerve and hollow viscus, tumours near neural structures.

Cancer pain also comprises visceral pain, e.g. al pain which arises from pancreatic cancer and/or metastases in the abdomen, somatic pain, e.g. somatic pain due to one or more of bone cancer, metastasis in the bone, postsurgical pain, sarcomas cancer of the connective tissue, cancer of bone tissue, cancer of blood-forming cells of the bone marrow, multiple myeloma, leukaemia, primary or secondary bone cancer.

INFLAMMATORY PAIN Inflammatory conditions include acute inflammation, persistent acute inflammation, chronic inflammation, and combined acute and chronic inflammation.

Inflammatory pain includes acute inflammatory pain and/or chronic inflammatory pain wherein the chronic inflammatory pain can be pain involving both eral and central isation and/or mixed etiology pain involving both inflammatory pain and athic pain or ptive pain components. matory pain also comprises hyperalgesia, e.g. primary and/or secondary hyperalgesia. Additionally or atively the inflammatory pain can e allodynia. Inflammatory pain also comprises pain that persists beyond tion 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 40 to trauma, disease e.g. an inflammatory disease, immune on, the ce of foreign substances, chemicals or infective particles for example micro-organisms. Inflammatory conditions can be either acute or chronic inflammation or both.

Inflammatory pain can result from an inflammatory condition due to an inflammatory e such as matoryjoint diseases, inflammatory connective tissue diseases, inflammatory autoimmune diseases, inflammatory myopathies, matory digestive system diseases, matory air way es, cellular immune inflammation diseases, hypersensitivities and allergies, vasular inflammation diseases, non-immune inflammatory disease, synovitis, villonodular synovitis, arthralgias, ankylosing spondylitis, spondyloarthritis, spondyloarthropathy, gout, Pagets disease, periarticular disorders such as bursitis, rheumatoid disease, rheumatoid arthritis and osteoarthritis, rheumatoid arthritis or osteoarthritis.

Rheumatoid arthritis in particular, represents ongoing inflammation associated with severe pain. Arthritic pain is a form of inflammatory pain and arises from inflammation in a joint which causes both peripheral sensitization and central sensitization. Under inflammatory conditions the nociceptive system is activated by normally innocuous and nful mechanical stimuli. Additionally when the joint is at rest pain is present and appears as spontaneous pain and hyperalgesia (augmented pain response on noxious stimulation and pain on normally nonpainful stimulation). Inflammatory processes in peripheral tissues lead to central sensitization in the spinal cord, which contributes to hyperalgesia and allodynia lly 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 a, fibromyalgia, litis, sero-negative (non-rheumatoid) pathies, non-articular rheumatism, dystrophinopathy, Glycogenolysis, polymyositis, sitis; - Central pain or ‘thalamic pain’ as defined by pain caused by lesion or dysfunction of the nervous system including but not limited to central post-stroke pain, multiple sclerosis, spinal cord injury, Parkinson’s disease and epilepsy; - Heart and vascular pain including but not limited to angina, myocardical infarction, mitral is, pericarditis, Raynaud’s phenomenon, doma, scleredoma, skeletal muscle ischemia; - al pain, and gastrointestinal disorders. The viscera encompasses the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain. Commonly tered gastrointestinal (GI) disorders include the functional bowel disorders (FBD) and the inflammatory bowel diseases (IBD). These GI disorders e a wide range of e states that are tly only moderately controlled, including — for FBD, gastro-esophageal reflux, dyspepsia, the irritable bowel syndrome (IBS) and onal abdominal pain syndrome (FAPS), and — for IBD, Crohn’s disease, ileitis, and ulcerative colitis, which all regularly produce visceral pain. Other types of visceral pain include the pain ated with dysmenorrhea, pelvic pain, cystitis and pancreatitis; Head pain including but not limited to ne, 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, ss leg syndrome and blocking development of abuse potential. r pain conditions may include, back pain (e.g. chronic lower back pain), cancer pain, complex regional syndrome, HIV-related neuropathic pain, post-operative induced neuropathic pain, post-stroke pain, spinal cord injury pain, tic nerve injury pain, diabetic peripheral neuropathy, moderate / severe interstitial cystitis pain, irritable bowel syndrome pain, moderate / severe endometriosis pain, moderate / severe pelvic pain, moderate / severe prostatitis pain, moderate / severe osteoarthritis ost-herpetic neuralgia, rheumatoid arthritis pain, dysmenorrhea pain, pre-emptive post-operative pain, trigeminal neuralgia, bursitis, dental pain, fibromyalgia or myofacial pain, menstrual pain, migraine, athic pain (including painful diabetic neuropathy), pain associated with post- herpetic neuralgia, post-operative pain, ed pain, trigeminal gia, visceral pain (including interstitial cystitis and IBS) and pain associated with AIDS, nia, 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 salt f, wherein R1 is H, or C1_5 alkyl optionally substituted by up to 3 substituents ndently selected from OH, CON(R5R6), SOZR7, SR7, 0R7, CHZOH, COZR5, SONR7R7, NR7SOZR5, 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), sozR7, 0R7, CHZOH, COZR5, SONR7R7, R5, CN, N02 and R8; R2 is H or methyl; R3 is H, NH2 or NH(C1_3 alkyl optionally substituted with up to 3 substituents independently selected from OH and O(C1_3 alkyl)); R101 is H, OH, methyl, cyclopropyl, methoxy, ethyl, ethoxy or CN, x is a bond, 0, (CH-R4)n, NR1“, OCH2 or CHZO; R4 is ndently H, CH3, CHZOH, CHZOCHg, OH, NH2, NHCH3, N(CH3)2, CHZNHZ, CHZNHCH3,Or CH2N(CH3)2, R104 is H, C1_3 alkyl or a C4_6 ted carbocycle, each of which is optionally substituted by up to 3 substituents independently selected from C1_3 alkyl, CHZOH and NH2; nis1or2; R102 is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic system, or an 8 ed bicyclic system, which ring system may be saturated or partially or fully unsaturated, wherein the heterocyclic ring system may have up to 5 ring hetero-atoms selected from N, S, and 0, wherein the ic 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 le - halo, CN, NR5R6, SOZR7, SR7, C1_4 alkyl optionally substituted by up to 3 OH and/or C1_3 alkoxy groups, C3_6 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(C1_3 alkyl), O(C3_6 cycloalkyl ally substituted by up to 3 OH and/or C1_3 alkoxy groups, O(C1_3 alkyl substituted by up to 3 halogen), O(C1_3 alkyl substituted by up to 3 OH and/or C1_3 alkoxy groups), NR5SOZR7, :0, R8, C(O)R8, N02, NR5COZR7, NR5COR7,OR8, S(O)R7, and CH2R8; R5and R6 are each independently H, or C1_5 alkyl optionally tuted by up to 3 substituents independently selected from OH, CONR7R7, sozR7, 0R7, CHZOH, COZR7, SONR7R7, NR7SOZR7, CN, N02 and R9 , a ring system selected from 03.5 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, R7, CN, N02, halo, NR7R7,SR7,C1_4 alkyl ally substituted by up to 3 OH and/or C1_3 alkoxy groups, C3_6 cycloalkyl optionally substituted by up to 3 OH and/or C1_3 alkoxy , C1_3 alkyl substituted by 1 to 3 halogen, O(C3_6 cycloalkyl optionally substituted W0 2012/137089 10 by up to 3 OH and/or C1_3 alkoxy groups, O(C1_3 alkyl substituted by up to 3 halogen, O(C1_3 alkyl substituted by up to 3 OH and/or c1.3 alkoxy, NR7SOZR7,=O,NOZ,NR7COZR7, and S(O)R7 or R5 and R6 together with the N to which they are attached can be a 4-7 membered ring ally including up to 2 further ring hetero-atoms independently selected from N, O, S, which ring is optionally substituted by C1_3 alkoxy and / or C1_3 alkyl; R7 is H, c,_5 alkyl or c,_5 alkoxy, which C1_5 alkyl or C1_5 alkoxy is optionally substituted by up to 3 substituents independently selected from halogen; R8 is a is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic system, or an 8- 14-membered bicyclic system, which ring system may be saturated or lly or fully unsaturated, wherein the heterocyclic ring system may have up to 5 ring hetero-atoms selected from N, S, and 0, wherein the bicyclic ring system can be 2 rings (carbocyclic-carbocyclic, carbocyclic-heterocyclic, cyclic-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, SOZR7, SR7, C1_4 alkyl optionally substituted by up to 3 OH and/or C1_3 alkoxy groups, C3_6 cycloalkyl optionally substituted by up to 3 OH and/or C1_3 alkoxy groups, C1_3 alkyl substituted by 1 to 3 halogen, OH, O(C1_3 alkyl), O(C3_6 cycloalkyl ally substituted by up to 3 OH and/or C1_3 alkoxy groups, O(C1_3 alkyl substituted by up to 3 halogen, O(C1_3 alkyl tuted by up to 3 OH and/or C1_3 alkoxy, NR5SOZR7, :0, N02, NR7COR7,NR5COZR7, and S(O)R7; R9 is a is a ring system which is a 3-7 membered monocyclic yclic or heterocyclic system, or an 8- 14-membered bicyclic system, which ring system may be saturated or lly or fully unsaturated, n the heterocyclic ring system may have up to 5 ring hetero-atoms selected from N, S, and 0, 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 tuted by up to 3 substituents independently selected from, where possible - halo, CN, NR7R7, SOZR7, SR7, C1_4 alkyl optionally substituted by up to 3 OH and/or C1_3 alkoxy , C3_6 cycloalkyl optionally substituted by up to 3 OH and/or C1_3 alkoxy groups, C1_3 alkyl substituted by 1 to 3 halogen, OH, O(C1_3 alkyl), O(C3_6 cycloalkyl optionally substituted by up to 3 OH and/or C1_3 alkoxy , O(C1_3 alkyl substituted by up to 3 n, O(C1_3 alkyl substituted by up to 3 OH and/or C1_3 alkoxy, NR7SOZR7, :0, N02, NR7COZR7, NR7COR7,and S(O)R7; wherein each CH moiety can be replaced by a CF moiety.

Embodiment 2 of the ion is a compound or salt according to embodiment 1 wherein R1 is H, C1_5 40 alkyl optionally substituted by up to 2 OH, W0 2012/137089 11 or R1 is 01.5 alkyl substituted by CONHZ, CONHCH3, CON(CH3)2, COZH, COZCH3, OCH3, SCH3, SOZCH3, or R1 is a ring system selected from 03.5 cycloalkyl, propellanyl, or oxetanyl, which ring system is ally substituted by methyl, OH or CHZOH.

Embodiment 3 of the invention is a nd or salt according to any one of embodiments 1 or 2 wherein R1 is t-butyl, hydroxy—t-butyl, dihdyroxy—t-butyl, 1-hydroxypropyl or 1,3-dihydroxypropyl.

Embodiemnt 4 of the invention is a nd or salt according to any one of ments 1 to 3 wherein R2 is H.

Embodiemt 5 of the invention is a compound or salt according to any one of embodiments 1 to 4 wherein R3 is H or NHZ. ment 6 of the invention is a compound or salt ing to any one of embodiments 1 to 5 wherein R3 is NH2.

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

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

Embodiment 9 of the invention is a compound or salt ing to any one of embodiments 1 to 7 wherein R101 is OH.

Embodiment 10 of the invention is a compound or salt according to any one of embodiments 1 to 9 wherein X is a bond, 0, CH2, C2H4, CH(CH3)CH2, CH(CH3), CH(CHZOH), CHZO, CH(NHZ), CH(OH) or NH.

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

Embodiment 12 of the invention is a compound or salt according to any one of embodiments 1 to 11 wherein R - is an optionally substituted nitrogen-containing ring system which is linked to the X moiety via a nitrogen ring atom.

Embodiment 13 of the invention is a compound or salt according to any one of embodiments 1 to 11 wherein R is an optionally substituted ring system where the ring system is selected from - benzimidazolyl, benzisoxazolyl, benzofuranyl, azolyl, benzotriazolyl, biphenyl, bipyrazolyl, cinnolinyl, cyclobutylimidazolyl, cyclobutylpyrazolyl, cyclobutylthiazolyl, cyclopentyltriazolyl, 40 cyclopropylisoxazolyl, cyclopropyloxazolyl, cyclopropylpyrazolyl, cyclopropyltriazolyl, diazirenylphenyl, dihydronaphthyridinyl, dihydropyrrolopyrazolyl, dioxinopyridinyl, furazanyl, furopyridinyl, furopyrrolyl, W0 2012/137089 12 olyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazothiadiazolyl, imidazothiazolyl, indanyl, indazolyl, indolyl, isoindolyl, isoxazolopyridinyl, isoxazolyl, isoquinolinyl, naphthyridinyl, oxazolyl, , phenylcyclopropyl, phenylimidazolyl, phenylpyrazolyl, phenylpyrrolyl, phenyltetrazolyl, phthalazinyl, purinyl, pyrazinyl, pyrazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, lotriazinyl, pyridinyl, pyridazinyl, pyridinyltriazolyl, pyrimidinyl, pyrroloimidazolyl, pyrrolopyrazinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrrolyl, quinolinyl, quinazolyl, alinyl, tetrahydrobenzisoxazolyl, ydrocyclopentapyrazolyl, tetrahydrotriazolopyridinyl, tetrazolopyridazinyl, tetrazolopyridinyl, thiazolyl, thiazolopyridinyl, thiazolopyrimidinyl, thienylpyrazolyl, thienopyridinyl, lopyridinyl and triazolyl, Embodiment 14 of the invention is a compound or salt according to embodiment 13 where the optional substituents are independently selected from, where possible - halo, methyl, ethyl, propyl, isopropyl, cyclopropyl, CF3, CHFZ, CHZF, CHZOCH3, CN, CHZOH, OCH3, =0, NH2, SCH3, SOZCH3, phenoxy, fluorophenoxy, benzyl, SCF3, OCF3, SOZCF3, NHSOZCH3, NH802CF3, C(O)CF3, C(O)CH3, benzoyl, azetidinylmethyl, fluoroazetidinylmethyl and morpholinomethyl. ment 15 of the invention is a compound or salt according to any one of embodiments 1 to 11, 13 102- or 14, wherein R IS selected from phenyl, pyrazolyl, 1,2,3-triazolyl, benzotriazolyl, nyl, pyridinyl and pyridinyl, each of which is optionally substituted by halo, methyl, ethyl, propyl, isopropyl, cyclopropyl, CF3, CHFZ, CHZF, CH20CH3, CN, CHZOH, OCH3, =0, NH2, SCH3, SOZCH3, phenoxy, fluorophenoxy, benzyl, SCF3, OCF3, 802CF3, NH802CH3, NHSOZCF3, C(O)CF3, C(O)CH3, benzoyl, azetidinylmethyl, fluoroazetidinylmethyl and/or morpholinomethyl.

Embodiment 16 of the invention is a nd or salt according to any one of embodiments 1 to 15 with R5 and R6 groups present, wherein R5 and R6 are each independently H, C1_3 alkyl optionally substituted by C1_3 alkoxy, C3_5 cycloalkyl, propellanyl, yl, tetrahydrofuranyl or l, or R5 and R6 together with the N to which they are attached can be an azetidine, pyrrolidine, piperidine, piperazine or line ring, which ring is optionally substituted by C1_3 alkoxy and / or C1_3 alkyl.

Embodiment 17 of the invention is a compound according to embodiment 1 of the Formula IA: W0 2012/137089 13 (IA) or a pharmaceutically acceptable salt thereof, wherein R3 is H or NHZ; 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 ered heterocycle, which cycle 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 ally substituted by up to 3 substituents independently selected from halo, CF3, C1_4 alkyl and 03.5 lkyl.

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

Embodiment 19 of the invention is a nd or salt according to embodiment 18 wherein R1 is t-butyl, hydroxy—t-butyl or 1-hydroxypropyl; and R102 is 4-trifluromethylphenyl, 4-chlorophenyl, 2,4-difluorophenyl, 5-chloropyridinyl, 5-fluoropyridin- 2-yl, 3-trifluromethylpyrazolylyl, 4-trifluromethylpyrazolyl, 3-trifluromethylmethylpyrazoly|, 3-cyclopropylpyrazolyl, opropylpyrazolyl, 4-trifluromethyl (1 ,2,3-triazolyl), 4-cyclopropyl- (1 ,2,3-triazolyl), or benzotriazolyl.

Embodiment 20 of the invention is a compound according to embodiment 1, selected from: N-(5-{[2-amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridinyl)—2-[4- (trifluoromethyl)phenyl]acetamide; N-(5-{[2-amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridin yl)(4-chlorophenyl)acetamide; N-(5-{[2-amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridin yl)(5-fluoropyridinyl)acetamide; W0 2012/137089 14 N-(5-{[2-amino—7-(2-hydroxy—1,1-dimethylethyl)-7H-pyrro|o[2,3-d]pyrimidinyl]carbonyl}pyridin yl)[3-(trif|uoromethy|)-1H-pyrazoIy|]acetamide; N-(5-{[2-amino—7-(2-hydroxy—1,1-dimethylethyl)-7H-pyrro|o[2,3-d]pyrimidinyl]carbonyl}pyridin y|)(3-cyc|opropyI-1H-pyrazoIy|)acetamide; N-{5-[(2-amino—7-tert-butyI-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}(4-cyc|opropy|— 1H-1,2,3-triazoly|)acetamide; N-{5-[(2-amino—7-tert-butyI-7H-pyrro|o[2,3-d]pyrimidinyl)carbonyl]pyridinyI}[4- (trifluoromethyI)-1H-pyrazoIy|]acetamide; N-{5-[(2-amino—7-tert-butyI-7H-pyrro|o[2,3-d]pyrimidinyl)carbonyl]pyridinyI}[4- (trifluoromethy|)-1H-1,2,3-triazo|—1-y|]acetamide; N-{5-[(2-amino—7-tert-butyl-7H-pyrro|o[2,3-d]pyrimidinyl)carbonyl]pyridiny|}(5-ch|oropyridin- cetamide; N-(5-{[2-Amino—7-(2-hydroxy—1,1-dimethylethyl)—7H-pyrro|o[2,3-d]pyrimidinyl]carbonyl}pyridin yl )(5-ch|oropyrid inyl)acetamide; N-{5-[(7-tert-butyI-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridiny|}[4-(trif|uoromethy|)-1H- 1,2,3-triazo|—1-y|]acetamide; 2-(4-chlorophenyl)-N-[5-({7-[(1S)—2-hydroxy—1-methylethyI]-7H-pyrrolo[2,3-d]pyrimidin yl}carbonyl)pyrid inyl]acetamide (7-tert-butyI-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridiny|}[4-(trif|uoromethy|)-1H- pyrazoIyl]acetamide; N-[5-({7-[(1S)—2-Hydroxy—1-methy|ethyl]—7H-pyrro|o[2,3-d]pyrimidinyl}carbonyl)pyridinyl]—2-[4- (trifluoromethyl)phenyl]acetamide; N-[5-({7-[(1R)—2-hydroxy—1-methylethyI]-7H-pyrrolo[2,3-d]pyrimidinyl}carbonyl)pyridinyI][4- (trifluoromethyl)phenyl]acetamide; 2-(4-chlorophenyl)-N-[5-({7-[(1R)—2-hydroxy—1-methylethyI]-7H-pyrrolo[2,3-d]pyrimidin yl}carbonyl)pyrid inyl]acetamide; N-(5-{[7-(2-hydroxy—1,1-dimethylethyl)-7H-pyrro|o[2,3-d]pyrimidinyl]carbonyl}pyridinyl)—2-[5- methyl(trifluoromethyl)-1H-pyrazoIy|]acetamide; 2-(5-chloropyridinyl)-N-(5-{[7-(2-hydroxy—1,1-dimethylethyl)-7H-pyrro|o[2,3-d]pyrimidin yl]carbonyl}pyridinyl)acetam ide; [2-Amino—7-(2-hydroxy—1-methy|ethy|)-7H-pyrro|o[2,3-d]pyrimidinyl]carbonyl}pyridiny|)- 2-(4-chlorophenyl)acetamide; N-(5-{[2-amino—7-(2-hydroxy—1-methylethyl)-7H-pyrro|o[2,3-d]pyrimidinyl]carbonyl}pyridinyl)—2- [4-(trifluoromethyl)phenyl]acetamide; N-(5-{[2-amino—7-(2-hydroxy—1-methylethyl)-7H-pyrro|o[2,3-d]pyrimidinyl]carbonyl}pyridinyl)—2- (4-chlorophenyl)acetamide; N-(5-{[2-amino—7-(2-hydroxy—1-methylethyl)-7H-pyrro|o[2,3-d]pyrimidinyl]carbonyl}pyridinyl)—2- [4-(trifluoromethyl)phenyl]acetamide; N-(5-{[2-Amino—7-(2-hydroxy—1,1-dimethylethyl)-7H-pyrro|o[2,3-d]pyrimidinyl]carbonyl}pyridin 40 yl)[5-methyl(trifluoromethyl)-1H-pyrazoIy|]acetamide; N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}(4-cyclopropyl-1H-1,2,3- triazolyl)acetamide; or a pharmaceutically acceptable salt thereof.

Embodiment 21 of the invention is a pharmaceutical ition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of the preceding embodiments 1 to 20, and a pharmaceutically acceptable carrier.

Embodiment 22 of the invention is a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 20, for use as a medicament.

Embodiment 23 of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 20 for use in the treatment of a disease for which an Trk receptor antagonist is indicated ment 24 of the invention is a compound of formula (I) or a ceutically acceptable salt thereof, as defined in any one of embodiments 1 to 20 for use in the treatment of pain.

Embodiment 25 of the invention is the use of a nd of the formula (I) or a pharmaceutically acceptable salt or composition thereof, as defined in any one of ments 1 to 20, for the manufacture of a medicament to treat a e 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 ceutically acceptable salt or ition thereof, as d in any one of embodiments 1 to 20, for the manufacture of a medicament to treat pain.

Embodiment 27 of the invention is a method of treatment of a mammal, to treat a disease for which an Trk receptor antagonist is indicated, comprising treating said mammal with an effective amount of a compound of the formula (I) or a pharmaceutically able salt thereof, as defined in any one of embodiments 1 to 20.

Embodiment 28 of the invention is a method of treatment of pain in a , comprising treating said mammal with an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 1 to 20.

Embodiment 29 of the invention is nd or salt according to any one of embodiments 1 to 20 for use in a medical treatment in combination with a r drug susbtance.

Further embodiments of the invention include: W0 2012/137089 16 Compounds or salts of a (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 R has a value as exemplified in the Examples below; Compounds or salts of formula (I) where R1, R2, R3, R101, X and R102 have a value as exemplified in the Examples below; A compound selected from any one of the es below or a pharmaceutically acceptable salt thereof; and any novel intermediate compound herein disclosed.

Other embodiments may be envisaged based on the ption below.

“Halogen” means a fluoro, chloro, bromo or iodo group.

“Alkyl” groups, containing the requisite number of carbon atoms, can be unbranched or branched. es of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.

“Pharmaceutically acceptable salts” of the nds 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 xic salts. Examples include the acetate, aspartate, benzoate, besylate, onate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, e, te, mesylate, methylsulphate, ylate, 2-napsylate, nicotinate, e, orotate, oxalate, palmitate, e, phosphate/hydrogen phosphate/dihydrogen phosphate, rate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

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

For a review on suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

The compounds of the invention include compounds of formula I and salts thereof as hereinbefore defined, polymorphs, and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter d 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 , tautomeric isomerism omerism’) can occur. It follows that a single compound may exhibit more than one type of isomerism.

Included within the scope of the claimed compounds of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting 17 2012/051363 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 e, D-lactate or L-lysine, or racemic, for e, DL-tartrate or DL-arginine. es of types of ial tautomerisms shown by the compounds of the invention include hydroxypyridine <:> pyridone; amide <:> hydroxyl-imine and keto <:> enol tautomersims: H O OH o OH HO N\ o )L A I NH__ N Ai __ ‘— \ / | l 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 sis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or other derivative) using, for e, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable lly 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 enantiomerically— enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase ting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine.

Concentration of the eluate affords the enriched mixture.

Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art. [see, for example, ochemistry of c nds” by E L Eliel , New York, 1994).] The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

W0 2012/137089 18 Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, 123 iodine, such as l and 125' nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and , 18O, phosphorus, such as 32P, and sulphur, such as 35S.

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 m, i.e. 3H, and -14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

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

Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron on Topography (PET) studies for examining substrate receptor occupancy. ically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labelled reagents in place of the non- labelled reagent previously employed.

The routes below, including those mentioned in the Examples and Preparations, illustrate methods of synthesising compounds of formula (I). The skilled person will appreciate that the compounds of the ion, and ediates thereto, could be made by methods other than those ically described , for example by adaptation of the methods described herein, for example by methods known in the art. le guides to synthesis, functional group interconversions, use of protecting groups, etc., are for example:“Comprehensive Organic Transformations” by RC , VCH Publishers Inc. (1989); Advanced c Chemistry” by J. March, Wiley lnterscience (1985); “Designing Organic Synthesis” by S Warren, Wiley lnterscience (1978); “Organic Synthesis — The Disconnection Approach” by S Warren, Wiley lnterscience ; book to c 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 ; and any updated versions of said standard works.

In the general synthetic methods below, unless otherwise specified, the substituents are as defined above 1011 101 with reference to the compounds of formula (I) above. R is the same as R or a suitably protected version thereof.

W0 2012/137089 19 Scheme 1 illustrates the preparation of the intermediates of general formula (Int 1), where they can be made from amine (lnt3) where, in those cases where R1 contains an l, 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 c Synthesis” 3rd edition T.W. Greene and PG. Wuts, Wiley-lnterscience, 1999). Common oxygen protecting groups suitable for use herein e tert- 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 Scheme 1 I N \ + R1—NH —> \ N \ )L _> \ / H 2 R N CI / R301 N/ N R301)LN N ‘R1 ‘R1 |nt4 |nt3 |nt2 |nt1 n R301 can be H or halogen, lly chlorine.

Compounds of formula (Int 1) may be prepared from amine (Int 3) and (lnt4) in a cyclisation step followed by a dechlorination step. Typical conditions employed involve stirring the amine of general formula (Int 3) and the aldehyde (Int 4) er, preferably in ethanol at a temperature from room temperature up to 80°C. e.g. as exemplified in Preps. 1-5 The intermediate chloride (Int 2) is reduced using rd literature conditions, for example hydrogenation using a suitable catalyst such as palladium on carbon and an additive such as ammonia in a suitable solvent such as l. Alternatively the chloride may be d by displacing the chloro with methane thiol followed by Raney Nickel l 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 suitable oxygen protecting group protection/deprotection system may be used (as described in cting Groups in Organic Synthesis” 3rd edition T.W. Greene and PG.

Wuts, Wiley-lnterscience, 1999). Common oxygen protecting groups suitable for use herein include tert- butyldimethylsilyl (TBDMS) and tetrahydropyranyl (THP).

Intermediates of general formula (Int 3) and (Int 4) are either commercially available or will be nown to those skilled in the art with reference to literature precedents and/or the preparations herein.

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

Scheme 2 W0 37089 20 2012/051363 Br Br N \ 1 301i / + R—NH _. 301A“ll/j —> NI?0\Me / 301A R N CI R N lTJH R N lTJH R1 R1 |nt7 |nt3 |nt6 |nt5 A /NI \ R301 N N\ |nt1 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 on followed by an acidic cyclisation.

Typical conditions se stirring the amine of general formula (Int 3) and the intermediate of l formula (Int 7) together with a suitable base, such as triethylamine, in a t 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 c ester and a suitable base, such as sodium hydroxide and a suitable catalyst such as tetrakis(triphenylphosphine)palladium (0) in a solvent such as THF at a temperature from room temperature up to 70°C.

Intermediates of formula (Int 1) can be made by treatment of intermediate (Int 5) with an acid such as hydrogen de in an organic solvent such as isopropanol at a temperature from room temperature up to 70°C. e.g. as exemplified in Preps. 60-62 Intermediates of general formula (Int 3) and (Int 7) are either commercially available or will be well-known to those skilled in the art with reference to literature precedents and/or the preparations .

Compounds of formula (Int 8) can be prepared from compounds of formula (Int 1) as illustrated in Scheme 3.

Scheme 3 N \ \ \ )L / 301i / 301 N R N N\ (Int 1) (Int 8) Wherein R301 is H or halogen, typically chlorine; W0 37089 21 nds of formula (Int 8) are lly prepared by iodination of the pyrrolopyrimidine intermediates (Int 1).Typical conditions ed involve stirring the intermediate of general formula (XI) with an ting 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.

Scheme4 R1—LG ' \ (lnt10) N \ \ 301i / Ram)NL N/ N R N N, H R1 (lnt9) (lnt8) Wherein R301 is H or halogen, typically chlorine; LG is halogen or tosylate, triflate or mesylate; Alternatively ediates 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 m carbonate or potassium carbonate in an organic solvent. A suitable alternative is to use an additive (such as potassium iodide) as well as a base. Preferred conditions comprise cesium carbonate in DMF at room temperature.

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

E.g. as exemplified in Preparation 20.

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

Scheme 5 W0 2012/137089 22 I I I r \ ~ R3011\ / / R301 N/H N R301 N N MeHon/I9 Me9\\ (lnt9) (lnt11) R2°° O (lnt12) ) (lnt14) Wherein R301 is H or n, 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 nd of general formula (Int 14), where R200 is a H or methyl group. As previously mentioned in Scheme 1 the hydroxy group can be protected with a suitable oxygen protecting group (PG), where the preferred protecting groups are TBDMS, TBS and THP.

Typical conditions employed for the alkylation involve stirring the compound of l formula (Int 9) with the appropriate halide together with a suitable base, as described in Scheme 4. Compounds of general a (Int 11) where R200 is H can be converted to intermediates (Int 13) where R is methyl by a further alkylation, typically involving a suitable alkylating agent such as methyl iodide and a suitable base such as potassium xide in an organic solvent such as THF. e.g. as exemplified in Preps. 20, 21, 41, 53 Reduction of the ester intermediates (Int 11) and (Int 13) can be done by using a le reducing reagent such as lithium dride, lithium nium hydride or diisobutylalumnium hydride in a suitable solvent such as ethanol or THF. Alternatively intermediates of general formula (Int 12) can be made in a two step reaction by hydrolysing the ester of formula (Int 11) or (Int 13) to the appropriate acid using a suitable base such as aqueous lithium hydroxide in a suitable organic solvent such as THF then activating the acid using a suitable reagent such as isobutyl chloroformate and using a suitable reducing agent such as sodium borohydride. e.g. as exemplified in Preps. 22, 42, 43, 54 Compounds of general formula (Int 14) can be made by protection of the hydroxy group of intermediates (Int 12) with a suitable oxygen protecting group (PG), where the red protecting groups are TBDMS and THP,as bed in Scheme 1. e.g. as exemplified in Preps. 44, 45, 55.

W0 2012/137089 23 Compounds of formula (Int 16) can be prepared from compounds of formula (Int 8) as illustrated in Scheme 6.

Scheme 6 O N|\ \ O R1o11 N/ \/N/ MeO\N / N R301 N\ “I/Ie I R 1011 R (mm) 301* /Nl \ R N N X1 \R1 (Int 15) (Int 16) ) l Nil/W/N I HO R1011 O Dd \ / HJKQ R301 N/ NR1 R1011 301A / (Int 8) R N N X1 R1 (Int 17) (Int 18) Wherein R301 is H or n, typically ne; and X1 is a suitable halogen, typically bromine or iodine; Compounds of formula (Int 16) can be prepared from compounds of formula (Int 8) and (Int 15) through a metallation of intermediate (Int 8) (using a suitable organometallic reagent such as butyllithium or isopropylmagnesium chloride) and reacting with the Weinreb amide intermediate (Int 15) at a temperature from -78°C up to room temperature. e.g. as exemplified in Preps. 26, 27, 46, 47, 56, 58, 64 Alternatively compounds of formula (Int 15) may be converted into aldehydes of formula (Int 17) by reduction of the Weinreb amide ediate using a suitable reducing agent. Preferred conditions comprise diisopropylaluminium hydride in THF at -78°C, exemplified in Preparation 106.

Compounds of formula (Int 17) may then be reacted with compounds of formula (Int 8) according to the same ation procedure described above. The intermediate alcohol (Int 18) may then be oxidised to the ketone (Int 16). l oxidation conditions involve using an oxidising reagent such as the Dess- Martin reagent in DCM or 2-iodoxybenzoic acid in a suitable solvent such as ethyl acetate at a ature from room ature to reflux temperature. e.g. as exemplified in Preps. 29, 30 Intermediates of general a (Int 15) and (Int 17) are either commercially ble or will be well- known to those skilled in the art with reference to literature precedents and/or the preparations herein.

W0 2012/137089 24 Corresponding intermediates and compounds of formula (I) where R is OH are considered as tautormers of pyridones and can be made using an analogous methodology using a benzyl protecting 1011 group for the Weinreb amide step, viz R is benzyloxy (OBn), e.g. as illustrated below: N \ /N 0 \ 31/ o OBn MeO\ R N ”‘1 \ / N / N R | I \\ Me \\ \\ OBn 3//l\\W ’/ R N N H N O O o / / o Pd-C; hydrogen Bromine, AcOH / N \\ Br \ A / / N 3 R N R N N \1 \R1 R O / O / R102-X-COZH NH4OH W \ NH2 —> ((I),R101=OH) u R3AN/N|\ N R Compounds of formula (Int 20) can be prepared from compounds of formula (Int 8) as illustrated in Scheme7 l O ND MeO \ + W / /|N 301 N Me R N \ PhYN ('"t 8) (Int 19) (Int 20) Wherein R301 is H or halogen, lly chlorine; Compounds of formula (Int 20) may be ed from compounds of formulae (Int 8) and (Int 19) ing to a metallation procedure as described in Scheme 6 above.

Typical ions employed involve metallation of the intermediate halide (Int 8) (using a suitable organometallic reagent such as butyllithium or isopropylmagnesium chloride) and reacting with the Weinreb amide intermediate (Int 19) at a temperature from -78°C up to room temperature in a suitable solvent such as THF. e.g. as exemplified in Preps. 24, 25, 28, 50 Intermediates (Int 19) will be nown to those skilled in the art with reference to literature precedents and/or the preparations herein. e.g. as exemplified in Prep. 23 nds of formula (Int 21) can be prepared from compounds of formula (Int 16) as rated in Scheme 8.

Scheme 8 R Unt16) unt21) 1011 untzz) Wherein X1 is bromine or iodine; Compounds of formula (Int 21) may be prepared from compounds of a (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 (ll) sulphate or copper (l) oxide in suitable solvent such as NMP in a sealed vessel at a temperature n room temperature and 140°C.

Where R301 is Cl this is also displaced by ammonia under the same conditions to provide amines of general formula (Int 21) where R3 is NH2. e.g. as exemplified in Preps. 31, 32, 36, 48, 49, 57, 59, 65 De-protection of a hydroxyl ting group on R1 (if present) can also occur under these conditions. In these cases, either the protecting group can be reapplied as previously described in Scheme 5 or the amine of l formula (Int 21) can be used directly.

Alternatively compounds of general formula (Int 21) where R3 is H, can be made by converting intermediates of general formula (Int 16) where R is H, via compounds (Int 22). Typical conditions W0 2012/137089 26 ed involve stirring the halide of general formula (Int 16), where R301 is H, with benzophenone imine, a suitable base such as potassium phosphate, a le ligand such as 2-di-tert—butylphosphino— 6'—triisopropylbiphenyl and a suitable catalyst such as tris(dibenzylideneacetone)dipalladium in an organic solvent such as 1,2-dimethoxyethane at a temperature from room temperature up to the boiling point of the solvent.

Intermediate (Int 22) can be deprotected to furnish the amines of general formula (Int 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) ('"t 20) nds of formula (Int 20) may be prepared from compounds of formula (Int 22) where R is chloro h an ion reaction as ed above. Wherein the ne is is reacted with 2,4- dimethoxybenzylamine and the amine can be deprotected as previously.

Typical conditions employed involve stirring the chloro-pyrimidine of general formula (Int 22), where 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 temperature from room temperature up to reflux temperature. 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 /N /N O R1011 O R1011 \ / o \ / O NI \ NH \ sz—XJLOH —> )NL \ \ ”4x RBAN/ N\ R3 N/ [102 R1 R (Int 21) (Int 23) (I) 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 ve (such as DMAP), and a suitable solvent (such as ne).

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 temperature from room temperature up to 50°C. A suitable alternative is to use an additive (such as 4-dimethylaminopyridine) as well as a base. Any suitable solvent may be used in place of those mentioned above. At least one equivalent of the acid (Int 23) and at least one equivalent of the coupling t 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 yl protecting group in intermediate (Int 21), removal of the ting group (PG) can be done in situ or as an additional step, adding a suitable acid and organic solvent to the crude residue after the amide formation has taken place. Common protecting groups to use include TBDMS, which is readily removed by treatment with an acid such as aqueous hydrogen chloride or aqueous citric acid in an organic solvent such as THF or by treatment with a fluoride source such as tetrabutylammonium fluoride in an organic solvent such as THF, and THP, which is also readily removed by treatment with an acid such as aqueous hydrogen chloride in an c 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 nown to those skilled in the art with reference to ture precedents and/or the preparations herein.

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

Scheme11 /N /N O R1011 O R1011 \ / \ / 0 NH \ N4 1\ \ 2 J1 e i \ . / / i N N N\ + x OH R3 N N\ R H R1 IIRWZ R1 MeO OMe (Int 24) (Int 23) (I) Compounds of formula (I) can be prepared from compounds of formula (Int 24) via amide bond formation as previously described in Scheme 10 ed by removal of the dimethoxbenzylamine group in situ, by adding a suitable acid and organic solvent to the crude residue after the amide formation has taken place.

Suitable acids for this de-protection include hydrogen choride or oroacetic acid in an organic solvent such as THF. e.g. as exemplified in Examples 46-47 W0 2012/137089 28 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 R (Int 21 ) Compounds of a (I) where R2 is methyl can be prepared from compounds of a (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 NR104 can be prepared from compounds of formula (Int 21) as illustrated in Scheme 13.

Scheme13 /N /N O R1011 O R1011 \ / \ R104\ R102 ND + —> i\ \ H/ \ m X R3)\N/ N\ R3 N/ N\1 R102/ \R104 R1 R (Int25) (Int 21) (I) Compounds of a (I) where X is NR104 may be prepared from compounds of formula (Int 21), (Int 25) and phenylchloroformate. Typical conditions comprise phenyl chloroformate and compounds of a (Int 24) with pyridine in THF from 0 to 100°C, as exemplified in Example 526.

W0 2012/137089 29 Compounds of formula (I) where a substituent on the ) of R102 is an aminomethyl CHZNRZ group may be prepared from nds of formula (1) as illustrated in Scheme 14.

Scheme14 /N R1011 O R1011 \ / o R3)\N/ N|\ \ NW N OH R3)\ R1011 —, N\ ”WW5N Compounds of formula (I) where a primary alcohol exists may be oxidised to the aldehyde using Dess Martin periodinane in DCM at room temperature followed by a reductive amination with a le amine HNR2 using sodium triacetoxyborohydride and acetic acid in DCM.

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

Scheme 15 Int 27 Int 26 Wherein R103 is Me or CHZOH; Compounds of formula (Int 26) can be prepared from compounds of formula (Int 27) through conversion of an alcohol into a suitable leaving group followed by cyclisation under basic conditions. Preferred conditions comprise tosyl chloride with n-butyl lithium in THF.

According to a further embodiment the present invention provides novel intermediate compounds.

W0 2012/137089 30 ceutically acceptable salts of a compound of formula (I) may be readily prepared by mixing er solutions of the compound of a (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by tion or may be recovered by ation of the solvent. The degree of tion in the salt may vary from completely ionised to almost non-ionised.

The compounds of the invention intended for pharmaceutical use may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drug agent (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any biologically inactive ingredient other than the compounds and salts of the ion. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. For example, a compound of the formula I, or a pharmaceutically able salt or solvate thereof, as defined above, may be stered 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: o a Nav1.7 channel modulator, such as a compound disclosed in WO 2009/012242 or W02010/079443; c 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 , more particularly N- [6-Amino(2-chloromethoxyphenyl)pyridinyl]—1-methyl-1H-pyrazolecarboxamide); c 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; o a compound which ses the levels of endocannabinoid, such as a compound with fatty acid amid hydrolase inhibitory (FAAH) activity, in particular those disclosed in (e.g. N- pyridazinyl(3-{[5-(trifluoromethyl)pyridineyl]oxy}benzylidene)piperidenecarboxamide); c an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, hanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, one, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or ocine; o a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, inal, etodolac, en, ofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, tone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac; o a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, al, theamylal or thiopental; W0 2012/137089 31 a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or lam; an H1 antagonist having a sedative , e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine; a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone; a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine; an NMDA receptor antagonist, e.g. dextromethorphan ((+)—3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)hydroxy—N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis(phosphonomethyl)piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®, a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NRZB antagonist, e.g. odil, traxoprodil or (—)-(R)—6-{2-[4-(3-fluorophenyl) hydroxypiperidinyl]hydroxyethyl-3,4-dihydro-2(1H)-quinolinone; an alpha-adrenergic, e.g. doxazosin, tamsulosin, ine, guanfacine, dexmetatomidine, modafinil, or 4-amino-6,7-dimethoxy—2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinolyl)—5-(2-pyridyl) quinazoline; a lic antidepressant, e.g. desipramine, imipramine, ptyline or nortriptyline; an anticonvulsant, e.g. azepine, lamotrigine, topiratmate or valproate; a inin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (dR,9R)—7-[3,5- bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydromethyl(4-methylphenyl)—7H-[1,4]diazocino[2,1- g][1,7]-naphthyridine13-dione (TAK-637), 5-[[(2R,3S)—2-[(1R)—1-[3,5- bis(trifluoromethyl)phenyl]ethoxy—3-(4-fluorophenyl)morpholinyl]-methyl]—1,2-dihydro-3H-1,2,4- triazolone (MK-869), aprepitant, lanepitant, dapitant or methoxy—5-(trifluoromethoxy)phenyl]- methylamino]phenylpiperidine (28,38); a inic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium; a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; a coal-tar analgesic, in particular paracetamol; a eptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, dazine, trifluoperazine, fluphenazine, clozapine, olanzapine, idone, ziprasidone, quetiapine, sertindole, razole, sonepiprazole, blonanserin, iloperidone, perospirone, ride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, ridone, 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; W0 2012/137089 32 a 5-HT receptor agonist or antagonist, particularly a 5-HT1B/1D agonist such as eletriptan, iptan, naratriptan, zolmitriptan or rizatriptan; a 5-HT2A receptor antagonist such as R(+)—alpha-(2,3-dimethoxy-phenyl)—1-[2-(4-fluorophenylethyl)] piperidinemethanol (MDL-100907); a 5-HT3 antagonist, such as ondansetron a cho|inergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)—N-methyl(3-pyridinyl) butenamine (RJR-2403), (R)—5-(2-azetidinylmethoxy)—2-chloropyridine (ABT-594) or nicotine; Tramadol®; a PDEV inhibitor, such as 5-[2-ethoxy(4-methylpiperazinyl-sulphonyl)phenyl]methyln- propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone (sildenafil), aR)—2,3,6,7,12,12ahexahydromethyl (3,4-methylenedioxyphenyl)—pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione (lC-351 or tadalafil), thoxy(4-ethyl-piperazinylsu|phonyl)-phenyl]methylpropyl-3H- o[5,1-f][1,2,4]triazinone (vardenafil), 5-(5-acetylbutoxypyridinyl)ethyl(1-ethyl azetidinyl)-2,6-dihydro-7H—pyrazolo[4,3-d]pyrimidinone, 5-(5-acetylpropoxypyridinyl)ethyl (1-isopropylazetidinyl)-2,6-dihydro-7H—pyrazolo[4,3-d]pyrimidinone, 5-[2-ethoxy(4- ethylpiperaziny|sulphonyl)pyridinyl]ethyl[2-methoxyethyl]—2,6-dihydro-7H-pyrazolo[4,3- d]pyrimidinone, 4-[(3-chloromethoxybenzyl)amino][(28)—2-(hydroxymethyl)pyrrolidinyl]-N- (pyrimidinylmethyl)pyrimidinecarboxamide, 3-(1-methyloxopropyl-6,7-dihydro-1H- pyrazolo[4,3-d]pyrimidinyl)—N-[2-(1-methylpyrrolidinyl)ethyl]propoxybenzenesulfonamide; an 2-delta ligand such as gabapentin, pregabalin, ylgabapentin, (1d,3d,5d)(3-aminomethyl-bicyclo [3.2.0]heptyl)—acetic acid, (3S,5R)—3-aminomethylmethyl-heptanoic acid, (3S,5R)— 3-aminomethyl-heptanoic acid, (3S,5R)—3-aminomethyl-octanoic acid, (28,4S)(3- chlorophenoxy)proline, (28,4S)—4-(3-fluorobenzyl)-proline, [(1R,5R,68)—6- (aminomethyl)bicyclo[3.2.0]heptyl]acetic acid, 3-(1-aminomethyl-cyclohexylmethyl)—4H- [1 ,2,4]oxadiazolone, C-[1-(1H-tetrazolylmethyl)-cycloheptyl]-methylamine, (3S,4S)—(1- aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)—3-aminomethylmethyl-octanoic acid, (3S,5R)—3-aminomethyl-nonanoic acid, (3S,5R)—3-aminomethyl-octanoic acid, (3R,4R,5R)—3- amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)—3-amino-4,5-dimethyl-octanoic acid; metabotropic glutamate subtype 1 receptor (mGluR1) antagonist; a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, oxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, amine and trazodone; a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, amine, mirtazepine, oxaprotiline, fezolamine, tine, mianserin, buproprion, buproprion lite hydroxybuproprion, nomifensine and zine (Vivalan®), especially a selective enaline reuptake inhibitor such as reboxetine, in particular (S,S)—reboxetine; W0 2012/137089 33 o a dual serotonin-noradrenaline reuptake tor, such as venlafaxine, venlafaxine metabolite O- desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine; c an inducible nitric oxide synthase (iNOS) inhibitor such as S—[2-[(1-iminoethyl)amino]ethyl]-L- homocysteine, S—[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, (1-iminoethyl)amino]ethyl]— 2-methyl-L-cysteine, (28,5Z)—2-aminomethyl[(1-iminoethyl)amino]heptenoic acid, 2-[[(1R,3S)— 3-amino hydroxy(5-thiazolyl)-butyl]thio]chloropyridinecarbonitrile; 2-[[(1R,3S)—3-amino y(5-thiazolyl)butyl]thio]chlorobenzonitrile, (28,4R)—2-amino[[2-chloro (trifluoromethyl)phenyl]thio]thiazolebutanol, 2-[[(1R,3S)—3-aminohydroxy(5-thiazolyl) thio](trifluoromethyl)-3 pyridinecarbonitrile, 2- [[(1R,3S)—3- aminohydroxy— 1 iazolyl)butyl]thio]chlorobenzonitrile, N-[4-[2-(3- chlorobenzylamino)ethyl]phenyl]thiophenecarboxamidine, or guanidinoethyldisulfide; c an acetylcholinesterase inhibitor such as donepezil; o a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5- c]pyridinyl)phenyl]ethyl}amino)-carbonyl]methylbenzenesulfonamide or )—1-({[5-chloro (3-fluorophenoxy)pyridinyl]carbonyl}amino)ethyl]benzoic acid; 0 a microsomal prostaglandin E synthase type 1 (mPGES—1) inhibitor; 0 a leukotriene B4 antagonist; such as 1-(3-biphenylylmethylhydroxy—chromanyl)— cyclopentanecarboxylic acid 5696), 5-[2-(2-Carboxyethyl)[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]—valeric acid (ONO-4057) or DPC-11870, a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro[4-methoxy-3,4,5,6-tetrahydro-2H-pyran yl])phenoxy—methyl]methylquinolone (ZD-2138), or 2,3,5-trimethyl(3-pyridylmethyl),1,4- benzoquinone (CV-6504).

Pharmaceutical compositions suitable for the delivery of compounds and salts of the present ion and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in ‘Remington’s ceutical Sciences’, 19th Edition (Mack Publishing Company, 1995).

Compounds and salts of the invention intended for pharmaceutical use may be ed and administered as crystalline or ous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

Oral Administration The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

W0 2012/137089 34 Formulations suitable for oral administration include solid formulations, such as s, capsules containing particulates, liquids, or s; lozenges (including -filled), chews; multi- and nano- particulates; gels, solid solution, me, films (including muco-adhesive), , sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as s in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, hylene glycol, propylene glycol, methylcellulose, or a le 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, isintegrating dosage forms such as those bed in Expert Opinion in Therapeutic Patents, fl (6), 6 by Liang and Chen (2001).

For tablet dosage forms, depending on dose, the drug may make up from 1 weight% to 80 weight% of the dosage form, more typically from 5 weight% to 60 weight% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight% to 25 weight%, preferably from 5 weight% to 20 weight% of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.

Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, e, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. s may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight% of the tablet, and glidants may comprise from 0.2 weight% to 1 weight% of the .

Tablets also generally contain lubricants such as ium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight% to 10 weight%, preferably from 0.5 weight% to 3 % of the 40 tablet.

Other possible ingredients include anti-oxidants, ants, flavoring agents, preservatives and taste- masking 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 % diluent, from about 2 weight% to about 10 weight% disintegrant, and from about 0.25 weight% to about 10 weight% lubricant. [Make sure these specific ranges are relevant] Tablet blends may be compressed directly or by roller to form s. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final ation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

The formulation of tablets is discussed in aceutical Dosage Forms: Tablets, Vol. 1”, by H.

Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 06918—X).

The ing formulations for the various types of administration discussed above may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, - and programmed release. , controlled-, ed Suitable modified release formulations for the purposes of the ion 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 e, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. eral Administration The compounds and salts of the invention may be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral stration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, -free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may n excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

W0 2012/137089 36 The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (I) and salts used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release.

Thus, compounds and salts of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified e of the active compound. An example of such ations include drug-coated .

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, ons, creams, ointments, g powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include l, water, mineral oil, liquid petrolatum, white petrolatum, in, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated [see, for example, Finnin and Morgan, J Pharm Sci, Q (10), 955-958 (October 1999).] Other means of topical administration include delivery by electroporation, iontophoresis, horesis, sonophoresis and microneedle or needle-free (e.g.

PowderjectTM, BiojectTM, etc.) injection. d/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 atidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser rably an er using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a le lant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

A pressurised container, pump, spray, atomizer, or nebuliser may contain a solution or suspension of the compound(s) or salt(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for sing, 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 t is ised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting , such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure nisation, or spray drying.

Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound or salt of the invention, a le powder base such as lactose or starch and a performance er such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the . Other suitable excipients include dextran, glucose, maltose, ol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an er using electrohydrodynamics to produce a fine mist may contain from 1ug to 20mg of the compound or salt of the invention per actuation and the actuation volume may vary from 1pl to 100ul. A typical formulation may comprise a compound of formula (I) or salt thereof, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or ners, such as saccharin or saccharin sodium, may be added to those ations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA). Modified release formulations e delayed-, sustained-, pulsed-, controlled-, ed and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by a prefilled capsule, blister or pocket or by a system that utilises a gravimetrically fed dosing chamber . Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1 to 5000 pg of the compound or salt. 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 y, as divided doses throughout the day.

Rectal/lntravaginal Administration The compounds and salts of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various well known alternatives may be used as appropriate.

Ocular and Aural Administration W0 2012/137089 38 The compounds and salts of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or on in isotonic, pH-adjusted, sterile . Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid; a cellulosic r, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose; or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium de.

Such formulations may also be delivered by iontophoresis.

Other Technologies The compounds and salts of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their lity, dissolution rate, taste-masking, bioavailability and/or ity for use in any of the aforementioned modes of administration.

Drug-cyclodextrin complexes, for example, are found to be lly 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 extrin may be used as an auxiliary additive, i.e. as a r, diluent, or solubiliser. Most commonly used for these purposes are , beta- and gamma- cyclodextrins, es of which may be found in International Patent Applications Nos. WO 72, WO 94/02518 and WO 98/55148.

For stration to human patients, the total daily dose of the nds and salts of the invention is typically in the range 0.1 mg to 200 mg depending, of course, on the mode of administration, preferred in the range 1 mg to 100 mg and more preferred in the range 1 mg to 50 mg. The total daily dose may be administered in single or divided doses.

These dosages are based on an average human subject having a weight of about 65kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.

For the above-mentioned therapeutic uses, the dosage administered will, of course, vary with the compound or salt employed, the mode of administration, the treatment desired and the disorder indicated.

The total daily dosage of the compound of formula (|)/salt/solvate (active ingredient) will, generally, be in the range from 1 mg to 1 gram, preferably 1 mg to 250 mg, more preferably 10 mg to 100 mg. The total W0 2012/137089 39 daily dose may be administered in single or divided doses. The present invention also asses sustained release compositions.

The pharmaceutical composition may, for example, be in a form suitable for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of e dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or ceutical , carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions or suspensions of active compounds in e aqueous solutions, for e, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, s, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, or, include lactose or milk sugar and high molecular weight polyethylene s. When aqueous suspensions or elixirs are desired for oral administration the active compound n may be combined with various ning or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

Dosage regimens may be adjusted to provide the optimum desired response. For e, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally d or increased as indicated by the cies of the therapeutic situation. It is especially advantageous to ate parenteral itions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit ning a predetermined quantity of active nd calculated to e the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly ent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

W0 2012/137089 40 Thus, the skilled artisan would appreciate, based upon the disclosure ed herein, that the dose and dosing regimen is adjusted in ance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be y established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to e a detectable therapeutic benefit to the patient. Accordingly, while n dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration n that may be provided to a patient in practicing the present ion.

It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person stering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may e clinical effects such as toxic effects and/or laboratory values. Thus, the present invention encompasses intra-patient dose-escalation as determined by the skilled artisan.

Determining appropriate dosages and regiments for administration of the chemotherapeutic agent are well- known 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 ion may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a "unit dose" is discrete amount of the pharmaceutical composition comprising a ermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be stered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

For parenteral dosages, this may conveniently be ed as a solution or as a dry powder requiring ution by a pharmacist, medical practitioner or the patient. It may be provided in a bottle or sterile syringe. For e it may be provided as a powder in a multicompartment syringe which allows the dry powder and solvent to be mixed just prior to administration (to aid long-term stability and storage).

Syringes could be used which allow le doses to be administered from a single device.

The relative amounts of the active ient, the pharmaceutically acceptable carrier, and any additional ients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.

W0 2012/137089 41 In on to the active ingredient, a pharmaceutical composition of the invention may further comprise one or more additional pharmaceutically active agents.

Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using tional technology.

As used herein, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, stration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by ation of the composition through a tissue-penetrating non-surgical wound, and the like. In ular, parenteral stration 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 eral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for uous stration. lnjectable ations may be prepared, packaged, or sold in unit dosage form, such as in s or in multi-dose containers containing a preservative. ations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations as discussed below. Such formulations may further comprise one or more additional ingredients including, but not d to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e. powder or granular) form for reconstitution with a suitable vehicle (e.g. sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

A composition of the present invention can be administered by a y 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 ation, ing implants, transdermal patches, and microencapsulated delivery systems.

Biodegradable, patible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are bed 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 itions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the 40 known art, and may comprise, in addition to the active ingredient, additional ingredients such as the W0 2012/137089 42 sing agents, wetting agents, or suspending agents described herein. Such sterile able ations may be prepared using a non-toxic parenterally-acceptable diluent or t, such as water or 1,3-butane diol, for example. Other acceptable diluents and ts include, but are not d to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di- glycerides. Other parentally-administrable formulations which are useful e those which comprise the active ingredient in microcrystalline form, in a liposomal ation, or as a component of a biodegradable polymer system. Compositions for sustained release or tation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly e salt.

The e dosage administered of each active ingredient will vary depending upon any number of factors, including but not limited to, the type of animal and type of disease state being treated, the age of the , and the route(s) of administration.

The following non-limiting Preparations and Examples illustrate the preparation of compounds and salts of the present invention.

GENERAL EXPERIMENTAL The Preparations and Examples that follow illustrate the invention but do not limit the invention in any way. All starting materials are available commercially or described in the literature. All temperatures are in OC. 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” ents the distance travelled by a compound divided by the distance travelled by the t 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 lnova 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 APCl mass spectrometer.

Where it is stated that compounds were prepared in the manner described for an earlier Preparation or Example, the skilled person will appreciate that reaction times, number of equivalents of reagents and reaction temperatures may be modified for each specific reaction, and that it may nevertheless be necessary or desirable to employ different work-up or purification conditions.

The invention is illustrated by the ing non-limiting examples in which the following abbreviations and definitions are used: The Preparations and Examples that follow illustrate the invention but do not limit the invention in any way. All starting materials are available commercially or described in the literature. All temperature are in °C. Flash column chromatography was carried out using Merck silica gel 60 (9385) or Redisep silica.

NMR was carried out using a Varian y 400MHz NMR spectrometer or a Jeol ECX 400MHz NMR.

W0 2012/137089 43 The mass spectra were obtained using: Waters ZQ ESCI Applied tem's 00 5 min LC-MS Waters Alliance 2795 with ZQ2000 (ESI) Aglient 110 HPLC 5 min (System 5) Waters ZQ ESCI 8min LC-MS Waters ce 2695 with ZQ2000 (ESI) 25 min HP 1100 HPLC with Waters Micromass ZQ mass detector 12.5 min LC-MS UPLC mass spectra were obtained using a Waters Acquity ZQD (ESI) 1.5 min LC-MS WATERS ACQUITY UPLC/WATERS 3100 MSD/PL-ELS 2100 ICE ELSD Where singleton compounds have been analysed by LCMS, there are six methods used. These are illustrated below.

System 1 6 minute LC-MS gradient and instrument conditions A: 0.1 % formic acid in water B: 0.1 % formic acid in acetonitrile Column: C18 phase Waters Sunfire 50 x 4.6 mm with 5 micron particle size nt: 95-5% A over 3 min, 1 min hold, 2 min re-equilibration, 1.5mL/min flow rate UV: 210nm - 450nm DAD Temperature: 50°C System 2 2 minute LC-MS gradient and instrument conditions A: 0.1 % formic acid in water B: 0.1 % formic acid in acetonitrile Column: C18 phase Phenomenex 20 x 4.0 mm with 3 micron particle size nt: 70-2% A over 1.5min, 0.3 min hold, 0.2 re-equilbration, 1.8mL/min flow rate UV: 210nm - 450nm DAD Temperature: 75°C System 3 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% oner 3 min, 1 min hold, 1 min re-equilibration, min flow rate UV: 225nm — ELSD - MS Temperature: ambient System 4 minute LC-MS gradient and instrument conditions 40 A: 0.1 % ammonium hydroxide in water WO 37089 44 B: 0.1 % ammonium hydroxide in acetonitrile Column: C18 phase XTerra 50 x 4.6 mm with 5 micron particle size Gradient: 95-5% oner 3 min, 1 min hold, 1 min re-equilibration, 1.5mL/min flow rate UV: 225nm — ELSD - MS Temperature: 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 ilibration, 0.8 mL/min flow rate UV: 225nm — ELSD - MS Temperature: 50°C System 6 5 minute LC-MS gradient and instrument conditions A: 0.0375 % TFA in water B: 0.01875 % 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 Temperature: 50°C System 7 minute LC-MS nt and instrument conditions A: 10 mmol ammonium bicarbonate in water B: acetonitrile Column: C18 phase XBridge 150 x 3.0 mm with 5 micron le size Gradient: 95-5% A over 15 min, 10 min hold, 2 min re-equilibration, 0.5mL/min flow rate UV: 200nm - 350nm DAD Temperature: 30°C System 8 3 minute LC-MS gradient and instrument conditions A: 0.05% formic acid in water B: acetonitrile Column: 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, min flow rate UV: 200nm - 350nm DAD Temperature: 50°C System 9 minute LC-MS gradient and instrument conditions 40 A: 0.05% formic acid in water WO 37089 45 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, 1min re-equilibration, min flow rate UV: 200nm - 260nm DAD Temperature: 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, 1min ilibration, 1.2mL/min flow rate UV: 200nm - 260nm DAD Temperature: 25°C Where singleton compounds have been purified by High Performance Liquid Chromatography, unless otherwise stated, one of four s were used, and these are shown below.

Waters Purification Systems with mass spec or UV detection 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 Temperature: 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 X190 mm Gradient: 95-2% A over 7 min, 2 min hold, 1 min re-equilibration, 18 mL/min flow rate Temperature: ambient Prep system 3 7 minute prep LC-MS gradient and instrument conditions A: 0.05% ammonia in water B: acetonitrile : C18 phase e 50 x19.0 mm Gradient: 90-20% A over 7 min, 20 mL/min flow rate Temperature: ambient Prep system 4 40 8 minute prep LC-MS gradient and instrument conditions W0 2012/137089 46 A: 0.1% TFA in water B: acetonitrile : C18 phase Sepax BR 100 x 21.2 mm nt: 96-33% A over 8 min, 30 mL/min flow rate Temperature: ambient Where it is stated that compounds were ed in the manner described for an earlier Preparation or Example, the skilled person will appreciate that on times, number of equivalents of reagents and reaction temperatures may have been modified for each specific reaction, and that it may nevertheless be necessary, or ble, to employ different work-up or cation conditions. The invention is illustrated by the following non-limiting Examples in which the following abbreviations and definitions are used: AcOH — acetic acid; APCI - atmospheric pressure chemical ionization; Arbocel is a filter agent; br s — broad singlet; BINAP — 2,2’-bis(diphenylphosphino)-1,1’-binapthyl; nBuLi — n-Butyllithium; CDCI3— deuterated chloroform; Cs2C03 is caesium carbonate; Cul is copper (l) iodide; Cu(OAc)2 is copper (ll) acetate; 6 — chemical shift; d — doublet; DAD — diode array detector; DCE — 1,2-dichloroethane DCM — dichloromethane; DEA — lamine; DIBAL — utylaluminium hydride; DlPEA — diisopropylethylamine; DMAP — 4-dimethylaminopyridine; DME — dimethoxyethane; DMF — N,N- dimethylformamide; DMF-DMA - methylformamide-dimethylacetal; DMSO — dimethylsulphoxide DPPF — 1,1’-bis(diphenylphosphino)ferrocene; ELSD — evaporative light scattering detector; ESI - electrospray ionization; EtZO — diethylether; EtOAc/EA — ethyl acetate; EtOH — ethanol; g — gram; HATU - zabenzotriazolyl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HBTU is O-benzotriazolyl- N,N,N’,N’-tetramethyluronium hexafluorophosphate; HCI is hydrochloric acid;HOBT is N- hydroxybenzotriazole hydrate; HPLC — high pressure liquid chromatography; IPA — isopropyl alcohol; K2C03 is potassium carbonate; KHSO4 is potassium hydrogen te; KOAc is potassium acetate; KOH is potassium hydroxide; K3PO4 is potassium phosphate tribasic; KF - potassium fluoride; L is litre; LCMS — liquid tography mass spectrometry; LiHMDS — Lithium hexamethyldisilazide; m — multiplet; mg — milligram; mL — itre; M/Z — Mass Spectrum Peak; MeCN — acetonitrile; MeOH — methanol; 2-MeTHF — 2-methyltetrahydrofuran; MgSO4 is magnesium sulphate; MnOZ — manganese dioxide; NaClOZ — sodium chlorite; NaH - sodium hydride; NaHC03- sodium hydrogencarbonate; Na2C03 - sodium carbonate; NaH2PO4- sodium phosphate; NaH803 - sodium bisulphite; NaHSO4 - sodium hydrogensulphate; NaOH - sodium ide; NaZSO4 - sodium sulphate; NH3 — ammonia; NH4C| — ammonium chloride; NMM — N- MethylMorpholine; NMR — nuclear magnetic resonance; Pd/C — palladium on carbon; PdCl2 — palladium dichloride; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0); Pd(PPh3)4 - palladium tetrakis(triphenylphosphine); Pd(OAc)2 — palladium acetate; PTSA — para-toluenesulfonic acid; Prep — preparation; Rt — retention time; q — quartet; s — singlet; TBDMS — tertbutyldimethylsilyl; TBME — tertbutyldimethylether; TCP — 1-propylphosphonic acid cyclic anhydride; TEA — triethylamine; TFA — oroacetic acid; THF — tetrahydrofuran; TLC — thin layer tography; (R, S) — racemic mixture; WSCDI - 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride.

For the avoidance of doubt, named compounds used herein have been named using IUAPC, Chemdraw and/or Name Pro ACD Labs Name Software v7.11TM 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]pyrimidinyl)carbonyl]pyridinyl}(5-fluoropyridin yl)acetam ide \/ O / F N/|\ ” ‘N/ KN N Me Me 2-(5-Fluoropyridinyl)acetic acid (23.1 mg, 0.149 mmol) (see Preparation 92) was added to (5- aminopyridinyl)(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (40 mg, 0.135 mmol ) (see Preparation 31), 1-propylphosphonic acid cyclic anhydride (0.2 mL, 0.338 mmol, 50% in EtOAc) and triethylamine (0.65 mL, 0.474 mmol) in THF (3 mL). The mixture was stirred at 25°C for 18 hours, ated in vacuo and ioned 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 = 2.86 min; m/z 433 [M+H]+.

Examples 2 to 8 were prepared according to the method bed above for Example 1, starting from (5- aminopyridinyl)(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (see Preparation 31) and the appropriate acids.

N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 4): R = 3.26 yl)carbonyl]pyridinyl}[4-(trifluoromethyl)-1H-1,2,3-triazol- min; m/z 473 [M+H]+ cetamide N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 4): R = 3.04 yl)carbonyl]pyridinyl}(3-cyclopropyl-1H-pyrazol min; m/z 444 [M+H]+ yl)acetamide N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 4): R = 2.75 yl)carbonyl]pyridinyl}(4-cyclopropyl-1H-1,2,3-triazol min; m/z 445 [M+H]+ yl)acetamide N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 4): R = 3.04 bonyl]pyridinyl}[3-(trifluoromethyl)-1H-pyrazol min; m/z 472 [M+H]+ yl]acetamide W0 37089 48 N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin LCMS m 4): R = 2.92 y|)carbonyl]pyridinyl}(5-ch|oropyridinyl)acetamide min; m/z 449 [M+H]+ N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 4): R = 2.96 y|)carbonyl]pyridinyl}(4-cyc|opropyl-1H-pyrazol min; m/z 443 [M+H]+ y| )acetamide N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin LCMS(system 4) y|)carbonyl]pyridinyl}[4-(trif|uoromethy|)-1H-pyrazol : R = 3.00 min; m/z 472 yl]acetamide [M+H]+ Example 9: N-[5-({7-[(1S)—2-Hydroxymethylethy|]-7H-pyrrolo[2,3-d]pyrimidinyl}carbonyl)pyridin y|][4-(trif|uoromethyl)phenyl]acetamide KN' N HofMe 4-(Trifluoromethyl)phenylacetic acid (33.6 g, 165 mmol) was added to (5-aminopyridinyl){7-[(1S)—2- —butyl(dimethy|)si|y|]oxy}methy|ethy|]-7H-pyrro|o[2,3-d]pyrimidinyl}methanone (45.2 g, 110 mmol) (see Preparation 37), ylphosphonic 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 d at 25°C for 2 hours then saturated aqueous sodium bicarbonate (250 mL) was added and the organic layer was separated. The aqueous phase was extracted with EtOAc (2 x 200 mL) and all organic phases were ed and dried over sodium sulfate then evaporated in vacuo.

The residue brown solid was dissolved in THF (400 mL) and aqueous HCI (200 mL, 2M) was added. The mixture was stirred at room temperature for 2 hours then cooled to 0°C and sodium hydroxide (28 g) was added. The mixture was stirred for 3 hours then water (100 mL) was added. The organic layer was separated and the aqueous phase was extracted with EtOAc (2 x 300 mL) and all organic phases were combined and dried over sodium sulfate then evaporated in vacuo. The crude solid was recrystallised using ethyl acetate (150 mL) to afford the title compound as a white solid in 63% yield, 33.4 g. 1H NMR (400 MHz, DMSO) 6: 1.51 (d, 3H), 3.68-3.79 (m, 1H), 3.81-3.93 (m, 3H), 4.93-5.06 (m, 2H), 7.55- 7.63 (m, 2H), 7.67-7.75 (m, 2H), 8.41-8.49 (m, 2H), 8.73 (d, 1H), 8.98 (s, 1H), 9.00 (d, 1H), 9.44 (s, 1H), .72 (s, 1H); LCMS (System 1): Rt = 4.53 min; m/z 484 [M+H]+.

W0 2012/137089 49 Example 10: N-[5-({7-[(1S)—2-Hydroxy—1-methy|ethy|]-7H-pyrro|o[2,3-d]pyrimidinyl}carbonyl)pyridin y|][5-methyl(trifluoromethy|)-1H-pyrazolyl]acetamide K|N\ FF % Hydrochloric acid in 1,4- dioxane (0.2 mL) was added to Preparation 66 (59 mg, 0.098 mmol) in THF (2 mL) and the mixture was stirred at room temperature 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 from the appropriate protected alcohol. 2-(4-chlorophenyl)-N-[5-({7-[(1S)—2-hydroxy—1-methy|ethy|]- LCMS m 4): Rt = 2.89 7H-pyrrolo[2,3-d]pyrimidinyl}carbonyl)pyridin min; m/z 450 [M+H]+ N--[5-({7-[(18)--h-ydroxy-1methylethy|]--7H--pyrro|o[2, 3- LCMS (system 4): Rt = 2.88 d]pyrimidin--y|}carbonyl)pyridin--y-|]-[3-(trifluoromethyl)— min; m/z 474 [M+H]+ 1H--p razol- 1- N--[5-({7-[(18)--h-ydroxy-1methylethy|]-H-pyrro|o[2, 3- LCMS (system 4): Rt = 2.68 d]pyrimidin--y|}carbonyl)pyridin--y-|]-[4-(trifluoromethyl)— min; m/z 475 [M+H]+ 1H- 1 ,2 ,3-triazol- 1- 2--(-5chloropyridin--y-|)-N--[5-({7-[(18)--hydroxy LCMS (system 4): Rt = 2.72 ethy|]-H-p,yrro|o[23--d]pyrimidin--y|}carbony|)pyridin- min; m/z 451 [M+H]+ 2--(-2H-benzotriazol-y-|)-N--[5-({7-[(18)--hydroxy LCMS m 4): Rt = 2.64 methylethy|]-H-p,yrro|o[23--d]pyrimidin--y|}carbony|)pyridin- min; m/z 457 [M+H]+ 2-(,24--difluorophenyl)—-N--[5-({7-[(18)--hydroxy LCMS m 4) Rt = 2.74 methylethy|]-H-p,yrro|o[23--d]pyrimidin--y|}carbony|)pyridin- min; m/z 452 [M+H]+ Example 17: N-[5-({7-[(1R)—2-Hydroxy—1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}carbonyl)pyridin y|][5-methyl(trifluoromethy|)-1H-pyrazolyl]acetamide HOJqu Me (5-Methy|trif|uoromethyl-pyrazoly|)acetic acid (46.8 mg, 0.225 mmol) was added to (R,S) (5- aminopyridinyl){7-[(1R)—1-methyl(tetrahydro-2H-pyranyloxy)ethy|]-7H-pyrro|o[2,3-d]pyrimidin yl}methanone (66 mg, 0.173 mmol ) (see ation 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 onate (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.

% 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 temperature for 1.5 hours. The mixture was evaporated in vacuo and triturated with e:diethyl ether (3:1, 1 mL) to afford the title compound as an off white solid in 94% yield, 42 mg. 1H NMR (400 MHz, DMSO) 6: 1.49 (d, 3H), 2.32 (d, 3H), 3.56 (m, 1H), 5.00 (m, 1H), 5.20 (s, 2H), 6.56 (s, H), 8.45 (s, 1H), 8.54 (s, 1H), 8.79 (s, 1H), 9.02 (s, 2H), 9.48 (s, 1H), 11.05 (s, 1H); LCMS(system 4): R = 2.86 min; m/z 488 [M+H]+.

Examples 18 to 24 were prepared according to the method described above for Example 17, starting from (5-aminopyridinyl){7-[(1R)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3- d]pyrimidinyl}methanone (see Preparation 36). 2--(-4cyclopropyl- 1H- 1 ,2 ,3-triazol- 1--y-|)-N--[5-({7-[(1R)— LCMS (system 4): Rt = 2.21 2--h-ydroxy-1methy-lethyl]-H-pyrrolo[2, 3--d]pyrimidin- min; m/z 474 [M+H]+ 2--(5-f|uoropyridin--y|)--N--[5-({7-[(1R)—-hydroxy LCMS (system 4): Rt = 2.24 methylethyl]--7H-p—yrrolo[2, 3--d]pyrimidin- min; m/z 435 [M+H]+ N--[5-({7-[(1R)—-hydroxymethylethyl]-7H- LCMS m 4): Rt = 2.98 pyrrolo[2,3-d]pyrimidinyl}carbonyl)pyridinyl] min; m/z 484 [M+H]+ N-[5-({7-[(1R)—2-hydroxymethylethyl]-7H- LCMS (system 4): Rt = 2.70 pyrrolo[2,3-d]pyrimidinyl}carbonyl)pyridinyl] min; m/z 475 [M+H]+ N--[5-({7-[(1R)—hydroxy1-1i-methylethyl]--7H- LCMS (system 4): Rt = 2.80 pyrrolo[2, 3--d]pyrimidin--yl}carbonyl)pyridin--y-|] min; m/z 474 [M+H]+ 2--(5-chloropyridin--y|)--N--[5-({7-[(1R)—-hydroxy LCMS (system 4): R = 2.49 methylethyl]--7H-p—yrrolo[2, yrimidin- min; m/z 451 [M+H]+ chlorophenyl)--N--[5-({7-[(1R)—-hydroxy LCMS (System 2): R = 1.01 methylethyl]--7H-p—yrrolo[2, 3--d]pyrimidin- min; m/z 450 [M+H]+ Example 25: (R,S) 2-(4-CyclopropyI-1H-pyrazoIy|)-N-(5-{[7-(2-hydroxymethy|ethy|)-7H-pyrro|o[2,3- d]pyrim idiny|]carbony|}pyridiny|)acetamide The title compound was prepared according to the method bed for Example 9 using (R,S) (5- aminopyridiny|){7-[2-{[tert-buty|(dimethy|)si|y|]oxy}methy|ethy|]-7H-pyrro|o[2,3-d]pyrimidin yl}methanone (see Preparation 39) and (4-cyc|opropy|-1H-pyrazoIy|)acetic acid (see Preparation 88) to afford the title compound as a white solid in 14% yield, 20 mg. 1H NMR (400 MHz, DMSO) 6: 0.46 (d, 2H), 0.79 (d, 2H), 1.49 (d, 3H), 1.70 (m, 1H), 3.73 (m, 1H), 3.87 (m, 1H), 5.00 (s, 4H), 7.26 (s, 1H), 7.54 (s, 1H), 8.40 (s, 1H), 8.47 (s, 1H), 8.75 (d, 1H), 8.98 (s, 1H), 9.00 (d, 1H), 9.44 (s, 1H), 10.75 (s, 1H); LCMS (system 4): R = 2.53 min; m/z 445 .

Examples 26 to 33 were prepared according to the method described above for Example 10, starting from the appropriate ted a|coho| TBDMS ether.

N--(-5{[7-(2-hydroxy—1, 1--d-imethy|ethy|)Hp-y,rro|o[2 3- LCMS (system 4): 2.89 d]pyrimidin--y|]carbony|}pyridin--y-|)-[5-methyl- min; m/z 502 [M+H]+t N--(-5{[7-(2-hydroxy—1, 1--dimethy|ethy|)-Hp-yrro|o[2,3- LCMS (system 4): R = 3.03 d]pyrimidiny|]carbony|}pyridiny|)[4- min; m/z 498 [M+H]+ 2-(4-ch|oropheny|)-N-(5-{[7-(2-hydroxy-1,1-dimethy|ethy|)- H NMR (400 MHz, DMSO) 6. 7H-pyrro|o[2,3-d]pyrim idiny|]carbony|}pyridin 1.73 (s, 6H), 3.75 (s, 2H), 3.96 y| )acetamide (s, 2H), 7.39 (s, 4H), 8.22 (s, H), 8.51 (s, LCMS (system 4): t: 3.02 min; m/z 464.1 [M+H]+ 2-(5-ch|oropyridiny|)-N-(5-{[7-(2-hydroxy-1,1- dimethylethy|)-7H-pyrro|o[2,3-d]pyrimidin LCMS m 4): R = 2.72 y|]carbony|}pyridiny|)acetamide min; m/z 465 [M+H]+ N--(-5{[7-(2-hydroxy—1, 1--d-imethy|ethy|)H-pyrro|o[2, 3- LCMS (system 4): R = 2.80 d]pyrimidin--y|]carbony|}pyridin--y-|)-[3-(trifluoromethy|)- min; m/z 488 [M+H]+ 1H--p razol- 1- 2--(-4cyc|opropy|- 1H- 1 ,2 ,3-triazol- 1--y-|)-N--(-5{[7-(2-hydroxy- LCMS m 4): R: 2.47 1 ,1--dimethy|ethy|)-H-p,yrro|o[23--d]pyrimidin- min; m/z 461 [M+H] N--(-5{[7-(2-hydroxy—1, 1--dimethy|ethy|)-H-p,yrro|o[2 3- LCMS (system 4): R = 2.78 d]pyrimidin--y|]carbony|}pyridin--y-|)-[4-(trifluoromethy|)- min; m/z 489 [M+H]+ 1H- 1 ,2 ,-3triazol- 1- 2--(-4cyc|opropy|- yrazo| 1--y-|)-N--(-5{[7-(2-hydroxy-1,1- LCMS(system 4): R = 2.68 dimethylethy|)--7H--p,yrro|o[23--d]pyrimidin- min; m/z 460 [M+H]+ Example 34: N-(5-{[2-Amino(2-hydroxymethy|ethy|)-7H-pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridin- 3-yl)(4-ch|oropheny|)acetamide iomer 1) 4-Chlorophenylacetic acid (25 mg, 0.14 mmol) was added to [2-amino(2-hydroxymethy|ethy|)-7H- pyrrolo[2,3-d]pyrimidinyl](5-aminopyridinyl)methanone (50 mg, 0.16 mmol) (see Preparation 57) and HATU (91 mg, 0.24 mmol) in pyridine (2 mL). The mixture was stirred at room temperature for 16 hours. ted aqueous sodium bicarbonate (5 mL) was added then extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with brine (5 mL) then dried over sodium sulfate and evaporated in vacuo. The residue was ed by preparative TLC (95:5 DCM:MeOH) to afford the title nd 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(2-hydroxymethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl](5-aminopyridin y|)methanone (see Preparation 57, omer1 or Preparation 59, enantiomer 2) and the appropriate acids.

N-(5-{[2-amino(2-hydroxymethylethyl)—7H- Enantiomer 1 pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridiny|)(5- LCMS (system 5): Rt = 2.63 min; m/z 466 [M+H]+ N-(5-{[2-amino(2-hydroxymethylethyl)—7H- Enantiomer 1 pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridiny|)[4- LCMS (system 5): Rt = 2.88 min; m/z 499 [M+H]+ N-(5-{[2-amino(2-hydroxymethylethyl)—7H- Enantiomer 1 pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridiny|)(5- LCMS (system 5): Rt = 2.25 min; m/z 450 [M+H]+ N-(5-{[2-amino(2-hydroxymethylethyl)—7H- Enantiomer 1 pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridiny|)[3- LCMS (system 4): Rt = 2.39 trifluorometh | -1H-p razol |]acetamide min; m/z 489 [M+H]+ N-(5-{[2-amino(2-hydroxymethylethyl)—7H- Enantiomer 1 o[2,3-d]pyrimidinyl]carbonyl}pyridiny|)[4- LCMS (system 5): Rt = 2.61 trifluorometh | -1H-1,2,3-triazol | acetamide min; m/z 490 M+H N-(5-{[2-amino(2-hydroxymethylethyl)—7H- Enantiomer 2 pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridiny|)(5- LCMS (system 4): Rt = 1.89 fluorop ridin | acetamide min; m/z 450 [M+H]+ N-(5-{[2-amino(2-hydroxymethylethyl)—7H- Enantiomer 2 pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridiny|)(5- LCMS (system 4): Rt = 2.16 chlorop ridin | acetamide min; m/z 466 [M+H]+ N-(5-{[2-amino(2-hydroxymethylethyl)—7H- Enantiomer 2 o[2,3-d]pyrimidinyl]carbonyl}pyridiny|)(4- LCMS (system 4): Rt = 2.63 chlorophen | acetamide min; m/z 465 [M+H]+ N-(5-{[2-amino—7-(2-hydroxymethy|ethy|)-7H- omer 2 o[2,3-d]pyrimidinyl]carbonyl}pyridiny|)[4- LCMS (system 4): Rt = 2.73 min; m/z 499 [M+H]+ N-(5-{[2-amino—7-(2-hydroxymethy|ethy|)-7H- Enantiomer 2 pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridiny|)[3- LCMS (system 4): Rt = 2.38 orometh | -1H-p razol ' min; m/z 489 [M+H]+ N-(5-{[2-amino—7-(2-hydroxymethy|ethy|)-7H- Enantiomer 2 pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridiny|)[4- LCMS (system 5): Rt = 2.60 trifluorometh | -1H-1,2,3-triazol ' min; m/z 490 [M+H]+ e 46: N-(5-{[2-Amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin yl]carbonyl}pyridinyl)(5-ch|oropyridinyl )acetam ide \ /N o N/ \ H \ / )\\ I H2N N Me)$Me oropyridinyl)acetic acid (26.1 g, 152 mmol) (see Preparation 90) was added to (5-aminopyridin- 3-y|){7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethy|ethy|)[(2,4-dimethoxybenzyl)amino]—7H-pyrrolo[2,3- d]pyrimidinyl}methanone (75.0 g, 130 mmol ) (see Preparation 51), ylphosphonic 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 ted aqueous sodium bicarbonate (400 mL) was added and the organic layer was separated. The aqueous phase was extracted with EtOAc (400 mL) and all 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 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 ethanol (3 x 200 mL).

Potassium carbonate (87.7 9, mmol) was added to the crude trifluoroacetamide in methanol (300 mL) and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water (2000 mL) and filtered. The solid was washed with water (200 mL) then triturated with ethanol (2 x 200 mL at room temperature then 380 mL at 50°C) to afford the title compound as a yellow solid in 48% yield, 29.9 g. 1H NMR (400 MHz, DMSO-d6) 6: 1.64 (s, 6H), 3.90 (d, 2H), 3.95 (s, 2H), 5.05 (t, 1H), 6.54 (br s, 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), .71 (s, 1H); LCMS (System 3): R: 9.92 min; m/z 480 [M+H]+.

Example 47: N-(5-{[2-Amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin yl]carbonyl}pyridinyl)[5-methyl(trifluoromethy|)-1H-pyrazolyl]acetamide \ / OMe N/ N4, — F I \ ” N‘ / x N N F H2N N F Me>§Me The title compound was prepared according to the method described for Example 46 using (5- yridinyl){7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)[(2,4-dimethoxybenzyl)amino]— 7H-pyrrolo[2,3-d]pyrimidinyl}methanone (see ation 51) and (5-methyltrifluoromethyl-pyrazol- 1-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(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl](5-aminopyridin yl)methanone (see Preparation 48) and the appropriate acids.

N-(5-{[2-amino(2-hydroxy-1,1-dimethylethyl)—7H- LCMS (system 5): pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridiny|) R: 3.12 min; m/z 513 M+H N-(5-{[2-amino(2-hydroxy-1,1-dimethylethyl)—7H- LCMS (system 5): pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridiny|) R: 2.89 min; m/z 479 [M+H]+ [2-amino(2-hydroxy-1,1-dimethylethyl)—7H- MS (ESCI): m/z pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridiny|) 481 [M+H]+ N-(5-{[2-amino(2-hydroxy-1,1-dimethylethyl)—7H- LCMS (system 5): pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridiny|) R: 2.42 min; m/z -fluorop ridin l acetamide 464 [M+H]+ N-(5-{[2-amino(2-hydroxy-1,1-dimethylethyl)—7H- LCMS m 4): pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridiny|) R: 2.54 min; m/z [3- trifluorometh l-1H-p 1- l]acetamide 503 [M+H]+ N-(5-{[2-amino(2-hydroxy-1,1-dimethylethyl)—7H- LCMS (system 4) pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridiny|) R = 2.23 min; m/z 3-c cloprop l-1H-p razol lacetamide 475 [M+H]+ Example 54: N-(5-{[2-Amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin yl]carbonyl}pyridinyl)[4-(trifluoromethyl)-1H-1,2,3-triazolyl]acetamide \ / o F Jk/ — F I \ N N‘N’zN )\\ N HO The title compound was ed according to the method described for Example 9 using [7-(2-{[tert- butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)amino-7H-pyrrolo[2,3-d]pyrimidinyl]{5-aminopyridin hanone (see Preparation 48a) and [4-(trifluoromethyl)-1H-1,2,3-triazolyl]acetic acid (see Preparation 81) to afford the title compound as a brown solid in 85% yield, 62 mg. 1H NMR (400 MHz, DMSO-d6) 6: 1.63 (s, 6H), 3.89 (d, 2H), 5.01 (br, 1H), 5.56 (s, 2H), 6.67 (br s, 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 .

Example 55: N-(5-{[2-Amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin yl]carbonyl}pyridinyl)(2H-benzotriazolyl)acetamide \ / O / N NI 1 | \ H ‘N/ \N N Me>$Me H0 The title compound was ed according to the method described for Example 9 using {2-amino [1 ,1-dimethyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}(5-aminopyridin yl)methanone (see Preparation 49) to afford the title compound as a brown solid in 46% yield, 20 mg. 1H NMR (400 MHz, DMSO-d6) 6: 1.63 (s, 6H), 3.88 (d, 2H), 5.04 (t, 1H), 5.80 (s, 2H), 6.54 (s, 2H), 7.46- 7.49 (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, 1H), 11.06 (s, 1H); MS (ESCI): m/z 486 [M+H]+.

Example 56: N-(5-{[2-Amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin yl]carbonyl}pyridinyl)(4-cyclopropyl-1H-1,2,3-triazolyl)acetamide The title nd was prepared according to the method described for Example 10 using N-[5-({2- amino[1,1-dimethyl(tetrahydro-2H-pyranyloxy)ethyl]—7H-pyrrolo[2,3-d]pyrimidin yl}carbonyl)pyridinyl](4-cyclopropyl-1H-1,2,3-triazolyl)acetamide (see Preparation 52) to afford the title compound as a yellow solid in 24% yield, 14 mg. 1H NMR (400 MHz, DMSO-D6) 6: 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 (2-aminotert-butyl-7H-pyrrolo[2,3-d]pyrimidinyl)(5-aminopyridinyl)methanone (see Preparation 65) and the appropriate acids.

N-{5-[(2-aminotert-butyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 5): R: yl)carbonyl]pyridinyl}(3-cyclopropyl-1H-pyrazol 2.90 min; m/z 459 [M+H]+ N-{5-[(2-aminotert-butyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 5, 12 min yl)carbonyl]pyridinyl}(4-cyclopropyl-1H-1 ,2,3-triazol run): R = 6.13 min; m/z 460 [M+H]+ LCMS (system 4): R = 2.60 min; m/z 448 [M+H]+ N-{5-[(2-aminotert-butyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 5): R = 2.99 yl)carbonyl]pyridinyl}[4-(trifluoromethyl)-1H-pyrazol-1 min; m/z 487 [M+H]+ |]acetamIde (2-aminotert-butyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 5): R = 3.04 yl)carbonyl]pyridinyl}[4-(trifluoromethyl)-1H-1,2,3- min; m/z 488 [M+H]+ triazol |]acetamide N-{5-[(2-aminotert-butyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 5): R = 3.09 yl)carbonyl]pyridinyl}[3-(trifluoromethyl)-1H-pyrazol-1 min; m/z 487 [M+H]+ amide N-{5-[(2-aminotert-butyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 5): R = 2.95 lcarbon |]p ridin l 5-chlorop ridin lacetamide min; m/z 464 [M+H]+ N-{5-[(2-aminotert-butyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 5): R = 3.09 yl)carbonyl]pyridinyl}[5-methyl(trifluoromethyl)-1H- min; m/z 501 [M+H]+ amide The following Examples were prepared according to Method a le 34 at 50°C) or Method b (Example 1 using DIPEA) as described above starting from (5-Aminopyridinyl)(7-isopropyl-7H- pyrrolo[2,3-d]pyrimidinyl)methanone ration 95) and the riate acid. 65 2-(4-fluorophenyl)-N-{5-[(7-isopropyl-7H- LCMS (system 1): R = 2.73 min; m/z pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridin 418[M+H]+. yl}acetamide ‘N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 9): R = 3.22 min; m/z yl)carbonyl]pyridinyl}[3- 468 [M+H]+. (trifluoromethyl)phenyl]acetamide 67 N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 9): R = 3.22 min; m/z yl)carbonyl]pyridinyl}[4- 468 [M+H]+. (trifluoromethyl)phenyl]acetamide 2-(3,4-dichlorophenyl)-N-{5-[(7-isopropyl-7H- LCMS (system 7): R = 11.34 min; m/z pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridin 468 [M+H]+ yl}acetamide 57 2012/051363 2-(4-chlorophenyl)-N-{5-[(7-isopropy|-7H- m/z 434 [M+H]+ pyrro|o[2,3-d]pyrim idiny|)carbony|]pyridin yl}acetam ide \lO 2-[2-(cyclopropyloxy)phenyl]-N-{5-[(7-isopropy|- LCMS m 4): R = 3.13 min; m/z 7H-pyrrolo[2,3-d]pyrimidin 456 [M+H]+ y|)carbony|]pyridiny|}acetamide Prep HPLC (method 2) Using [2-(cyclopropyloxy)pheny|]acetic acid Preparation 160 . \l _\ 2-(4-cyanophenyl)-N-{5-[(7-isopropy|-7H- LCMS (system 2): R = 1.16 min; m/z pyrro|o[2,3-d]pyrim idiny|)carbony|]pyridin 425 [M+H]+ yl}acetam ide \lN 2-[4-cyano(trifluoromethyl)pheny|]-N-{5-[(7- LCMS (system 1): R = 2.82 min; m/z isopropyI-7H-pyrrolo[2,3-d]pyrimidin 493 [M+H]+ y|)carbony|]pyridiny|}acetamide Using [4-cyano (trifluoromethy|)pheny|]acetic acid (Preparation 164). \l (JO 2-[4-(cyclopropyloxy)phenyl]-N-{5-[(7-isopropy|- LCMS (System 3) R = 3.05 min; m/z 7H-pyrrolo[2,3-d]pyrimidin 456 [M+H]+ y|)carbony|]pyridiny|}acetamide Using [4-(cyclopropyloxy)pheny|]acetic acid (Preparation 161).

Prep method 2 N4; cyclopropyloxy)phenyl]-N-{5-[(7-isopropy|- LCMS (system 1) R = 2.52 min; m/z 7H-pyrrolo[2,3-d]pyrimidin 456 [M+H] y|)carbony|]pyridiny|}acetamide Using [3-(cyclopropyloxy)pheny|]acetic acid (Preparation 162). 2-[3-(hydroxymethyl)pheny|]-N-{5-[(7-isopropy|- LCMS (System 2): R = 1.3 min; m/z 7H-pyrrolo[2,3-d]pyrimidin 430 [M+H]+ bony|]pyridiny|}acetamide \l O) 2-(4-cyanofluorophenyl)-N-{5-[(7-isopropy|- LCMS (System 2): R = 1.5 min; m/z 7H-pyrrolo[2,3-d]pyrimidin 443 [M+H]+ y|)carbony|]pyridiny|}acetamide \l \l 2-(4-cyanomethoxyphenyl )-N-{5-[(7- LCMS m 2): R = 1.3 min; m/z isopropyI-7H-pyrrolo[2,3-d]pyrimidin 455 [M+H]+ y|)carbony|]pyridiny|}acetamide \l (D 2-(6-fluorooxo-1,3-dihydro—2H-isoindoIy|)- LCMS (System 2): R = 1.5 min; m/z (7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin 473 [M+H]+ y|)carbony|]pyridiny|}acetamide \l (O N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (System 2): R = 1.2 min; m/z y|)carbony|]pyridiny|}(3-pyridiny|-1H- 467 [M+H]+. pyrazoIy|)acetamide 2-(1H-benzimidazoIyl)-N-{5-[(7-isopropyI-7H- LCMS (System 2): R = 1.0 min; m/z pyrro|o[2,3-d]pyrim idiny|)carbony|]pyridin 440 [M+H]+ tam ide CO _\ N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (System 2): R = 1.1 min; m/z y|)carbony|]pyridiny|}quinoxa|in 452 [M+H]+ ylacetam ide 00N N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (System 9): R: 2.63 min; m/z y|)carbony|]pyridiny|}(1,5-naphthyridin 452 [M+H]+ yl)acetamide Using 1,5-naphthyridinylacetic acid (Preparation 188).

WO 37089 58 2-(3-amino-1,2-benzisoxazoIyl)-N-{5-[(7- LCMS (System 9): R: 2.76 min; m/z isopropyI-7H-pyrrolo[2,3-d]pyrimidin 456 [M+H]+ using (3-amino- y|)carbony|]pyridiny|}acetamide benzo[d]isoxazolyl)-acetic acid ethyl ester (Preparation 129) N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (System 9): R: 2.90 min; m/z y|)carbony|]pyridiny|}[2-(trif|uorom ethyl)- 508 [M+H]+ 1H-benzimidazoIy|]acetamide CO 01 2-imidazo[1,2-a]pyridiny|-N-{5-[(7-isopropyl- LCMS (System 10): R: 2.57 min; m/z 7H-pyrrolo[2,3-d]pyrimidin 440 [M+H]+ using imidazo[1,2- y|)carbony|]pyridiny|}acetamide a]pyridiny|-acetic acid (Preparation 132) N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (System 9): R: 2.54 min; m/z y|)carbony|]pyridiny|}(1H-pyrazolo[4,3- 441 [M+H]+ diny|)acetamide Using 1H-pyrazolo[4,3-b]pyridin y|)acetic acid (Preparation 190).

CD \I N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (System 9): R = 2.74 min; m/z y|)carbony|]pyridiny|}[3- 478 [M+H]+ (methylsulfonyl)pheny|]acetamide 2-(4-cyclopropyI-1H-1,2,3-triazoly|)-N-{5-[(7- LCMS (System 9): R = 2.68 min; m/z isopropyI-7H-pyrrolo[2,3-d]pyrimidin 431 . y|)carbony|]pyridiny|}acetamide Using 4-cyclopropyI-1H-1,2,3-triazol ic acid (Preparation 83). 2-(1,3-benzoxazoIyl)-N-{5-[(7-isopropy|-7H- LCMS (System 9): R = 2.79 min; m/z pyrrolo[2,3-d]pyrim idiny|)carbonyl]pyridin 441.1 [M+H]+ yl}acetam ide 2-(3-cyclopropyI-1H-pyrazoIy|)-N-{5-[(7- LCMS (System 9): R = 2.75 min; m/z isopropyI-7H-pyrrolo[2,3-d]pyrimidin 430 [M+H]+ y|)carbony|]pyridiny|}acetamide (3-cyclopropyI-1H-pyrazoIy|)acetic acid (Preparation 80).

(D _\ 2-[5-(cyclopropyloxy)pyrid |]-N-{5-[(7- LCMS (system 3) R = 2.36 min; m/z isopropyI-7H-pyrrolo[2,3-d]pyrimidin 457 [M+H]+ y|)carbony|]pyridiny|}acetamide Prep method 2 Using [5-(cyc|opropy|oxy)pyridin |]acetic acid Preparation 163 .

(DN 2-(2,3-dihydrobenzofuranyl)—N-{5-[(7— LCMS (system 3): R = 2.91 min; m/z pyI-7H-pyrrolo[2,3-d]pyrimidin 442 [M+H]+ bony|]pyridiny|}acetamide Prep HPLC (method 1) (9 0O 2-(2H-indazoIyl)-N-{5-[(7-isopropy|-7H- LCMS (system 3): R = 2.74 min; m/z pyrrolo[2,3-d]pyrim idiny|)carbonyl]pyridin 440 [M+H]+ yl}acetam ide Prep HPLC (method 1) (9 4s 2-(5-f|uoro-2H-indazoIyl)-N-{5-[(7-isopropy|- LCMS (system 9): R: 2.96 min; m/z 7H-pyrrolo[2,3-d]pyrimidin 458 [M+H]+ y|)carbony|]pyridiny|}acetamide Using -(5-f|uoro-2H-indazoIy|)acetic acid Preparation 174 .

WO 37089 59 (9 U1 2-(5-fluoro-1H-indazoIy|)-N-{5-[(7-isopropy|- LCMS (system 9): R: 2.97 min; m/z rolo[2,3-d]pyrimidin 458 [M+H]+ y|)carbony|]pyridiny|}acetamide Using (5-fluoro-1H-indazoIy|)acetic acid (Preparation 172).

N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.62 min; m/z y|)carbony|]pyridiny|}[5-methy| 472 [M+H]+ (trifluorom ethyl )-1 H-pyrazoI-1 -y|]acetam ide (9 \l (7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 3): R = 2.97 min; m/z y|)carbony|]pyridiny|}[3-(trif|uorom ethyl)- 458 [M+H]+ 1H-pyrazoIy|]acetamide Prep HPLC (method 1) 2-(5-chloropyridiny|)-N-{5-[(7-isopropy|-7H- LCMS (system 9): R = 2.86 min; m/z pyrrolo[2,3-d]pyrim idiny|)carbony|]pyridin 435 [M+H]+ yl}acetam ide Using (5-ch|oropyridiny|)acetic acid Preparation 90 . 2-(1H-indazoIyl)-N-{5-[(7-isopropy|-7H- m/z 440 [M+H]+ pyrrolo[2,3-d]pyrim idiny|)carbony|]pyridin Using 1H-indazoIylacetic acid yl}acetam ide (Preparation 182).

N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 7): R = 8.73 min; m/z y|)carbony|]pyridiny|}quino|in 451 [M+H]+ am ide 2-(7-f|uoro-2H-indazoIyl)-N-{5-[(7-isopropy|- LCMS m 9): R: 2.95 min; m/z 7H-pyrrolo[2,3-d]pyrimidin 458 [M+H]+ y|)carbony|]pyridiny|}acetamide Using (7-fluoro-2H-indazoIyl)acetic acid (Preparation 178).

N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 9): R: 2.72 min; m/z y|)carbony|]pyridiny|}(1H-pyrazolo[3,4- 441 [M+H]+ b]pyridiny|)acetamide Using 1 H-pyrazolo[3,4-b]pyridin y|)acetic acid (Preparation 180). 2-(1H-indazoIy|)-N-{5-[(7-isopropy|-7H- LCMS (system 3): R = 2.82 min; m/z o[2,3-d]pyrimidiny|)carbony|]pyridin 440 [M+H]+ yl}acetamide Prep HPLC (method 1) 2-(3-isopropyImethyl-1H-pyrazoIy|)-N-{5- LCMS (system 8): R = 1.65 min; m/z [(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin 446 [M+H]+ y|)carbony|]pyridiny|}acetamide Using (3-isopropyImethyI-1H- pyrazoIy|)acetic acid (Preparation 167). (7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.52 min; m/z y|)carbony|]pyridiny|}(4-isopropy|-1H- 433 [M+H]+ 1,2,3-triazo|y|)acetamide N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 9): R = 2.98 min; m/z y|)carbony|]pyridiny|}[4-(trif|uorom ethyl)- 459 [M+H]+ 1H-1,2,3-triazo|y|]acetamide Using [4-(trifluoromethy|)-1H-1,2,3- triazoIy|]acetic acid ration 81). 2-(7-fluoro-1H-indazoIy|)-N-{5-[(7-isopropy|- LCMS (system 9): R = 2.96 min; m/z 7H-pyrrolo[2,3-d]pyrimidin 458 [M+H]+ y|)carbony|]pyridiny|}acetamide Using (7-fluoro-1H-indazoIy|)acetic acid Preparation 176 . 2-(2H-benzotriazoIyl)-N-{5-[(7-isopropy|-7H- LCMS (system 8): R = 1.57 min; m/z pyrrolo[2,3-d]pyrim idiny|)carbony|]pyridin 441 [M+H]+ yl}acetam ide W0 2012/137089 60 2-(7-fluoro—2-methyI-1H-indoIy|)-N-{5-[(7- LCMS (system 8): R 1.64 min; m/z isopropyI-7H-pyrro|o[2,3-d]pyrimidin 471 [M+H]+ y|)carbonyl]pyridinyl}acetamide 2-(5-chloro—2-methyI-1H-indoIy|)-N-{5-[(7- LCMS (system 8): R 1.69 min; m/z isopropyI-7H-pyrro|o[2,3-d]pyrimidin 487 [M+H]+ y|)carbonyl]pyridinyl}acetamide 2-(1H-indoIy|)-N-{5-[(7-isopropy|—7H- LCMS (system 8): R 1.66 min; m/z pyrro|o[2,3-d]pyrimidinyl)carbonyl]pyridin 439 [M+H]+ y|}acetamide N-{5-[(7-isopropy|—7H-pyrro|o[2,3-d]pyrimidin LCMS m 9): R = 3.13 min; m/z y|)carbonyl]pyridiny|}[1-isopropy| 500 [M+H]+ (trifluoromethy|)-1H-pyrazoIy|]acetamide Using 1-isopropyI(trifluoromethyl)- azoIy|]acetic acid (Preparation 185).

N-{5-[(7-isopropy|—7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.50 min; m/z y|)carbonyl]pyridiny|}(3-methy|-1H- 404 [M+H]+ pyrazoIy|)acetamide N-{5-[(7-isopropy|—7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.45 min; m/z y|)carbonyl]pyridiny|}(1H-pyrazoI 390 [M+H]+ y|)acetamide -dimethy|-1H-pyrazoIy|)-N-{5-[(7- LCMS (system 8): R = 1.55 min; m/z isopropyI-7H-pyrro|o[2,3-d]pyrimidin 418 [M+H]+ y|)carbonyl]pyridinyl}acetamide N-{5-[(7-isopropy|—7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.62 min; m/z y|)carbonyl]pyridiny|}(2-methy|-1H-indoI 453 [M+H]+ y|)acetamide N-{5-[(7-isopropy|—7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.57 min; m/z yl)carbonyl]pyridiny|}(5-methoxy-1H-indol- 469 [M+H]+ 3-y|)acetamide N-{5-[(7-isopropy|—7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.35 min; m/z y|)carbonyl]pyridinyl}pyridin 401 [M+H]+ ylacetamide 2-(5-chloro—1H-benzotriazoIy|)-N-{5-[(7- LCMS m 8): R = 1.61 min; m/z isopropyI-7H-pyrro|o[2,3-d]pyrimidin 475 [M+H]+ y|)carbonyl]pyridinyl}acetamide N-{5-[(7-isopropy|—7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.61 min; m/z y|)carbonyl]pyridiny|}[3-(2-thieny|)-1H- 472 [M+H]+ pyrazoIy|]acetamide N-{5-[(7-isopropy|—7H-pyrro|o[2,3-d]pyrimidin LCMS m 8): R = 1.37 min; m/z bonyl]pyridiny|}(7- 455 [M+H]+ methylimidazo[1,2-a]pyrimidinyl)acetamide 2-(2,6-dimethyl-9H-puriny|)-N-{5-[(7- LCMS (system 8): R = 1.43 min; m/z isopropyI-7H-pyrro|o[2,3-d]pyrimidin 470 [M+H]+ y|)carbonyl]pyridinyl}acetamide WO 37089 61 2012/051363 N-{5-[(7-isopropy|—7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.60 min; m/z y|)carbonyl]pyridiny|}(6-nitro-1H-indazol- 485 [M+H]+ 1-y|)acetam ide 2-(5-chloro—1-methyI-1H-indazoIy|)-N-{5-[(7- LCMS (system 8): R = 1.73 min; m/z isopropyI-7H-pyrrolo[2,3-d]pyrimidin 488 [M+H]+ J. Med Chem. y|)carbonyl]pyridinyl}acetamide 1992, 35, 2155-2165 2-(5-fluoro—2-methyI-1H-indoIy|)-N-{5-[(7- LCMS (system 8): R = 1.63 min; m/z isopropyI-7H-pyrrolo[2,3-d]pyrimidin 471 [M+H]+ y|)carbonyl]pyridinyl}acetamide 2-(6-chloroimidazo[1,2—a]pyridinyl)—N-{5-[(7- LCMS (system 8): R = 1.45 min; m/z isopropyI-7H-pyrrolo[2,3-d]pyrimidin 474 [M+H]+ y|)carbonyl]pyridinyl}acetamide N-{5-[(7-isopropy|—7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.36 min; m/z y|)carbonyl]pyridiny|}(2-methy|-1H- 454 [M+H]+ benzimidazoIy|)acetamide 2-imidazo[1,2-a]pyridinyI-N-{5-[(7-isopropyl- LCMS (system 8): R = 1.31 min; m/z 7H-pyrro|o[2,3-d]pyrimidin 440 [M+H]+ y|)carbonyl]pyridinyl}acetamide N-{5-[(7-isopropy|—7H-pyrro|o[2,3-d]pyrimidin LCMS m 8): R = 1.49 min; m/z y|)carbonyl]pyridiny|}(5-methoxy-1H- 470 [M+H]+ pyrro|o[3,2-b]pyridiny|)acetamide (7-isopropy|—7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.49 min; m/z y|)carbonyl]pyridiny|}(5-methy|-1H- 404 [M+H]+ pyrazoIy|)acetamide N-{5-[(7-isopropy|—7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.43 min; m/z y|)carbonyl]pyridiny|}(7-methy|-1H- 454 [M+H]+ benzimidazoIy|)acetamide 2-(1H-indoIyl)-N-{5-[(7-isopropy|—7H- LCMS (system 8): R = 1.59 min; m/z pyrro|o[2,3-d]pyrim idinyl)carbonyl]pyridin 439 [M+H]+ yl}acetam ide 2-(1H-benzimidazoIy|)-N-{5-[(7-isopropy|—7H- LCMS (system 8): R = 1.40 min; m/z pyrro|o[2,3-d]pyrimidinyl)carbonyl]pyridin 440 [M+H]+ yl}acetamide N-{5-[(7-isopropy|—7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.45 min; m/z y|)carbonyl]pyridiny|}(3-methy|-1H- 404 [M+H]+ pyrazoIy|)acetamide 2-(1H-benzotriazoIy|)-N-{5-[(7-isopropyI-7H- LCMS (system 8): R = 1.52 min; m/z pyrro|o[2,3-d]pyrim idinyl)carbonyl]pyridin 441 [M+H]+ yl}acetam ide N-{5-[(7-isopropy|—7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.68 min; m/z y|)carbonyl]pyridiny|}(1-methy|-1H-indoI 453 [M+H]+ yl)acetamide (7-i80propyI-7H-pyrrolo[2,3-d1pyrimidin—5— LCMS (system 8): R = 1.66 min; m/z y|)carbonyl]pyridiny|}(4-pheny|-1H-pyrro|_ 465 [M+H]+ 2-y|)acetam ide 2-(2-ethyI-3H-imidazo[4,5-b]pyridiny|)-N-{5- LCMS (system 8): R = 1.49 min; m/z [(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin 469 [M+H]+ bony|]pyridiny|}acetamide 2-(5-chloro-1H-indoIyl)-N-{5-[(7-isopropy|- LCMS (system 8): R = 1.67 min; m/z 7H-pyrrolo[2,3-d]pyrimidin 473 [M+H]+ y|)carbony|]pyridiny|}acetamide N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.71 min; m/z y|)carbony|]pyridiny|}(1-pheny|-1H-pyrro|_ 465 [M+H]+ Can be prepared by a 3-y|)acetam ide similar method to Harrak, Y. et aI.

Bioorganic & Medicinal Chemistry 14 890.

, , N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.63 min; m/z y|)carbony|]pyridiny|}(5-methy|-1H-indoI 453 [M+H]+ yl)acetamide thyI-1H-benzimidazoIy|)-N-{5-[(7- LCMS (system 8): R = 1.37 min; m/z isopropyI-7H-pyrrolo[2,3-d]pyrimidin 468 [M+H]+ y|)carbony|]pyridiny|}acetamide 2-imidazo[1,2-a]pyrimidinyI-N-{5-[(7- LCMS (system 8): R = 1.38 min; m/z isopropyI-7H-pyrrolo[2,3-d]pyrimidin 441 [M+H]+ y|)carbony|]pyridiny|}acetamide 2-(1H-indazoIyl)-N-{5-[(7-isopropy|-7H- LCMS (system 8): R = 1.55 min; m/z pyrro|o[2,3-d]pyrim idiny|)carbony|]pyridin 440 [M+H]+ yl}acetam ide 2-(5-fluoro—7-methoxy—1H-indoIy|)-N-{5-[(7- LCMS (system 8): R = 1.67 min; m/z isopropyI-7H-pyrrolo[2,3-d]pyrimidin 487 [M+H]+ y|)carbony|]pyridiny|}acetamide 2-(1-benzyI-1H-1,2,3-triazoIyl)-N-{5-[(7- LCMS (system 8): R = 1.57 min; m/z isopropyI-7H-pyrrolo[2,3-d]pyrimidin 481 [M+H]+ y|)carbony|]pyridiny|}acetamide 2-(6-chloromethyI-1H-indazoIy|)-N-{5-[(7- LCMS (system 8): R = 1.72 min; m/z isopropyI-7H-pyrrolo[2,3-d]pyrimidin 488 [M+H]+ y|)carbony|]pyridiny|}acetamide Using -(6-ch|oromethy|-1H-indazol- 3- | acetic acid Preparation 170 . 2-(7-chloro-1H-indoIyl)-N-{5-[(7-isopropy|- LCMS m 8): R = 1.67 min; m/z 7H-pyrrolo[2,3-d]pyrimidin 473 [M+H]+ y|)carbony|]pyridiny|}acetamide N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.68 min; m/z y|)carbony|]pyridiny|}(5-methylpheny|- 480 [M+H]+ 1 zoIy|)acetamide romopyridiny|)-N-{5-[(7-isopropy|-7H- LCMS (system 8): R = 1.60 min; m/z pyrro|o[2,3-d]pyrim idiny|)carbony|]pyridin 479 [M+H]+ yl}acetam ide N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.41 min; m/z y|)carbony|]pyridiny|}pyridin 401 [M+H]+ ylacetamide N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 8): R = 1.55 min; m/z yl)carbonyl]pyridinyl}(6-methoxypyridin 431 [M+H]+ yl)acetam ide 2-(2,5-dimethy|-1H-indoIy|)-N-{5-[(7- LCMS (system 8): R = 1.67 min; m/z isopropyl-7H-pyrrolo[2,3-d]pyrimidin 467 [M+H]+ yl)carbonyl]pyridinyl}acetamide (7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 8): R = 1.33 min; m/z yl)carbonyl]pyridinyl}(6-methylpyrid in 415 [M+H]+ yl)acetam ide (7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 8): R = 1.40 min; m/z yl)carbonyl]pyridinyl}(2-methquu inol in 465 [M+H]+ yl)acetam ide Using (2-methquuinolinyl)acetic acid (Preparation 165).

N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 8): R = 1.60 min; m/z bonyl]pyridinyl}(5-methoxy 483 [M+H]+ methyl-1H-indolyl)acetamide N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 8): R = 1.46 min; m/z yl)carbonyl]pyridinyl}tetrazolo[1,5- 443 [M+H]+. (can be ed via a b]pyridazinylacetam ide similar method to W02010/129379, 11 Nov 2010 2-(5-hydroxy-1H-indolyl)-N-{5-[(7-isopropyl- LCMS (system 8): R = 1.45 min; m/z 7H-pyrrolo[2,3-d]pyrimidin 455 [M+H]+ yl)carbonyl]pyridinyl}acetamide N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 8): R = 1.47 min; m/z yl)carbonyl]pyridinyl}(5H-pyrrolo[2,3- 441 [M+H]+ b]pyrazinyl)acetam ide 2-(5,6-dimethyl-1H-benzimidazoly|)-N-{5-[(7- LCMS (system 8): R = 1.43 min; m/z pyl-7H-pyrrolo[2,3-d]pyrimidin 468 [M+H]+ yl)carbonyl]pyridinyl}acetamide N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 8): R = 1.48 min; m/z yl)carbonyl]pyridinyl}(4-pyridinyl-1H- 468 [M+H]+ 1,2,3-triazolyl)acetamide N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 8): R = 1.43 min; m/z yl)carbonyl]pyridinyl}(4-methyl-1H-1,2,3- 405 [M+H]+ lyl)acetamide N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 8): R = 1.55 min; m/z yl)carbonyl]pyridinyl}(5-methylphenyl- 480 [M+H]+ 1H-pyrazolyl)acetam ide N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (system 8): R = 1.55 min; m/z yl)carbonyl]pyridinyl}[2- 448 [M+H]+ can be prepared via a (m ethylthio)pyrim idinyl]acetamide r method to Smrz, R. et al.

Collection of Czechoslovak Chemical Communications (1976), 41(9), 2771-87 W0 2012/137089 64 N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 8): R = 1.44 min; m/z y|)carbony|]pyridiny|}pyrimidin 402 [M+H]+ ylacetamide Example 166: 2-(5-Cyanopyridiny|)-N-{5-[(7-isopropy|-7H-pyrro|o[2,3-d]pyrimidiny|)carbony|]pyridin- cetam ide \ / O / ;N N“ \ H \N/ KN | N )‘Me Zinc cyanide (28 mg, 0.23 mmol) was added to romo-pyridiny|)-N-[5-(7-(propany|)-7H- pyrro|o[2,3-d]pyrimidinecarbony|)-pyridiny|]-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)dipa||adium (3 mg, 0.003 mmol) and 1,1’-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 e 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 preparative TLC (3% MeOH in DCM) to afford the title nd as a light brown solid in 18% yield, 12 mg. 1H NMR (400 MHz, DMSO) 6: 1.55 (d, 6H), 4.07 (s, 2H), 5.09 (m, 1H), 7.67 (d, 1H), 8.30 (m, 1H), 8.44 (s, 1H), 8.52 (s, 1H), 8.74 (d, 1H), 8.98-8.99 (m, 3H), 9.44 (s, 1H), 10.79 (s, 1H); LCMS (System 9): R = 2.75 min; m/z 426 [M+H]+.

Example 167: 2-[5-FIuoro(trif|uoromethy|)pheny|]-N-{5-[(7-methy|-7H-pyrro|o[2,3-d]pyrimidin y|)carbony|]pyridiny|}acetamide 1-(3-Dimethy|aminopropyl)ethy|carbodiimide HCI (150 uL, 0.5M in DMF) was added to 5-f|uoro (trif|uoromethy|)pheny|acetic acid (90 umol), N-methylmorpholine (25 uL, 150 umol), 1- hydroxybenzotriazole (15 umol, 0.05M in DMF) and (5-aminopyridiny|)(7-methy|-7H-pyrro|o[2,3- d]pyrimidiny|)methanone (Preparation 110, 75 umol, 0.25 M in DMF). The mixture was d 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 = 2.66 min; m/z 458 [M+H]+ The following es were prepared according to the method described above for Example 167 starting from (5-aminopyridiny|)(7-methy|-7H-pyrro|o[2,3-d]pyrimidiny|)methanone (Preparation 110) and the appropriate acid. 168 2-(3-methylphenyl)-N-{5-[(7-methy|-7H- LCMS (system 5): R = 2.53 min; pyrro|o[2,3-d]pyrimidiny|)carbony|]pyridin m/z 386 [M+H]+ yl}acetamide (7-m ethyl-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 5): R 2.61 min; y| )carbonyl]pyridiny|}[2- m/z 440 [M+H]+ uoromethyl)pheny|]acetamide 2-(3,5-difluorophenyl)-N-{5-[(7-methy|-7H- LCMS (system 5): R pyrro|o[2,3-d]pyrimidiny|)carbony|]pyridin m/z 408 [M+H]+ yl}acetamide (7-m ethyl-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 5): R y| )carbonyl]pyridinyI}(2,4,6- m/z 426 [M+H]+ trifluoropheny|)acetamide (7-m ethyl-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 5): R y| )carbonyl]pyridinyI}(2,3,6- m/z 426 [M+H]+ trifluoropheny|)acetamide N-{5-[(7-m ethyl-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 5): R y| nyl]pyridiny|}[4- m/z 450 [M+H]+ (methylsulfonyl)phenyl]acetamide 2-[3-f|uoro(trifluoromethyl)phenyI]-N-{5-[(7- LCMS (system 5): R methyl-7H-pyrro|o[2,3-d]pyrimidin m/z 458 [M+H]+ y|)carbonyl]pyridinyl}acetamide 2-(3-methoxyphenyl)-N-{5-[(7-methy|-7H- LCMS:Rt= 2.34 min; m/z 402 pyrro|o[2,3-d]pyrimidiny|)carbony|]pyridin [|V|+H]+ yl}acetamide N-{5-[(7-m ethyl-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 5): R 2.76 min; y| )carbonyl]pyridiny|}[3- m/z 456 [M+H]+ (trifluoromethoxy)phenyl]acetamide N-{5-[(7-m ethyl-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 5): R 2.54 min; y| )carbonyl]pyridinyI}(2,3,5- m/z 426 [M+H]+ trifluoropheny|)acetamide N-{5-[(7-m ethyl-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 5): R = 1.95 min; y| )carbonyl]pyridiny|}(2-methquuinolin m/z 437 [M+H]+ y| )acetamide Using (2-methquuinoliny|)acetic acid (Preparation 165).

N-{5-[(7-m ethyl-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 5): R = 2.37 min; y| )carbonyl]pyridiny|}pheny|acetamide m/z 372 [M+H]+ 2-(2-chIorofluorophenyl)-N-{5-[(7-m ethyl-7H- LCMS m 5): R = 2.51 min; pyrro|o[2,3-d]pyrimidiny|)carbony|]pyridin m/z 424 [M+H]+ yl}acetamide 2-(4-methoxyphenyl)-N-{5-[(7-m ethyl-7H- LCMS:Rt= 2.22 min; m/z 402 pyrro|o[2,3-d]pyrimidiny|)carbony|]pyridin [|V|+H]+ yl}acetamide W0 2012/137089 66 N-{5-[(7-methyl-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 5): R y|)carbonyl]pyridinyI}{4- m/z 472 [M+H]+ [(trifluoromethyl)thio]pheny|}acetamide 2-biphenyIyI-N-{5-[(7-methyl-7H-pyrro|o[2,3- LCMS (system 6): d]pyrimidinyl)carbonyl]pyridinyl}acetamide m/z 448 [M+H]+ N-{5-[(7-methyl-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 5): y|)carbonyl]pyridiny|}(2,4,5- m/z 426 [M+H]+ trifluoropheny|)acetamide N-{5-[(7-methyl-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 5): y|)carbonyl]pyridinyI}{3- m/z 472 [M+H]+ luoromethyl)thio]pheny|}acetamide 2-(4-methylphenyl)-N-{5-[(7-methy|-7H- LCMS (system 5): pyrro|o[2,3-d]pyrimidinyl)carbonyl]pyridin m/z 386 [M+H]+ y|}acetamide N-{5-[(7-methyl-7H-pyrro|o[2,3-d]pyrimidin LCMS (system 5): y|)carbonyl]pyridiny|}(3,4,5- m/z 426 [M+H]+ trifluoropheny|)acetamide 2-(2,4-dimethylphenyl)-N-{5-[(7-methy|-7H- LCMS (system 5): pyrro|o[2,3-d]pyrimidinyl)carbonyl]pyridin m/z 400 [M+H]+ y|}acetamide 2-(2,3-dihydro—1-benzofurany|)-N-{5-[(7- LCMS (system 5): methyl-7H-pyrro|o[2,3-d]pyrimidin m/z 414 [M+H]+ bonyl]pyridinyl}acetamide -difluorophenyl)-N-{5-[(7-methy|-7H- LCMS (system 5): pyrro|o[2,3-d]pyrimidinyl)carbonyl]pyridin m/z 408 [M+H]+ y|}acetamide 2-(2,4-difluorophenyl)-N-{5-[(7-methy|-7H- LCMS (system 5): pyrro|o[2,3-d]pyrimidinyl)carbonyl]pyridin m/z 408 [M+H]+ y|}acetamide 2-[2-fluoro(trifluoromethyl)phenyI]-N-{5-[(7- LCMS (system 5): methyl-7H-pyrro|o[2,3-d]pyrimidin m/z 458 [M+H]+ y|)carbonyl]pyridinyl}acetamide -difluorophenyl)-N-{5-[(7-methy|-7H- LCMS (system 5): pyrro|o[2,3-d]pyrimidinyl)carbonyl]pyridin m/z 408 [M+H]+ y|}acetamide N-{5-[(7-methyl-7H-pyrro|o[2,3-d]pyrimidin LCMS (System 2): Rt y|)carbonyl]pyridinyI}[3- m/z 440 [M+H]+ (trifluoromethyl)phenyl]acetamide 2-(3,4-difluorophenyl)-N-{5-[(7-methy|-7H- LCMS m 2): Rt pyrro|o[2,3-d]pyrimidinyl)carbonyl]yridine m/z 408 [M+H]+ y|}acetamide N-{5-[(7-methyl-7H-pyrro|o[2,3-d]pyrimidin LCMS (System 2): Rt bonyl]yridiney|}[4- m/z 456 [M+H]+ (trifluoromethoxy)phenyl]acetamide hlorophenyl)-N-{5-[(7-methy|-7H- LCMS m 2): R: 1.5 min; m/z pyrro|o[2,3-d]pyrimidiny|)carbony|]yridine 406 [M+H]+ yl}acetamide Example 198: 3-(2-chlorophenyl)-N-{5-[(7-methy|-7H-pyrro|o[2,3-d]pyrimidiny|)carbonyI]pyridin y|}propanamide The title compound was prepared according to the method described above for Example 167 starting from (5-aminopyridiny|)(7-methy|-7H-pyrro|o[2,3-d]pyrimidiny|)methanone (Preparation 110) and 3- (2-ch|oropheny|)propanoic acid.

LCMS (system 5): R = 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-aminopyridinyl)(7-tert-buty|-7H-pyrro|o[2,3-d]pyrimidiny|)methanone (Preparation 31) and the appropriate acids.

N-{5-[(7-tert-buty|-7H-pyrro|o[2,3- LCMS (system 9): R = 3.16 min; m/z 445 [M+H]+ d]pyrimidiny|)carbony|]pyridin- using (2-cyclopropyI-1,3-oxazoIy|)acetic acid 3-y|}(2-cyc|opropy|-1 ,3-oxazol- (Preparation 155). 4- | acetamide N-{5-[(7-tert-buty|-7H-pyrro|o[2,3- LCMS m 9): R = 2.87 min; m/z 492 [M+H]+ d]pyrimidiny|)carbony|]pyridin- 3-y|}[3- meth Isulfon | phen |]acetamide N-{5-[(7-tert-buty|-7H-pyrro|o[2,3- LCMS m 9): R = 2.76 min; m/z 432[M+H]+ d]pyrimidiny|)carbony|]pyridin- 2-(1,3-dimethyI-1H-pyrazol- 4- | acetamide N-{5-[(7-tert-buty|-7H-pyrro|o[2,3- LCMS (system 9): R = 2.73 min; m/z 418[M+H]+ d]pyrimidiny|)carbony|]pyridin- 3-y|}(1-methy|-1H-pyrazoI y|)acetamide N-{5-[(7-tert-buty|-7H-pyrro|o[2,3- LCMS (system 9): R = 2.80 min; m/z 458 [M+H]+ using d]pyrimidiny|)carbony|]pyridin- lopropyImethy|-1H-pyrazoIy|)-acetic acid 3-y|}(3-cyc|opropy|methy|- (Preparation 125) 1H-pyrazoIyl )acetamide Example 204: {7-[(1S)—2-hydroxymethy|ethy|]-7H-pyrro|o[2,3-d]pyrimidiny|}carbony|)pyridin y|][3-(trif|uoromethyl)phenyl]acetamide 10% Hydrochloric acid in 1,4- dioxane (0.2 mL) was added to N-(5-{7-[(S)(tert-Buty|-dimethyl- si|any|oxy)methy|-ethy|]-7H-pyr ro|o[2,3-d]pyrimidinecarbonyI}-pyridinyl)(3-trif|uoromethyl-phenyl)—acetamide (Preparation 105, 59 mg, 0.098 mmol) in THF (2 mL) and the mixture was stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and triturated with ether-pentane to afford the title nd as an off white solid in 86% yield, 41 mg.

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

The following es were prepared according to the method described above for Example 204 using the appropriate preparations as described. 205 N-[5-({7-[(1R)—2-hydroxy—1-methy|ethy|]-7H- LCMS (system 9): Rt = pyrrolo[2,3-d]pyrim -y|}carbony|)pyrid iny|] 2.89 min; m/z 484 [M+H]+ [3-(trifluoromethy|)pheny|]acetam ide Using (Preparation 142). 206 N-[5-({7-[(1R)—2-hydroxy—1-methy|ethy|]-7H- LCMS (system 9): Rt = pyrrolo[2,3-d]pyrim idiny|}carbony|)pyrid iny|] 2.52 min; m/z 449 [M+H]+ (4-isopropyI-1H-1,2,3-triazoly|)acetamide Using (Preparation 144). 207 N-[5-({7-[(1R)—2-hydroxy—1-methy|ethy|]-7H- LCMS (system 9): Rt = pyrrolo[2,3-d]pyrim idiny|}carbony|)pyrid iny|] 2.87 min; m/z 516 [M+H]+ [1 -isopropyI(trifluoromethyl)-1 H-pyrazoI Using (Preparation 150). y|]acetamide 208 2-(4-cyanophenyl )-N-[5-({7-[(1 R)—2-hyd roxy-1 - LCMS (system 9): Rt = ethy|]-7H-pyrro|o[2,3-d]pyrimidin 2.68 min; m/z 441 [M+H]+ y|}carbony|)pyridinyl]acetamide Using (Preparation 151). 209 N-[5-({7-[(1R)—2-hydroxy—1-methy|ethy|]-7H- LCMS (system 9): Rt = pyrrolo[2,3-d]pyrim idiny|}carbony|)pyrid iny|] 2.57 min; m/z 494 [M+H]+ [3-(methylsulfonyl)phenyl]acetamide Using (Preparation 152).

N-[5-({7-[(1R)—2-hydroxy—1-methy|ethy|]-7H- LCMS (system 9): Rt = o[2,3-d]pyrim idiny|}carbony|)pyrid |] 1.96 min; m/z 467 [M+H]+ quinolinylacetamide Using (Preparation 153).

W0 2012/137089 69 The following Examples were prepared according to the method described above for Example 34 at 50°C, starting from [2-amino(2-hydroxymethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl](5-aminopyridin- 3-yl)methanone (enantiomer 1, Preparation 57) and the appropriate acids.

N-(5-{[2-amino(2-hydroxymethylethyl)- LCMS (system 10): Rt = 2.48 7H-pyrrolo[2,3-d]pyrimidin . + min, m/z 482 [M+H]_ yl]carbonyl}pyridinyl)—2-quinolin ylacetamide 212 N-(5-{[2-amino(2-hydroxymethylethyl)- LCMS m 10): Rt = 2.57 7H-pyrrolo[2,3-d]pyrimidin . + mm’ ””2 456 [Mm]_ yl]carbonyl}pyridinyl)—2-(4- cyanophenyl)acetamide N-(5-{[2-amino(2-hydroxymethylethyl)- LCMS (system 10): Rt = 2.87 7H-pyrrolo[2,3-d]pyrimidin min; m/z 499 [M+H]+ yl]carbonyl}pyridinyl)—2-[3- (trifluoromethyl)phenyl]acetamide The following Examples were prepared according to the method described above for Example 34 at 50°C, starting from [2-amino(2-hydroxymethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl](5-aminopyridin- ethanone (enantiomer 2, Preparation 59) and the appropriate acids.

N-(5-{[2-amino(2-hydroxymethylethyl)-7H- _ _ pyrrolo[2,3-d]pyrimidinyl]carb0ny|}Pyridiny|)(4- LCMmSin(-sry1s/tzta;n5g)th/IIR:I:I]+2.26 cyanophenyl)acetamide ’ [2-amino(2-hydroxymethylethyl)-7H- LCMS (system 9): Rt = 2.72 pyrrolo[2,3-d]pyrim -yl]carbonyl}pyridinyl)—2-[3- min; m/z 499 [M+H]+ (trifluoromethyl)phenyl]acetamide N-(5-{[2-amino(2-hydroxymethylethyl)-7H- LCMS (system 9): Rt = 1.62 pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridinyl)—2- min; m/z 482 [M+H]+ quinolinylacetamide The following es were prepared according to the method described above for Example 34 at 50°C ng from (5-aminopyridinyl)(7-oxetan-3—yl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 100) and the appropriate acid. 2-(3,4-dichlorophenyl)-N-{5-[(7-oxetanyl-7H-pyrrolo[2,3- LCMS (system 3): R = 3.04 d]pyrimidinyl)carbonyl]pyridinyl}acetam ide min; m/z 482 [M+H]+ 2-(4-cyanophenyl)-N-{5-[(7-oxetanyl-7H-pyrrolo[2,3- LCMS (System 2): Rt = 1.3 d]pyrImIdInyl)carbonyl]pyrIdInyl}acetamIde min; m/z 439 [M+H]+ 2-(4-chlorophenyl)-N-{5-[(7-oxetanyl-7H-pyrrolo[2,3- LCMS m 2): Rt = 1.5 d]pyrImIdInyl)carbonyl]pyrIdInyl}acetamIde min; m/z 448 [M+H]+ 2-(3-chlorophenyl)-N-{5-[(7-oxetanyl-7H-pyrrolo[2,3- LCMS (System 2): Rt = 1.5 d]pyrimidinyl)carbonyl]pyridinyl}acetam ide min; m/z 448 [M+H]+ yanophenyl)-N-{5-[(7-oxetanyl-7H-pyrrolo[2,3- LCMS (System 2): Rt = 1.3 d]pyrImIdInyl)carbonyl]pyrIdInyl}acetamIde min; m/z 439 [M+H]+ N-{5-[(7-oxetanyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (System 2): Rt = 1.0 yl)carbonyl]pyrIdInyl}qumolInylacetamIde min; m/z 465 [M+H]+ 2-(6-chloroimidazo[1,2-a]pyridinyl)-N-{5-[(7-oxetanyl- LCMS m 2): Rt = 1.0 rolo[2,3-d]pyrimidinyl)carbonyl]pyridin _ + ml“, m/z 488 [M+H]_ y|}acetamide N-{5-[(7-oxetanyl-7H-pyrrolo[2,3-d]pyrimidin LCMS (System 2): Rt = 1.3 §I;acetamflgyl carbon l ridiny}l 1-oxo-1,3-dih( Vdro-2H-isoindol . + min; m/z 469 [M+H] The following Examples were prepared according to the method described above for Example 204, using the preparations as described. 225 2-(4-cyanophenyl)-N-(5-{[7-(2-hydroxy-1,1- LCMS (System 9): R = 2.74 min; m/z dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin 455.4 [M+H]+ yl]carbonyl}pyridinyl)acetamide Using Preparation 131 226 N-(5-{[7-(2-hydroxy-1,1-dimethylethyl)-7H- LCMS (System 9): R = 2.99 min; m/z 498 o[2,3-d]pyrimidinyl]carbonyl}pyridin [M+H]+ yl)[3-(trifluoromethyl)phenyl]acetamide Using Preparation 136 227 N-(5-{[7-(2-hydroxy-1,1-dimethylethy|)-7H- H NMR (400 MHz, DMSO) 6: 1.22 (d, pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridin 6H), 1.71 (s, 6H), 2.96 (m, 2H), 3.94 (s, y|)(4-isopropyl-1H-1,2,3-triazol 2H), 5.35 (s, 2H), 7.87 (s, 1H), 8.20 (s, yl)acetamide 1H), 8.44 (s, 1H), 8.75 (s, 1H), 8.98 (m, 2H), 9.46 (s, 1H), 11 (s,1H) Using Preparation 144 228 N-(5-{[7-(2-hydroxy-1,1-dimethylethyl)-7H- LCMS (System 9): R = 2.61 min; m/z 481 pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridin [M+H]+ yl)quinolinylacetamide Using Preparation 140 Example 229: racemic 2-{5-[(5-{[(4-Ch|oropheny|)acety|]amino}pyridiny|)carbonyI]-7H-pyrro|o[2,3- d]pyrimidinyl}propanamide LN/ “Hz/Q”.

O¥Me 2-bromopropionamide (46.5 mg, 0.31 mmol) was added to a e of 2-(4-ch|oropheny|)-N-[5-(7H- pyrro|o[2,3-d]pyrimidiny|carbony|)pyridiny|]acetamide (Example 308, 100 mg, 0.26 mmol) and cesium carbonate (150 mg, 0.46 mmol) in DMF (1.3 mL). The mixture was d at 60°C for 3 hours. The reaction e was cooled and water (10 mL) was added. The mixture was extracted with EtOAc (3 x 10 mL) and the combined c phases were passed through a phase separator and evaporated in vacuo.

Purification by preparative HPLC gave the title compound as a white solid in 34% yield, 15 mg.

LCMS (System 3): R = 2.13 min; m/z 463 [M+H]+.

Example 230: c 2-{5-[(5-{[(4-Ch|oropheny|)acety|]amino}pyridiny|)carbonyI]-7H-pyrro|o[2,3- d]pyrimidiny|}-N,N-dimethylpropanamide The title compound was prepared according to the method described for Example 34 at 50°C using racemic 2-{5-[(5-{[(4-ch|oropheny|)acety|]amino}pyridiny|)carbonyI]-7H-pyrro|o[2,3-d]pyrimidin y|}propanoic acid (Example 354) and dimethylamine. Purification was accomplished by preparative 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-Ch|oropheny|)acety|]amino}pyridiny|)carbonyI]-7H-pyrro|o[2,3- d]pyrimidiny|}-N-methy|propanamide The title compound was prepared according to the method described for Example 34 at 50°C using 2-{5- [(5-{[(4-ch|oropheny|)acety|]amino}pyridiny|)carbonyI]-7H-pyrro|o[2,3-d]pyrimidiny|}propanoic acid (Example 354) and methylamine. Purification was accomplished by preparative HPLC (method 1) to afford the title compound.

LCMS (system 3): R = 2.31 min; m/z 477 [M+H]+. e 232: 2-(4-Cyanophenyl)-N-[5-({7-[2-hydroxy(hydroxymethy|)methylethyI]-7H-pyrrolo[2,3- d]pyrimidiny|}carbony|)pyridiny|]acetamide \ 0W“ Nk/l \ H \N N 4-Cyanophenylacetic acid (19 mg, 0.10 mmol) was added to nopyridinyl){7-[2-{[tert— butyl(dimethyl)silyl]oxy}({[tert-butyl(dimethyl)silyl]oxy}methyl)methylethyl]-7H-pyrrolo[2,3-d]pyrimidin- -yl}methanone (Preparation 116, 54 mg, 0.97 mmol), 1-propylphosphonic acid cyclic ide (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 (3 x 7 mL). The combined organic phases were dried over magnesium sulphate and ated in vacuo.

The residue was dissolved in tetrahydrofuran (3 mL) and a utylammonium fluoride on 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 (3 x 5 mL). The combined organic phases were dried over ium sulphate, evaporated in vacuo and purified by preparative HPLC (method 2).

LCMS m 4): R = 2.52 min; m/z 471 [M+H]+ The following Examples were prepared according to the method described above for Example 232 starting from (5-aminopyridinyl){7-[2-{[tert—butyl(dimethyl)silyl]oxy}({[tert- butyl(dimethyl)silyl]oxy}methyl)—1-methylethyl]—7H-pyrrolo[2,3-d]pyrimidinyl}methanone (Preparation 116) and the appropriate acids. 233 N-[5-({7-[2-hydroxy(hydroxymethyl) LCMS (system 4) Rt = 2.52 min; m/z methylethyl]—7H-pyrrolo[2,3-d]pyrimidin 497 [M+H]+ yl}carbonyl)pyridinyl]quinolinylacetamide Prep method 1 234 N-[5-({7-[2-hydroxy(hydroxymethyl) LCMS m 4) Rt = 2.69 min; m/z methylethyl]—7H-pyrrolo[2,3-d]pyrimidin 518 [M+H]+ yl}carbonyl)pyridinyl][5-methyl Prep method 1 (trifluoromethyl)—1H-pyrazolyl]acetamide 235 2-(4-chlorophenyl)-N-[5-({7-[2-hydroxy LCMS (system 4) Rt = 2.83 min; m/z (hydroxymethyl)—1-methylethyl]—7H-pyrrolo[2,3- 480 [M+H]+ d]pyrimidinyl}carbonyl)pyridinyl]acetamide Prep method 1 236 N-[5-({7-[2-hydroxy(hydroxymethyl) LCMS (system 4) Rt = 2.81 min; m/z methylethyl]—7H-pyrrolo[2,3-d]pyrimidin 514 [M+H]+ yl}carbonyl)pyridinyl][4- Prep method 1 (trifluoromethyl)phenyl]acetamide 237 2-(5-chloropyridinyl)-N-[5-({7-[2-hydroxy LCMS (system 3) Rt = 2.37 min; m/z h drox meth lmeth leth l]-7H-p rrolo[2,3- 481 [M+H]+ W0 2012/137089 73 d]pyrimidinyl}carbonyl)pyridinyl]acetamide Prep method 1 Using (5-chloropyridinyl)acetic acid (Preparation 90).

N-[5-({7-[2-hydroxy(hydroxymethyl) LCMS m 4) Rt = 2.84 min; m/z methylethyl]-7H-pyrrolo[2,3-d]pyrim idin 514 [M+H]+ bonyl)pyrid inyl]—2-[3- Prep method 1 (trifluoromethyl)phenyl]acetamide N-[5-({7-[2-hydroxy(hydroxymethyl) LCMS (system 3) Rt = 2.59 min; m/z methylethyl]-7H-pyrrolo[2,3-d]pyrim idin 504 [M+H]+ yl}carbonyl)pyrid inyl]—2-[3-(trifl uorom ethy|)-1 H- Prep method 2 pyrazolyl]acetamide The following Examples were prepared ing to the method bed above for Example 1 using DIPEA and purification by preparative HPLC, starting from (2-aminoisopropyl-7H-pyrrolo[2,3- d]pyrimidinyl)(5-aminopyridinyl)methanone (Preparation 122) and the appropriate acids.

N-{5-[(2-aminoisopropyl-7H-pyrrolo[2,3- LCMS (System 9): R = 2.57 min; m/z d]pyrimidinyl)carbonyl]pyridinyl}[4- 474 [M+H]+ (trifluoromethyl)—1H-1,2,3-triazolyl]acetamide Using 4-(trifluoromethyl)-1H-1,2,3- triazolyl]acetic acid (Preparation 81 .

N-{5-[(2-aminoisopropyl-7H-pyrrolo[2,3- LCMS (System 9): R = 2.56 min; m/z d]pyrimidinyl)carbonyl]pyridinyl}(4- 440 [M+H]+ cyanophenyl)acetamide N-{5-[(2-aminoisopropyl-7H-pyrrolo[2,3- LCMS (System 9): R: 2.46 min; m/z d]pyrimidinyl)carbonyl]pyridinyl}(5- 450 [M+H]+ chloropyridinyl)acetamide Using -(5-ch|oropyridinyl)acetic acid Preparation 90 .

N-{5-[(2-aminoisopropyl-7H-pyrrolo[2,3- LCMS (System 9): R = 2.20 min; m/z d]pyrimidinyl)carbonyl]pyridinyl}(5- 434 [M+H]+ fluoropyrid inyl )acetamide Using (5-fluoropyridinyl)acetic acid (Preparation 92).

N-{5-[(2-aminoisopropyl-7H-pyrrolo[2,3- LCMS (System 10): R = 3.22 min; m/z d]pyrimidinyl)carbonyl]pyridinyl}[4- 483 [M+H]+ (trifluoromethyl)phenyl]acetamide N-{5-[(2-aminoisopropyl-7H-pyrrolo[2,3- LCMS (System 10): R = 3.22 min; m/z midinyl)carbonyl]pyridinyl}[3- 483 [M+H]+ (trifluoromethyl)phenyl]acetamide N-{5-[(2-aminoisopropyl-7H-pyrrolo[2,3- LCMS (System 9): R = 2.22 min; m/z d]pyrimidinyl)carbonyl]pyridinyl}(1,3- 456 [M+H]+ benzoxazolyl)acetamide (2-aminoisopropyl-7H-pyrrolo[2,3- LCMS (System 9): R = 2.15 min; m/z d]pyrimidinyl)carbonyl]pyridinyl}[3- 493 [M+H]+ lsulfonyl)phenyl]acetamide N-{5-[(2-aminoisopropyl-7H-pyrrolo[2,3- LCMS (System 9): R = 2.16 min; m/z d]pyrimidinyl)carbonyl]pyridinyl}(4- 448 [M+H]+ isopropyl-1H-1,2,3-triazolyl)acetamide N-{5-[(2-aminoisopropyI-7H-pyrro|o[2,3- LCMS m 9): R = 2.01 min; m/z d]pyrimidiny|)carbony|]pyridinyI}(4- 446 [M+H]+ ropyI-1H-1,2,3-triazo|y|)acetamide Using Preparation 83 N-{5-[(2-aminoisopropyI-7H-pyrro|o[2,3- LCMS (System 10): R = 3.03 min; m/z d]pyrimidiny|)carbony|]pyridinyI}(4- 449 [|\/|+|—|]+ ch|oropheny|)acetamide N-{5-[(2-aminoisopropyI-7H-pyrro|o[2,3- LCMS (System 10): R = 3.03 min; m/z d]pyrimidiny|)carbonyl]pyridinyI}[1- 515 [M+H]+ isopropyI(trifluoromethy|)-1H-pyrazoI Using Prep 185 y|]acetamide N-{5-[(2-aminoisopropyI-7H-pyrro|o[2,3- LCMS (System 10): R = 2.92 min; m/z d]pyrimidiny|)carbonyl]pyridinyI}[3- 473 [M+H]+ (trifluoromethy|)-1H-pyrazoIyl]acetamide N-{5-[(2-aminoisopropyI-7H-pyrro|o[2,3- LCMS (System 9) R 2.46 min; m/z 445 midiny|)carbony|]pyridinyI}(3- [m+H]+ cyclopropyI-1H-pyrazoIy|)acetamide N-{5-[(2-aminoisopropyI-7H-pyrro|o[2,3- LCMS (System 9): R = 2.77 min; m/z d]pyrimidiny|)carbonyl]pyridinyI}[1- 515 [|\/|+|—|]+ isopropyI(trifluoromethy|)-1H-pyrazoI y|]acetamide Example 255: N-{5-[(2-aminoisopropyI-7H-pyrro|o[2,3-d]pyrimidiny|)carbonyl]pyridinyI}(5- cyanopyridiny|)acetam ide I \ H \N / H2N)\\N N )‘Me The title nd was prepared according to the method described for Example 166 using N-{5-[(2- aminoisopropyI-7H-pyrro|o[2,3-d]pyrimidiny|)carbonyl]pyridiny|}(5-bromopyridiny|)acetamide (Example 318) to afford the title compound in 45% yield, 30 mg. 1H NMR (400 MHz, DMSO-d6) 6: 1.45 (d, 6H), 4.06 (s, 2H), 4.84 (m, 1H), 6.62 (s, 2H), 7.66 (d, 1H), 7.97 (s, 1H), 8.29 (dd, 1H), 8.37 (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 Examples were prepared according to the method described above for Example 34 at 50°C starting from [2-amino(2-hydroxy-1,1-dimethy|ethy|)-7H-pyrro|o[2,3-d]pyrimidiny|](5-aminopyridin y|)methanone (Preparation 48) and the riate acids.

Data [2-amino(2-hydroxy-1,1-dimethy|ethy|)-7H- LCMS (System 10): R = 2.91 pyrrolo[2,3-d]pyrimidiny|]carbony|}pyridiny|)[3- min; m/z 513 [M+H]+ trifluorometh Iphen |]acetamide N- 5- [2-amino 2-h drox -1,1-dimeth |eth |-7H- LCMS S stem 10 : R = 2.48 pyrro|o[2,3-d]pyrimidiny|]carbony|}pyridiny|)(1,3- min; m/z 486 [M+H] benzoxazoI | acetamide N-(5-{[2-amino(2-hydroxy-1,1-dimethy|ethy|)-7H- LCMS (System 10). =2.50 pyrrolo[2,3-d]pyrimidiny|]carbony|}pyridiny|)[3- min; m/z 523 [M+H]) meth Isulfon | phen |]acetamide N-(5-{[2-amino(2-hydroxy-1,1-dimethy|ethy|)-7H- LCMS m 10): R = 2.62 o[2,3-d]pyrimidiny|]carbony|}pyridiny|)(4- min; m/z 470 [M+H]+ c n | acetamide N-(5-{[2-amino(2-hydroxy-1,1-dimethy|ethy|)-7H- LCMS (System 10): R = 2.89 pyrrolo[2,3-d]pyrimidiny|]carbony|}pyridiny|)[1- min; m/z 545 [M+H]+ isoprop | trifluorometh | -1H-p razoI |]acetamide Usino Prep 185 Example 261: 4-cyano(trifluoromethyl)phenyl)-N-(5-(7-(1,3-dihydroxymethylpropanyl)—7H- pyrro|o[2,3-d]pyrimidinecarbonyl)pyridiny|)acetamide \ / o le \ N \ H N CF3 2-(4-cyano(trifluoromethyl)phenyl)acetic acid (Preparation 164, 29.8 mg, 0.13 mmol) was added to a stirred on of (5-aminopyridiny|){7-[2-{[tert-buty|(dimethy|)si|y|]oxy}({[tert- dimethy|)si|y|]oxy}methy|)methy|ethy|]-7H-pyrro|o[2,3-d]pyrimidiney|)methanone (Preparation 116, 55.6 mg, 0.10 mmol) and 2—(7—aza—‘Ei-f-benzotriazoi-i—yi)—1,1,3,3—tetramethyiurcnium hexaftuorophcsphate (57 mg, 0.15 mmol) in pyridine (0.5 mL). The mixture was stirred at 50°C for 16 hours, then cooled to room temperature 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 s solution of HCI.

The mixture was stirred rapidly for 4 hours at room temperature and then basified by the addition of 4 mL of a 1N aqueous NaOH solution. The mixture was extracted with three te 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 preparative HPLC to afford the title compound as an off white solid in 56% yield, 30 mg. 1H NMR (400 MHz, DMSO) 6: 1.68 (s, 3H), 3.83 (m, 2H), 4.01 (s, 2H), 4.19 (m, 2H), 5.00 (m, 2H), 7.82 (m, H), 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 m 2): R = 0.90 min; m/z 539 [M+H]+.

The following Examples were ed according to the method described above for Example 261, starting from ((5-aminopyridiny|){7-[2-{[tert-buty|(dimethy|)si|y|]oxy}({[tert- buty|(dimethy|)si|y|]oxy}methy|)methy|ethy|]-7H-pyrro|o[2,3-d]pyrimidiney|)methanone (Preparation 116) and the appropriate acids followed by si|y| group deprotection.

N-(5-(7-(1,3-dihydroxymethylpropanyl)—7H— LCMS (system 2): R = 0.96 pyrro|o[2,3-d]pyrimidinecarbony|)pyridiny|)(3- min; m/z 516 [M+H]+ oromethoxy)pheny|)acetamide N-(5-(7-(1,3-dihydroxymethylpropanyl)—7H— LCMS (system 2): R = 1.05 pyrro|o[2,3-d]pyrimidinecarbony|)pyridiny|)(4- min; m/z 532 [M+H]+ f|uoro(trif|uoromethy|)pheny|)acetamide N-(5-(7-(1,3-dihydroxymethylpropanyl)—7H— LCMS (system 2): R = 1.04 pyrro|o[2,3-d]pyrimidinecarbonyl)pyridiny|) min; m/z 500 [M+H]+ (trifluoromethyl)benzamide 7-(1,3-dihydroxymethylpropanyl)—7H— LCMS (system 2): R = 1.09 pyrro|o[2,3-d]pyrimidinecarbonyl)pyridiny|)f|uoro- min; m/z 532 [M+H]+ 4-(trif|uoromethy|)benzamide Example 266: 2-[3-(azetidiny|methy|)pheny|]-N-{5-[(7-isopropy|-7H-pyrro|o[2,3-d]pyrimidin y|)carbony|]pyridiny|}acetamide formate salt.

N\ 0 .HCOOH <\ H / \ N N NI | / W; Me"< ine hydrochloride (10 mg, 0.11 mmol) was added to a stirred solution of 2-(3-formylpheny|)-N-{5- [(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidiny|)carbony|]pyridiny|}acetamide (Preparation 192, 23 mg, 0.05 mmol) in DCM (1 mL) and acetic acid (0.04 mL, 0.60 mmol). The reaction mixture was d for 30 min at room temperature 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 preparative HPLC to afford the title compound as a formate salt in 12% yield, 3.4 mg.

LCMS: R = 2.95 min; m/z 469 [M+H]+.

Example 267: 2-{3-[(3-f|uoroazetidiny|)methyl]pheny|}-N-{5-[(7-isopropy|-7H-pyrro|o[2,3-d]pyrimidin y|)carbony|]pyridiny|}acetamide The title compound was prepared according to the method described for Example 266 using 2-(3- phenyl)-N-{5-[(7-isopropy|-7H-pyrro|o[2,3-d]pyrimidiny|)carbony|]pyridiny|}acetamide (Preparation 192, 60 mg, 0.14 mmol) and 3-fluoroazetidine to afford the title compound in 16% yield, 11 LCMS: R = 2.75 min; m/z 487 [M+H]+.

Example 268: N-{5-[(7-isopropy|-7H-pyrro|o[2,3-d]pyrimidiny|)carbonyl]pyridiny|}[3-(morpho|in y|methy|)pheny|]acetamide formate salt The title compound was prepared ing to the method bed for Example 266 using 2-(3- formy|phenyl)-N-{5-[(7-isopropy|-7H-pyrro|o[2,3-d]pyrimidiny|)carbony|]pyridiny|}acetamide (Preparation 192, 60 mg, 0.14 mmol) and morpholine to afford the title compound as a formate salt in % yield, 21 mg.

LCMS: R = 2.70 min; m/z 499 [M+H]+ es 269-283 General method: The mixture of (5-aminopyridinyl)(7-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecanyl)—7H- pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 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 temperature, 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 ing residue was dissolved in THF (2 mL) and 1 N aqueous HCI (2 mL) added to the solution. The reaction mixture was stirred for 2 hours at room temperature and quenched with 1 N aqueous NaOH (3 mL). The mixture was then treated according to one of the following methods: Method A The e was extracted with a mixture of DCM/MeOH (95/5, 5 mL x 3), the ed organic layers passed through a phase tor and concentrated in vacuo to obtain a crude residue. This residue was dissolved in DMSO (1 mL) and ed via HPLC to yield the desired compound.

Method B The mixture was suspended in DCM/MeOH (95/5, 5 mL), the solid ed 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 preparative HPLC to yield the desired compound.

N-(5-(7-(1,3-dihydroxypropanyl)-7H-pyrrolo[2,3-d]pyrimidine LCMS: R = 2.69 carbonyl)pyridinyl)(trif|uoromethyl)benzamide min; m/z 486 [M+H]+ 2-(4-chlorophenyl)-N-(5-(7-(1,3-dihydroxypropanyl)—7H- LCMS: R = 2.63 pyrrolo[2,3-d]pyrimidinecarbonyl)pyridinyl)acetamide min; m/z 466 [M+H]+ N- 5- 7- 1,3-dih drox propan l-7H-p 2,3-d]p rimidine LCMS: R: 2.68 carbonyl)pyrid inyl)(trif|uoromethoxy)benzam ide min; m/z 502 [M+H]+ N-(5-(7-(1,3-dihydroxypropan-Z-yl)-7H-pyrro|o[2,3-d]pyrimidine—5- LCMS: R = 1.27 min; carbonyl)pyrid inyl)—2-(quino| l)acetamide m/z 483 [M+H]+ N-(5-(7-(1,3-dihydroxypropan-Z-yl)-7H-pyrro|o[2,3-d]pyrimidine—5- LCMSI Rt = 2.69 carbonyl)pyrid inyl)(4-(trif|uoromethyl)phenyl)acetamide min; m/z 500 [M+H]+ N-(5-(7-(1,3-dihydroxypropan-Z-yl)-7H-pyrro|o[2,3-d]pyrimidine—5- m/Z 500 [M+H]+ carbon | o ridin I 3- trifluorometh | ohen | acetamide N-[5-({7-[2-hydroxy—1-(hydroxymethyl)ethyl]—7H-pyrro|o[2,3- m/z 497 [M+H]+ d]pyrimidinyl}carbonyl)pyridinyl]—2-(2-methy|quinolin Preparation 165 yl)acetamide 2-(3,4-dich|oropheny|)-N-[5-({7-[2-hydroxy—1-(hydroxymethy|)ethyl]- m/Z 500 [M+H]+ 7H-pyrro|o[2,3-d]pyrimidinyl}carbonyl)pyridinyl]acetamide 2-[3-fluoro(trifluoromethyl)pheny|]-N-[5-({7-[2-hydroxy m/z 518 [M+H]+ xymethyl)ethyl]—7H-pyrrolo[2,3-d]pyrimidin yl}carbonyl)pyrid inyl]acetam ide 2-(2,4-dichIorophenyl)-N-[5-({7-[2-hydroxy—1-(hydroxymethy|)ethyl]- m/Z 500 [M+H]+ 7H-pyrro|o[2,3-d]pyrimidinyl}carbonyl)pyridinyl]acetam ide N-[5-({7-[2-hydroxy—1-(hydroxymethyl)ethyl]—7H-pyrro|o[2,3- m/z 516 [M+H]+ d]pyrimidinyl}carbonyl )pyridinyl]—2-[3- (trifluoromethoxy)phenyl]acetamide N-[5-({7-[2-hydroxy—1-(hydroxymethyl)ethyl]—7H-pyrro|o[2,3- m/z 516 [M+H]+ d]pyrimidinyl}carbonyl inyl]—2-[4- (trifluoromethoxy)phenyl]acetamide ro—N-[5-({7-[2-hyd roxy-1 -(hyd roxym ethyl )ethy|]-7 H-pyrro|o[2,3- m/z 504 [M+H]+ d]pyrimidinyl}carbonyl)pyridiny|](trif|uoromethyl)benzamide 2-(5-chloropyridinyl)-N-[5-({7-[2-hydroxy—1-(hydroxymethy|)ethy|]— LCMS: Rt = 0.90 min, 7H-pyrro|o[2,3-d]pyrimidinyl}carbonyl)pyridinyl]acetam ide m/z 467 [M+H]+ N-[5-({7-[2-hydroxy—1-(hydroxymethyl)ethyl]—7H-pyrro|o[2,3- LCMSI Rt = 1.81 d]pyrimidinyl}carbonyl)pyridinyl]—2-[3-(trif|uoromethyl)-1H- min, m/z 490 [M+H]+ pyrazoIyl]acetamide Example 284: 4-benzoyl-N-alpha-(tert—butoxycarbonyl)-N-{5-[(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidin yl)carbonyl]pyridinyI}-L-phenylalaninamide k| / N N 0 )‘Me HNTo Me O EMe (5-aminopyridinyl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (20 mg, 0.07 mmol) (see Preparation 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 0C for 5 hours and then cooled, evaporated in vacuo and the crude material was ed by column tography on silica gel ent 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-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}-D- phenylalaninamide o \/O N\\ NH kI / N N 0 )‘Me NH2 4-benzoyl-Nal pha-(tert-butoxycarbonyl)-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridin- 3-yl}-D-phenylalaninamide (Example 284, 20 mg, 0.03 mmol) was stirred with 10% hydrochloric acid in oxane (5 mL) at room temperature for 1 hour. The mixture was evaporated in vacuo and purified by preparative HPLC to afford the title compound as a gum in 56% yield, 9 mg.

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

Example 286 :4-benzoyl-N-alpha—(tert-butoxycarbonyl)-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin yl)carbonyl]pyridinyl}-L-phenylalaninamide The title compound was prepared according to Example 284 using nopyridinyl)(7-isopropyl-7H- pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 95) and 4-benzoyl-N-(tert-butoxycarbonyl)-L- phenylalanine Example 287: 4-benzoyl-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}-L- phenylalaninamide W0 2012/137089 80 The title compound was prepared according to the method described for Example 285 using 4-benzoyl- Nalpha-(tert-butoxycarbonyl)-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}-L- phenylalaninamide le 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]pyrimidinecarbonyl)pyridin yl)acetam ide The title compound was prepared according to the method described for Example 34 ng from (5- aminopyridinyl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone ration 95) and 2-(3- benzoylphenyl)acetic 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 enzoylphenyl)-N-(5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinecarbonyl)pyridin yl)acetamide The title compound was prepared according to the method described for Example 34 starting from (5- aminopyridinyl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 95) and 2-(4- benzoylphenyl)acetic acid (JOC, 1961, 1635) to afford the title nd in 94% yield, 34 mg. LCMS (system 3): R = 3.12 min; m/z 504 [M+H]+.

Example 290: N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}[3- (trifluoromethyl)-3H-diazirenyl]benzam ide \/ FF N \ \ I2 kN/| 0 Me)\Me The title compound was prepared according to the method described for Example 34 ng from (5- aminopyridinyl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 95) and 3-[3- (trifluoromethyl)-3H-diazirenyl]benzoic acid (Preparation 197) to afford the title compound as a white solid in 36% yield, 23 mg. 1H NMR (400 MHz, d4-MeOH) 6:1.65 (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-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}[3- (trifluoromethyl)-3H-diazirenyl]benzam ide W0 2012/137089 81 The title compound was prepared according to the method described for Example 34 starting from (5- yridinyl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 95) and 4-[3- (trifluoromethyl)-3H-diazirenyl]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]pyrimidinyl)carbonyl]pyridinyl} (trifluoroacetyl)benzam ide N\\ M K/NN b/Z; Me}Me The title compound was prepared according to the method described for Example 34 ng from (5- aminopyridinyl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 95) and 3- (trifluoroacetyl)benzoic acid (Preparation 200) to afford the title compound as a white solid in 80% yield, 41 mg. LCMS (system 3): R = 2.52 min; m/z 482 [M+H]+.

Example 293: 1-(4-chlorophenyl){5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridin yl}urea \ / 0 KN | \ H H 1-ch|oroisocyanatobenzene (24 mg, 0.15 mmol) was added to (5-aminopyridinyl)(7-methyl-7H- pyrrolo[2,3-d]pyrimidinyl)methanone (30 mg, 0.12 mmol) (Preparation 232) in pyridine (1.0 mL). The mixture was stirred at room temperature overnight then evaporated in vacuo to yield the product as a crude residue. The crude residue was purified by ative HPLC to afford the title nd in 49% yield, 24 mg.

LCMS: R = 1.58 min; m/z 407 [M+H]+ The following Examples were prepared according to the method bed above for Example 293, starting from (5-aminopyridinyl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 232) and the appropriate isocyanates. 1-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin LCMS: R = 1.64 min; m/z 441 yl)carbonyl]pyridinyl}[4-(trifluoromethyl)phenyl]urea [M+H]+ 1-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin LCMS: Rt = 1.64 min; m/z 441 l carbon l]p ridin - trifluorometh l phen l]urea W0 37089 82 (7-methyl-7H-pyrrolo[2,3-d]pyrimidin LCMS: Rt = 1.67 min; m/z 457 yl)carbonyl]pyridiny|}[4-(trif|uoromethoxy)phenyl]urea [M+H]+ Example 297: 2-(4-chlorophenyl)-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}- ylacetamide \ / 0 / NW L | \ M; >‘Me (4-chlorophenyl)acetic acid (22 mg, 0.13 mmol) was added to a stirring mixture of (7-isopropyl-7H- pyrrolo[2,3-d]pyrimidinyl)[5-(methylamino)pyridinyl]methanone (30 mg, 0.10 mmol) (Preparation 149) andN-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridinyloxy)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 n saturated aqueous sodium bicarbonate (10 mL) and EtOAc (10 mL). The aqueous layer was washed with further EtOAc (2 x 10 mL). The combined organics were dried over NaZSO4, filtered and concentrated in vacuo and purified by preparative HPLC to afford the title compound 43% yield, 19 mg, 1H NMR (400 MHz, DMSO) 6: 1.52 (d, 6H), 3.40 (br. s, 3H), 3.59 (s, 2H), 5.00-5.18 (m, 1H), 7.00-7.42 (m, 4H), 8.21 (s, 1H), 8.50 (s, 1H), 8.86 (s, 1H), 8.90-9.12 (m, 2H), 9.48 (s, 1H); LCMS: R = 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]pyrimidinyl)[5-(methylamino)pyridinyl]methanone (Preparation 149) and the appropriate acid. 2-(4-cyanophenyl)-N-{5-[(7-isopropyl-7H-pyrrolo[2,3- LCMS: R = 2.86 min; d]p n | carbon l]p ridin l-N-meth lacetamide m/z 439 [M+H]+ Example 299: 2-(4-Chloro-phenyl)-N-{5-[7-(3-hydroxymethyl-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidine carbonyl]—pyridinyl}-acetamide W0 2012/137089 83 N \ N k /W | H N N OH CI N-(5-{7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-oxetanyl]-7H-pyrrolo[2,3-d]pyrimidinecarbonyl}- pyridinyl)(4-chloro-phenyl)-acetamide (Preparation 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 temperature. 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 ative HPLC to give the title compound in quantitative yield 28 mg.

LCMS (System 4): R = 3.03 min; m/z 478 [M+H]+ Example 300: 7—(3-Hydroxymethyl-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidinecarbonyl]-pyridin (4-trifluoromethyl-phenyl)—acetamide: The title compound was prepared according to the method described for Example 299 starting from N-(5- {7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-oxetanyl]-7H-pyrrolo[2,3-d]pyrimidinecarbonyl}-pyridin yl)(4-trifluoromethyl-phenyl)—acetamide (Preparation 204) to afford the title compound as a white solid in quantitative yield, 30 mg. LCMS: R = 2.74 min; m/z 512 [M+H]+.

Example 301: hloropyridinyl)-N-[5-({7-[3-(hydroxymethyl)oxetanyl]—7H-pyrrolo[2,3-d]pyrimidin- -yl}carbonyl)pyridinyl]acetamide The title compound was prepared according to the method bed for Example 299 starting from N-[5- ({7-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)oxetanyl]-7H-pyrrolo[2,3-d]pyrimidinyl}carbonyl)pyridin yl](5-chloropyridinyl)acetamide (Preparation 223) to afford the title nd as a pale yellow liquid in 87% yield, 23 mg. LCMS (System 4): R = 1.57 min; m/z 479 [M+H]+.

Example 302: N-[5-({7-[3-(hydroxymethyl)oxetan—3-yl]-7H-pyrrolo[2,3-d]pyrimidinyl}carbonyl)pyridin yl][3-(trifluoromethyl)-1H-pyrazolyl]acetamide \ / O CF3 N/I \ ”4’“; KN N 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)oxetanyl]-7H-pyrrolo[2,3-d]pyrimidin yl}carbonyl)pyridinyl][3-(trifluoromethyl)-1H-pyrazolyl]acetamide (34 mg, 0.055 mmol) (Preparation 224) to give the the title compound in 63% yield, 17.7mg.

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

W0 2012/137089 84 Example 303: [7-(2-aminooxoethyl)-7H-pyrro|o[2,3-d]pyrimidiny|]carbony|}pyridiny|)(4- chlorophenyl)acetamide To a stirred solution of 2-(4-ch|oropheny|)-N-[5-(7H-pyrro|o[2,3-d]pyrimidiny|carbony|)pyridin tamide (Example 308, 50 mg, 0.13 mmol) in DMF ( 1 ml) was added Cszcog (75mg, 0.23 mmol) followed by 2-bromoacetamide (21 .3mg, 0.154 mmol). The reaction was then stirred at room temperature overnight. The reaction was quenched with water (5 mL) and extracted with EtOAc (3 x 5 mL).

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

LCMS m 4): R = 1.56 min; m/z 449 [M+H]+.

Example 304: 2-{5-[(5-{[(4-ch|oropheny|)acety|]amino}pyridiny|)carbony|]-7H-pyrro|o[2,3-d]pyrimidin y|}-N,N-dimethylacetamide {5-[(5-{[(4-ch|oropheny|)acety|]amino}pyridiny|)carbony|]-7H-pyrro|o[2,3-d]pyrimidiny|}acetic acid potassium salt (Example 307, 50 mg, 0.102 mmol) was added to a stirred solution of dimethyl amine HCI (12.5 mg, 0.153 mmol) and HATU (58.2mg, 0.153 mmol) in pyridine (2 mL) and the resultant 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 (3 x 5 mL). The organics were ed, washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification by preparative HPLC gave the title compound in 55% yield, .

LCMS: R = 1.86 min; m/z 477 [M+H]+.

Example 305: 2-(4-ch|orophenyl)-N-[5-({7-[2-(methy|amino)oxoethy|]-7H-pyrro|o[2,3-d]pyrimidin y|}carbony|)pyridiny|]acetamide {5-[(5-{[(4-ch|oropheny|)acety|]amino}pyridiny|)carbony|]-7H-pyrro|o[2,3-d]pyrimidiny|}acetic acid potassium salt (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 resultant solution was stirred at 50 °C (reactivial) for 14 hours. The reaction was cooled to 25 oC, diluted with DCM (5 mL) then ed with saturated NaHC03 (aq) (5 mL) and ted with further DCM (3 x 5 mL).

The organics were combined, washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate and trated in vacuo. Purification by preparative HPLC gave the title compound in 65% yield, .5mg.

LCMS: R = 2.63 min; m/z 463 [M+H]+.

Example 306 Methyl {5-[(5-{[(4-ch|oropheny|)acety|]amino}pyridiny|)carbony|]-7H-pyrro|o[2,3- d]pyrimidinyl}acetate W0 2012/137089 85 \ / 0 \N N To a stirred solution of 2-(4-chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidinylcarbonyl)pyridin y|]acetamide (Example 308, 250mg, 0.638 mmol) in DMF (4 mL) was added Cszcog (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 (3 x 10 mL). The organics were combined, washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to give a pale yellow oil (356mg) which solidified on standing. Purification by column chromatography on silica gel ent 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) 6 3.78 (s, 2H), 3.81 (s, 3H), 5.15 (s, 2H), .41 (m, 4H), 7.51 (s, 1H), 7.88 (s, 1H), 8.46 (m, 1H), 8.78-8.82 (m, 2H), 9.04 (s, 1H), 9.65 (s, 1H). LCMS (System 4): R = 2.07 min; m/z 464 [M+H]+. e 307 {5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridinyl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidin yl}acetic acid potassium salt To a suspension of methyl {5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridinyl)carbonyl]-7H-pyrrolo[2,3- d]pyrimidinyl}acetate le 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 temperature. The on 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-pyrrolo[2,3-d]pyrimidinylcarbonyl)pyridinyl]acetamide The title compound was ed according to the method described for Example 46 to afford the title compound as a white solid in 87% yield, 930 mg. 0 \/ 0 N/ \ ”W0 1H NMR (400 MHz, DMSO) a: 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, 1H), 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-methyloxetanyl)-7H-pyrrolo[2,3-d]pyrimidin y|]carbonyl}pyridinyl)acetamide W0 2012/137089 86 \ /o Nl/\\ HNW0 N N (5-aminopyridinyl)[7-(3-methyloxetanyl)-7H-pyrrolo[2,3-d]pyrimidinyl]methanone (Preparation 222, 15.5 mg, 0.05 mmol) was added to a ng mixture of 4-chlorophenylacetic acid (11.1mg, 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 temperature and saturated sodium bicarbonate on (5 mL) was added. The mixture was extracted with ethyl acetate (3 x 5 mL) and the combined c fractions were washed with brine, dried (MgSO4) and the solvent was removed under reduced re to obtain the crude product which was autopurified.

LCMS (system 4): R = 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-aminopyridinyl)[7-(3-methyloxetanyl)-7H-pyrrolo[2,3-d]pyrimidinyl]methanone (Preparation 222) and the appropriate acids. 2-(5-chloropyridinyl)-N-(5-{[7-(3-methyloxetan LCMS (System 2): R = 0.88 min; yl)-7H-pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridin m/z 463 [M+H]+ yl)acetamide Using Preparation 90 N-(5-{[7-(3-methyloxetanyl)-7H-pyrrolo[2,3- LCMS (System 2): R = 0.97 min; d]pyrimidinyl]carbonyl}pyridinyl)[3- m/z 486 [M+H]+ (trifluoromethyl)—1H-pyrazolyl]acetamide N-(5-{[7-(3-methyloxetanyl)-7H-pyrrolo[2,3- LCMS (System 2): R = 0.92 min; d]pyrimidinyl]carbonyl}pyridinyl)[4- m/z 487 [M+H]+ (trifluoromethyl)—1H-1,2,3-triazolyl]acetamide Using Preparation 85 Example 313: 2-(4-chlorophenyl)—N-[5-({7-[(methylthio)methyl]-7H-pyrrolo[2,3-d]pyrimidin yl}carbonyl)pyridinyl]acetamide zN CI “i\ \ Mo Potassium carbonate (38 mg, 0.275 mmol) was added to a stirring solution of 2-(4-chlorophenyl)-N-[5- (7H-pyrrolo[2,3-d]pyrimidinylcarbonyl)pyridinyl]acetamide (Example 308, 60.0 mg, 0.153 mmol) in DMF (1.0 mL) at room temperature. After 10 min, methyl methyl sulfide (19 uL, 0.23 mmol) was added to the mixture and the reaction was stirred for 24 hours at room temperature. Water (3 mL) was added to the e and it was extracted with EtOAc (3 x 5 mL). The combined organic fractions were washed with water (5 mL), brine (5 mL), dried over magnesium e 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 OH/NH3) to give the title compound as a pale yellow solid in 36% yield, 25 mg. 1H NMR (400 MHz, CDCI3) 6: 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, 1H), 8.82-8.83 (d, 1H), 9.05 (s,1H), 9.65 (s, 1H); LCMS (system 4): R = 1.97 min; m/z 452; 454 [M+H]+. e 314 : hlorophenyl)-N-[5-({7-[(methylsulfonyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin yl}carbonyl)pyridinyl]acetamide Potassium peroxomonosulfate (Oxone, 67.2 mg, 0.110 mmol) was added to a stirring solution of 2-(4- chlorophenyl)-N-[5-({7-[(methylthio)methyl]-7H-pyrrolo[2,3-d]pyrimidinyl}carbonyl)pyridinyl]acetamide (Example 313, 25.0 mg, 0.055 mmol) in methanol (1.0 mL) and water (0.25 mL) at 0 0C. After 1 hour, the reaction was allowed to warm to room ature and stirred for 24 hours. The reaction mixture was cooled to 0 °C and sodium metabisulfite (0.5M, 1ml) 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 (3 x 5 mL). The combined organic fractions were washed with water (5 mL), brine (5 mL), dried over magnesium sulfate the solvent was removed under reduced pressure to give the crude product as an off-white solid. The crude material was ed by column chromatography on silica gel (gradient of 100% DCM to 90:10:1 OH/NH3) to give the title compound as a pale yellow solid in 17% yield, 27 mg. LCMS (system 4): R = 1.91 min; m/z 484; 486 [M+H]+.

Example 315: yclopropyl-5—trifluoromethyl-1H-pyrazolyl)-N-[5-(7-isopropyl-7H-pyrrolo [2, 3-d] pyrimidinecarbonyl)-pyridinyl]-acetamide To a on of (5-Amino-pyridinyl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)-methanone (Preparation 95, 50 mg, 0.17 mmol), (1-Cyclopropyltrifluoromethyl-1H-pyrazolyl)—acetic acid (Preparation 141, 47.1 mg, 0.21 mmol) and TEA (0.08 mL, 0.62 mmol) in THF (1 mL), 1- propylphosphonic acid cyclic anhydride (50% solution in EtOAc, 0.26 mL, 0.44 mmol) was added and the mixture was stirred at room temperature for 14 hours. The reaction mixture was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic layer was W0 2012/137089 88 washed with saturated sodium onate solution and dried (NaZSO4) and evaporated in vacuo. cation by column tography on silica gel (gradient of EtOAc:Hexane 0:100 to 80:20) gave the title compound as a white solid in 76 % yield, 67 mg. 1H NMR (400 MHz, DMSO-D6) 6: 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+H]+ Example 316: N-(5-{[2-amino(1-hydroxy—2-methylpropanyl)-7H-pyrrolo[2,3-d]pyrimidin bonyl}pyridinyl)(5-bromopyridinyl)acetamide The title compound was prepared according to the method described for Example 34 at 50°C using [2- amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl](5-aminopyridinyl)methanone (Preparation 48) and (5-bromopyridinyl)acetic acid to afford the title compound as a yellow solid in 60% yield, 75 mg. LCMS (System 10): R: 2.69 min; m/z 524 [M+H]+ Example 317: 2-(5-bromopyridinyl)-N-(5-{[7-(propanyl)-7H-pyrrolo[2,3-d]pyrimidin yl]carbonyl}pyridinyl)acetamide The title compound was prepared ing to the method described for Example 1 with DIPEA using (5- aminopyridinyl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 95) and (5- bromopyridinyl)acetic acid to afford the title compound as a yellow solid in 45% yield, 75 mg. LCMS (System 9): R = 2.97 min; m/z 479 [M+H]+.

Example 318 : N-{5-[(2-Aminoisopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}(5- bromopyridinyl)acetamide The title compound was prepared according to the method described for Example 1 with DIPEA using (2- aminoisopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)(5-aminopyridinyl)methanone (Preparation 122) and (5-bromopyridinyl)acetic acid to afford the title compound as a colourless oil in 57% yield, 75 mg.

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

Library Protocol 1 The compounds below were prepared in el in the ing manner. 2 “4 X_R102 o o / / \ N \ N N \ \ —> N \ \ k /| EDCI/HOBT/NMM/ k /| N N\ DMF/50C/2 hrs N N, Me Me A 0.25 M stock solution of (5-amino-pyridinyl)-(7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-methanone (Preparation 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 W0 2012/137089 89 were prepared. 300u| (90 umol, ) of each acid monomer solution was dispensed to 8 mL vials, followed by 300 pl (75 umol) of (5-amino-pyridinyl)-(7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-methanone solution.

N-methyl line (150 pmol, 2.0 eq), 300 pl EDCI solution (150 umol) 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 ac, and the final product purified by HPLC under the conditions listed to provide the final compounds. 2-(4-chlorophenyl)—N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin LCMS: R = 2.59 min; yl)carbonyl]pyridinyl}acetamide m/z 406 [M+H]+ 3-(4-chlorophenyl)—N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin LCMS: R = 2.70 min; yl)carbonyl]pyridinyl}propanamide m/z 420 [M+H]+ 3-(3-methylphenyl)-N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin LCMS: R = 2.69 min; yl)carbonyl]pyridinyl}propanamide m/z 400 [M+H]+ N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridin LCMS: R = 1.80 min; yl}(pyridinyl)propanamide m/z 387 [M+H]+ 3-(3-chlorophenyl)—N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin LCMS: R = 2.69 min; yl)carbonyl]pyridinyl}propanamide m/z 420 [M+H]+ 3-(3-fluorophenyl)-N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin LCMS: R = 2.56 min; yl)carbonyl]pyridinyl}propanamide m/z 404 [M+H]+ (7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridin LCMS: R = 2.80 min; yl}[2-(trifluoromethoxy)phenoxy]acetamide m/z 472 [M+H]+ ethylphenyl)-N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin LCMS:Rt = 2.63 min; yl)carbonyl]pyridinyl}propanamide m/z 400 [M+H]+ 3-(2-fluorophenyl)-N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin LCMS: R = 2.53 min; | carbon l]p ridin l propanamide m/z 404 [M+H]+ 3-(4-fluorophenyl)-N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin LCMS: R = 2.55 min; yl)carbonyl]pyridinyl}propanamide m/z 404 [M+H]+ (7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridin LCMS:Rt = 2.50 min; yl}phenylpropanamide m/z 386 [M+H]+ 3-(4-methylphenyl)-N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin LCMS:Rt = 2.65 min; yl)carbonyl]pyridinyl}propanamide m/z 400 [M+H]+ N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridin LCMS: R = 2.60 min; yl}(4-{[(trifluoromethyl)sulfonyl]amino}phenyl)acetamide m/z 519 [M+H]+ N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridin LCMS: R = 2.53 min; yl}phenoxyacetamide m/z 388 [M+H]+ 2-[4-(methoxymethyl)phenyl]-N-{5-[(7-methyl-7H-pyrrolo[2,3- LCMS: R = 2.31 min; d]pyrimidinyl)carbonyl]pyridinyl}acetamide m/z 416 [M+H]+ 2-(4-fluorophenoxy)—N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5— LCMS: R = 2.44 min; | carbon l]p ridin l acetamide m/z 406 [M+H]+ W0 2012/137089 90 Example 336: N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl} phenylcyclopropanecarboxamide The title compound was prepared according to the method described for Library protocol 1 starting from (5-amino-pyridinyl)-(7-methy|-7H-pyrrolo[2,3-d]pyrimidiny|)-methanone (Preparation 110) and 1- phenylcyclopropanecarboxylic 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]pyrimidinyl)carbonyl]pyridinyl}indanecarboxamide The title compound was prepared ing to the method described for y protocol 1 starting from (5-amino-pyridinyl)-(7-methy|-7H-pyrrolo[2,3-d]pyrimidiny|)-methanone ration 110) and indanecarboxylic acid to afford the title compound. LCMS: R = 2.58 min; m/z 398 [M+H]+' Example 338: -{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl} phenylpropanamide The title compound was prepared according to the method described for Library protocol 1 starting from (5-amino-pyridinyl)-(7-methy|-7H-pyrrolo[2,3-d]pyrimidiny|)-methanone (Preparation 110) and (2R)- ylpropanoic acid to afford the title compound. LCMS: R = 2.52 min; m/z 386 [M+H]+' Example 339: 3-hydroxy—2-phenyl-N-(5-{[7-(propanyl)-7H-pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridin- 3-yl)propanamide \ / o N/ \ H KN I N )‘Me OH The title compound was prepared according to the method described for Example 167 using (5- aminopyridinyl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 95) and tropic acid to afford the title compound as a yellow solid in 7% yield, 15 mg. 1H NMR (400 MHz, DMSO-d6) 6: 1.57 (d, 6H), 3.16-3.22 (m, 1H), 3.37-3.41 (m, 1H), 3.60-3.64 (m, 1H), .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, 1H), 8.96 (s, 1H), 9.44 (s, 1H).

LCMS (system 10): R: 2.36 min; m/z 430 [M+H]+.

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

W0 2012/137089 91 2012/051363 N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]- LCMS (system 8): R = pyridinyl}(5-methoxy-1H-indolyl)acetamide 1.63 min; m/z 469 [M+H]+ The following examples were prepared ing to Example 356 using (5-amino-pyridinyl)-(7- isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)—methanone (Preparation 95) and the appropriate acid.

LCMS R: 2.95 min; m/z 420 3-chloro-N-(5-{[7-(propanyl)-7H-pyrrolo[2,3- d]pyrimidinyl]carbonyl}pyridinyl)benzamide 4-chloro-N-(5-{[7-(propanyl)-7H-pyrrolo[2,3- LCMS R: 2.93 min; m/z 420 d]pyrimidinyl]carbonyl}pyridinyl)benzamide [M+H]+.

N-(5-{[7-(propanyl)-7H-pyrrolo[2,3-d]pyrimidin LCMS R: 2.99 min; m/z 454 yl]carbonyl}pyridinyl) [M+H]+. (trifluoromethyl)benzamide N-(5-{[7-(propanyl)-7H-pyrrolo[2,3-d]pyrimidin LCMS R: 3.05 min; m/z 470 yl]carbonyl}pyridinyl) [M+H]+. (trifluoromethoxy)benzamide 2-(2-cyanophenoxy)-N-(5-{[7-(propanyl)-7H- LCMS R: 0.67 min; m/z 441 o[2,3-d]pyrimidinyl]carbonyl}pyridin [M+H]+. yl)acetamide N-(5-{[7-(propanyl)-7H-pyrrolo[2,3-d]pyrimidin LCMS R: 3.01 min; m/Z 500 yl]carbonyl}pyridinyl)[4- [M+H]+. (trifluoromethoxy)phenoxy]acetamide Example 350 : 2-amino(4-chlorophenyl)-N-(5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine carbonyl)pyridinyl)acetamide To utyl (1-(4-chlorophenyl)((5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinecarbonyl)pyridin yl)amino)oxoethyl)carbamate (Preparation 299, 64 mg, 0.11 mmol) was added 4M HCI/dioxane (5 mL) and the reaction stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and purified by preparative reverse phase HPLC to give the title compound as a beige solid in 8% yield, 4 mg.

W0 2012/137089 92 1H NMR (400 MHz, MeOD) 6: 1.59 (d, 6H), 4.63 (s, 1H), 5.16 (m, 1H), 7.35 (d, 2H), 7.47 (d, 2H), 8.33 (s, 1H), 8.62 (s, 1H), 8.69 (s, 1H), 8.88 (s, 1H), 8.92 (s, 1H), 9.47 (s, 1H).

LCMS R = 2.81 min; MS m/z 449 [M+H]+ Example 351: N-{5-[2-Amino(2-hydroxy-1,1-dimethyl-ethy|)-7H-pyrrolo[2,3-d]pyrimidinecarbonyl]- nyl}(5-cyano-pyridinyl)-acetamide H N 0 /\ N|\\ HNJ\N/N To a solution of N-{5-[2-Amino(2-hydroxy-1,1-dimethyl-ethy|)-7H-pyrrolo[2,3-d]pyrimidinecarbonyl]— pyridinyl}(5-bromo-pyridiny|)-acetamide (Example 316, 75 mg, 0.143 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 is(diphenylphosphino)ferrocene 6 mg, 0.011 mmol) were then added and the resultant reaction mixture was heated at 1000C for 40 minutes under microwave irradiation.

The reaction mixture was diluted with EtOAc (20 mL) and washed with water (2 x 10 mL) and brine (10 mL). The c layer was dried (NaZSO4) and evaporated in vacuo. The crude material was purified by preparative TLC (7% MeOH in DCM) to afford the title compound as yellow solid in 31% yield, 21 mg. 1H NMR (400 MHz, DMSO-D6) 6: 1.63 (s, 6H), 3.89 (d, 2H), 4.06 (s, 2H), 5.04 (t, 1H), 6.53 (s, 2H), 7.65- 7.68 (m, 2H), 8.29 (dd, 1H), 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-Cyclopropyltrifluoromethyl-1H-pyrazo|y|)-N-[5-(7-isopropyl-7H-pyrrolo [2, 3-d] pyrimidinecarbony|)-pyridiny|]-acetamide To a solution of (5-Amino-pyridinyl)-(7-isopropy|-7H-pyrro|o[2,3-d]pyrimidiny|)-methanone (Preparation 95, 50 mg, 0.17 mmol), lopropyltrifluoromethyl-1H-pyrazolyl)—acetic acid (Preparation 148, 47.1 mg, 0.21 mmol) and TEA (0.08 mL, 0.62 mmol) in THF (1mL), 1- phosphonic acid cyclic anhydride (50% solution in EtOAc, 0.26 mL, 0.44 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated under d pressure and the residue partitioned between water and EtOAc. The organic layer was washed with saturated sodium bicarbonate solution, dried (NaZSO4) and evaporated in vacuo. Purification by W0 2012/137089 93 column chromatography on silica gel (EtOAc) gave the title nd as a white solid in 77 % yield, 68 1H NMR (400 MHz, DMSO-D6) 6: 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, 1H), 10.60 (s, 1H).

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

Example 353: racemic Methyl 2-{5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridinyl)carbonyl]—7H- o[2,3-d]pyrimidinyl}propanoate The title compound was prepared according to the method described for Example 229 using 2-(4- chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidinylcarbonyl)pyridinyl]acetamide (Example 308), methyl 2-bromopropionate and cesium carbonate. Purified using preparative HPLC (method 1) to afford the title compound.

LCMS (system 2): R = 1.42 min MS m/z 478 [M+H]+ Example 354: c 2-{5-[(5-{[(4-Chlorophenyl)acetyl]amino}pyridinyl)carbonyl]-7H-pyrrolo[2,3- d]pyrimidinyl}propanoic acid The title compound was prepared according to the method described for Preparation 155 using methyl 2- {5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridinyl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidinyl}propanoate (Example 353) to afford the title nd as a white solid in 100% yield, 97 mg.

LCMS (system 2): R = 1.40 min; m/z 464 [M+H]+.

Example 355: 2-(4,5-Dichloro-imidazoly|)-N-[5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinecarbonyl)- pyridinyl]-acetamide (method d) N \ NH KNwe:o N?0. (4,5-Dichloro-imidazoly|)-aceticacid (25.2 mg, 0.130 mmol) was added to (5-amino-pyridinyl)-(7- isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)-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 ated 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-Difluoromethylmethyl-[1,2,4]triazolo[1,5-a]pyrimidinecarboxylic acid [5-(7-isopropyl- 7H-pyrrolo[2,3-d]pyrimidinecarbonyl)-pyridinyl]-amide (method e) W0 2012/137089 94 7-Difluoromethylmethyl-[1,2,4]triazolo[1,5-a]pyrimidinecarboxylic acid (29.64 mg, 0.130 mmol) was added to (5-amino-pyridinyl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)-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 = 1.56 min; m/z 492 [M+H]+ The following Examples were prepared according to one of the methods for Examples 355 (Method d) and 356 d e) using (5-aminopyridinyl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 95).

LCMS (system 8): R = 1.55 2-(4,5-Dichloro-imidazoly|)-N-[5-(7- min; m/z 458 [M+H]+. isopropyl-7H-pyrrolo[2,3-d]pyrimidine Prep HPLC (method 5) carbonyl)—pyridinyl]-acetamide 2-(3,5-Dimethyl-1,2,4-triazoly|)-N-[5-(7- LCMS (system 8): R: 1.43 isopropyl-7H-pyrrolo[2,3-d]pyrimidine min; m/z 419 . carbonyl)-pyridinyl]-acetamide Prep HPLC d 5) 7-lsopropyl-7H-pyrrolo[2,3- LCMS (system 8): R: 1.27 d]pyrimidinecarbonyl)—pyridinyl](2- min; m/z 404 [M+H]+. methyl-imidazoly|)-acetamide Prep HPLC (method 5) 2-lmidazo[2,1-b]thiazolyl-N-[5-(7- LCMS (system 8): R: 1.42 isopropyl-7H-pyrrolo[2,3-d]pyrimidine min; m/z 446 [M+H]+. carbonyl)-pyridinyl]-acetamide Prep HPLC (method 5) 2-(4-Hydroxy-phthalaziny|)-N-[5-(7- LCMS m 8): R = 1.46 isopropyl-7H-pyrrolo[2,3-d]pyrimidine min; m/z 468 [M+H]+. carbonyl)—pyridinyl]-acetamide Prep HPLC (method 5) 2-(2,3-Dimethy|-imidazo[2,1-b]thiazo|—6-y|)-N- LCMS (system 8): R = 1.48 [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- min; m/z 474 [M+H]+. -carbonyl)—pyrid inyl]—acetam ide Prep HPLC (method 5) 2-[4-(1-Hydroxy-cyc|openty|)-1,2,3-triazo| LCMS (system 8): R = 1.44 y|]-N-[5-(7-isopropy|-7H-pyrro|o[2,3- min; m/z 475 [M+H]+. d]pyrimidinecarbonyl)—pyridiny|]- Prep HPLC d 5) acetamide (From Prep 294) N-[5-(7-|sopropy|-7H-pyrro|o[2,3- LCMS (system 8): R = 1.57 d]pyrim idinecarbonyl)—pyridiny|](5-m- min; m/z 482 [M+H]+. to|y|-tetrazo|y|)-acetamide Prep HPLC (method 5) 2-[4-(4-FIuoro—pheny|)-imidazoIy|]-N-[5-(7- LCMS (system 8): R = 1.45 isopropyI-7H-pyrro|o[2,3-d]pyrimidine min; m/z 484 [M+H]+. carbonyl)-pyridinyI]-acetamide Prep HPLC (method 5) LCMS (system 8): R = 1.60 min; m/z 432 [M+H]+. 2-(5-|sopropy|-pyrazo|y|)-N-[5-(7- Prep HPLC (method 5) isopropyI-7H-pyrro|o[2,3-d]pyrimidine (Acid can be prepared in an carbonyl)-pyridinyI]-acetamide analogus to method given in WOO3/072572) 2-(2-EthyI-imidazo[2,1-b]—1,3,4-thiadiazol LCMS (system 8): R = 1.60 y|)-N-[5-(7-isopropy|-7H-pyrro|o[2 ,3- min; m/z 475 . d]pyrimidinecarbonyl)—pyridiny|]- Prep HPLC (method 5) acetamide LCMS (system 8): R = 1.45 N-[5-(7-|sopropy|-7H-pyrro|o[2,3- min; m/z 460 [M+H]+. midinecarbonyl)—pyridiny|](2- Prep HPLC (method 5) methy|-imidazo[2,1-b]thiazo|y|)-acetamide (from Prep 289) hloromethyI-1,2,4-triazo|y|)-N-[5- LCMS (system 8): R: 1.48 (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine min; m/z 439 . yl)-pyridinyI]-acetamide Prep HPLC (method 5) N-[5-(7-|sopropy|-7H-pyrro|o[2,3- LCMS (system 8): R = 1.34 d]pyrimidinecarbonyl)—pyridiny|](2- min; m/z 466 [M+H]+. phenyl-imidazoIy|)-acetamide Prep HPLC (method 5) 2-(2-Chloro-imidazo[2,1-b]thiazo|y|)-N-[5- LCMS (system 8): R = 1.59 (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine min; m/z 480 [M+H]+. carbonyl)—pyridinyI]-acetamide Prep HPLC (method 5) LCMS (system 8): R = 1.26 2-|midazo|y|-N-[5-(7-isopropy|-7H- min; m/z 390 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbonyl)—pyridin- Prep HPLC d 5) 3-yI]-acetam ide LCMS (system 8): R = 1.46 N-[5-(7-|sopropy|-7H-pyrro|o[2,3- min; m/z 460 [M+H]+. d]pyrimidinecarbonyl)—pyridiny|](3- Prep HPLC (method 5) methy|-imidazo[2,1-b]thiazo|y|)-acetamide LCMS (system 8): R: 1.57 2-[1-(4-Hydroxy-pheny|)-1H-pyrroIy|]-N-[5- min; m/z 481 [M+H]+. (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine Prep HPLC (method 5) carbonyl)-pyridinyI]-acetamide N-[5-(7-|sopropy|-7H-pyrro|o[2,3- LCMS (system 8): R = 1.41 d]pyrimidinecarbonyl)—pyridiny|] min; m/z 442 [M+H]+. [1 ,2,4]triazo|o[1 ,5-a]pyrimidinyI-acetamide Prep HPLC (method 5) LCMS (system 8): R: 1.44 7-|sopropy|-7H-pyrro|o[2,3- min; m/z 402 . midinecarbonyl)—pyridiny|] Prep HPLC (method 5) pyrazinyI-acetamide LCMS (system 8): R = 1.48 2-[4-(3-Hydroxy—pheny|)-1,2,3-triazo|y|]-N- min; m/z 483 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) onyl)—pyrid inyl]—acetam ide (from Prep 292) LCMS (system 8): R = 1.63 N-[5-(7-|sopropy|-7H-pyrro|o[2,3- min; m/z 468 [M+H]+. d]pyrimidinecarbonyl)—pyridiny|](5- Prep HPLC (method 5) phenyl-tetrazoIy|)-acetamide 7-DifluoromethyImethyl-[1,2,4]triazo|o[1,5- LCMS (system 8): R = 1.56 midinecarboxylic acid [5-(7- min; m/z 492 . isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R = 1.73 Furo[3,2-c]pyridinecarboxylic acid [5-(7- min; m/z 427 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide 4-MethyI-furazancarboxylic acid [5-(7- LCMS (system 8): R: 1.61 min; py|-7H-pyrro|o[2,3-d]pyrimidine m/z 392 [M+H]+. carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) LCMS (system 8): R = 1.75 1-MethyI-1H-indazoIecarboxylic acid [5-(7- min; m/z 440 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R = 1.67 1H-Indolecarboxylic acid [5-(7-isopropyl- min; m/z 425 [M+H]+. 7H-pyrro|o[2,3-d]pyrim idinecarbony|)- Prep HPLC (method 5) pyridiny|]-amide yItrifluoromethy|-thiazo|e LCMS (system 8): R = 1.62 carboxylic acid [5-(7-isopropyI-7H- min; m/z 475 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC (method 5) 3-y|]-amide LCMS (system 8): R = 1.67 -CyclopropyI-oxazolecarboxylic acid [5- min; m/z 417 . (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R = 1.52 Pyridazinecarboxylic acid [5-(7-isopropyl- min; m/z 388 [M+H]+. 7H-pyrro|o[2,3-d]pyrim idinecarbony|)- Prep HPLC (method 5) Pyridinyl]—amide 3-MethyItrifluoromethyl-1H-pyrazoIe LCMS (system 8): R = 1.53 carboxylic acid [5-(7-isopropyI-7H- min; m/z 458 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC (method 5) 3-y|]-amide (Acid from prep 290) 4-MethyI-pyridinecarboxylic -(7- LCMS (system 8): Rt = 1.70 py|-7H-pyrro|o[2,3-d]pyrimidine min; m/z 401 [M+H]+. carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) 3-CyclobutyI-1H-pyrazoIecarboxylic acid LCMS (system 8): Rt = 1.59 [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- min; m/z 430 [M+H]+. ony|)-pyrid iny|]-am ide Prep HPLC (method 5) OxazoIecarboxylic acid [5-(7-isopropyl- LCMS (system 8): Rt = 1.46 ro|o[2,3-d]pyrim idinecarbony|)- min; m/z 377 [M+H]+. ny|]-amide Prep HPLC (method 5) 4-MethyI-1H-imidazoIecarboxylic acid [5- LCMS (system 8): Rt = 1.52 (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine min; m/z 390 [M+H]+. carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) LCMS (system 8): Rt = 1.56 1H-Pyrro|o[2,3-c]pyridinecarboxylic acid min; m/z 426 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide (Acid: Synthesis, 1993, 295- 297) -MethyI-pyrazinecarboxylic acid[5-(7- LCMS (system 8): Rt = 1.58 isopropy|-7H-pyrro|o[2,3-d]pyrimidine min; m/z 402 [M+H]+. carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) 1 ,3-DimethyI-1H-pyrazoIecarboxylic acid LCMS (system 8): Rt = 1.53 [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- min; m/z 404 [M+H]+. -carbony|)-pyrid iny|]-am ide Prep HPLC (method 6) 1H-Pyrazo|o[4,3-b]pyridinecarboxylic acid LCMS (system 8): Rt = 1.46 [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- min; m/z 427 [M+H]+. ony|)-pyrid iny|]-am ide Prep HPLC (method 5) (Acid: see US 20110111046) -EthyI-isoxazolecarboxylic acid[5-(7- LCMS (system 8): Rt = 1.63 isopropy|-7H-pyrro|o[2,3-d]pyrimidine min; m/z 405 [M+H]+. carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) 2-Methyl-2H-pyrazoIecarboxylic acid [5- LCMS (system 8): Rt = 1.54 (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine min; m/z 390 [M+H]+. carbony|)-pyrid |]-am ide Prep HPLC (method 5) Quinolinecarboxylic acid [5-(7-isopropyl- LCMS (system 8): Rt = 1.66 7H-pyrro|o[2,3-d]pyrim idinecarbony|)- min; m/z 437 [M+H]+.

Pyridinyl]—amide Prep HPLC (method 5) -Fluoro-1H-pyrro|o[2,3-b]pyridine LCMS (system 8): Rt = 1.61 carboxylic acid isopropyI-7H- min; m/z 444 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC d 5) 3-y|]-amide (Acid: W02008/107543) 1 ,5-DimethyI-1H-pyrazoIecarboxylic acid LCMS (system 8): Rt = 1.57 [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- min; m/z 404 [M+H]+. -carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) 2-CyclopropyI-oxazolecarboxylic acid [5- LCMS (system 8): Rt = 1.64 (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine min; m/z 417 [M+H]+. carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) 4-Trifluoromethy|-thiazoIecarboxylic acid LCMS (system 8): Rt = 1.58 [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- min; m/z 461 [M+H]+. -carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) LCMS (system 8): Rt = 1.51 min; m/z 416 [M+H]+. 6,7-Dihydro-5H-pyrro|o[1,2-c]imidazo|e Prep HPLC (method 5) carboxylic acid [5-(7-isopropyI-7H- (Acid can be preparaed by pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- oxidation of aldehyde bed 3-y|]-amide in Tetrahedron, 1999, 8111) Thieno[3,2-c]pyridinecarboxylic acid [5-(7- LCMS (system 8): Rt = 1.77 isopropy|-7H-pyrro|o[2,3-d]pyrimidine min; m/z 443 . carbony|)-pyrid iny|]-am ide Prep HPLC d 5) 1-Methy|trif|uoromethyl-1H-pyrazoIe LCMS (system 8): Rt = 1.60 carboxylic acid [5-(7-isopropyI-7H- min; m/z 458 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC (method 5) 3-y|]-amide WO 37089 100 |midazo[1,5-a]pyridinecarboxylicacid [5- LCMS (system 8): Rt = 1.47 (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine min; m/z 426 [M+H]+. carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) 1H-Pyrro|o[2,3-b]pyridinecarboxylic acid LCMS (system 8): Rt = 1.54 [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- min; m/z 426 [M+H]+. -carbony|)-pyrid iny|]-am ide Prep HPLC d 5) 3-EthyI-isoxazolecarboxylic acid[5-(7- LCMS (system 8): Rt = 1.60 isopropy|-7H-pyrro|o[2,3-d]pyrimidine min; m/z 405 [M+H]+. y|)-pyrid iny|]-am ide Prep HPLC (method 5) 4-Methoxy—pyridinecarboxylic acid [5-(7- LCMS (system 8): Rt = 1.67 isopropy|-7H-pyrro|o[2,3-d]pyrimidine min; m/z 417 [M+H]+. carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) Pyrimidinecarboxylic acid [5-(7-isopropyl- LCMS (system 8): Rt = 1.46 7H-pyrro|o[2,3-d]pyrim idinecarbony|)- min; m/z 388 . pyridiny|]-amide Prep HPLC (method 5) 3-MethyI-1H-pyrazoIecarboxylic acid [5- LCMS (system 8): Rt = 1.46 (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine min; m/z 390 [M+H]+. carbony|)-pyrid |]-am ide Prep HPLC (method 5) -MethyI-1H-pyrrolo[2,3-b]pyridine LCMS (system 8): Rt = 1.54 carboxylic acid [5-(7-isopropyI-7H- min; m/z 440 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC (method 5) 3-y|]-amide -MethyI-pyrimidinecarboxylic acid [5-(7- LCMS (system 8): Rt = 1.60 py|-7H-pyrro|o[2,3-d]pyrimidine min; m/z 402 [M+H]+. carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) Thieno[3,2-b]pyridinecarboxylic acid [5-(7- LCMS (system 8): Rt = 1.64 py|-7H-pyrro|o[2,3-d]pyrimidine min; m/z 443 [M+H]+. carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) Pyrazolo[1,5-a]pyrimidinecarboxylic acid LCMS (system 8): Rt = 1.54 [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- min; m/z 427 [M+H]+. ony|)-pyrid iny|]-am ide Prep HPLC (method 5) 4,5,6,7-Tetrahydro-1,2-benzisoxazoIe LCMS (system 8): Rt = 1.75 carboxylic acid [5-(7-isopropyI-7H- min; m/z 431 [M+H]+. o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC (method 5) 3-y|]-amide |midazo[1,5-a]pyridinecarboxylicacid [5- LCMS (system 8): Rt = 1.75 propyI-7H-pyrro|o[2,3-d]pyrim idine min; m/z 426 [M+H]+. carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) LCMS (system 8): Rt = 1.65 1H-Pyrro|o[2,3-b]pyridinecarboxylic acid min; m/z 426 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide 1,4,5,6-Tetrahydro-cyc|opentapyrazo|e LCMS (system 8): Rt = 1.59 carboxylic acid [5-(7-isopropyI-7H- min; m/z 416 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC (method 5) 3-y|]-amide LCMS (system 8): Rt = 1.41 4-Amino-pyrimidinecarboxylic acid [5-(7- min; m/z 403 [M+H]+. py|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): Rt = 1.32 1H-Pyrro|o[2,3-c]pyridinecarboxylic acid min; m/z 426 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide LCMS (system 8): Rt = 1.51 N-[5-(7-|sopropy|-7H-pyrro|o[2,3- min; m/z 401 [M+H]+. d]pyrimidinecarbony|)-pyridiny|] Prep HPLC (method 5) methyl-isonicotinamide LCMS m 8): Rt = 1.33 |midazo[1,2-a]pyridinecarboxylicacid [5- min; m/z 426 [M+H]+. (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide 1H-1,2,4-TriazoIecarboxylic acid[5-(7- LCMS (system 8): Rt = 1.38 isopropy|-7H-pyrro|o[2,3-d]pyrimidine min; m/z 377 [M+H]+. carbony|)-pyrid iny|]-am ide Prep HPLC (method 7) oxy—pyridinecarboxylic acid [5-(7- LCMS (system 8): Rt = 1.66 isopropy|-7H-pyrro|o[2,3-d]pyrimidine min; m/z 417 [M+H]+. carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) Cinnolinecarboxylic acid [5-(7-isopropyl- LCMS (system 8): Rt = 1.57 7H-pyrro|o[2,3-d]pyrim idinecarbony|)- min; m/z 438 [M+H]+. pyridiny|]-amide Prep HPLC (method 5) [1 ,2,4]Triazo|o[1 ,5-a]pyridinecarboxylic LCMS m 8): Rt = 1.51 acid [5-(7-isopropyI-7H-pyrro|o[2,3- min; m/z 427 [M+H]+. d]pyrim 5-carbony|)-pyridiny|]-am ide Prep HPLC (method 5) Pyrazolo[1,5-a]pyrimidinecarboxylic acid LCMS m 8): Rt = 1.54 [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- min; m/z 427 [M+H]+. -carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) Pyridinecarboxylic acid [5-(7-isopropyl- LCMS (system 8): Rt = 1.62 7H-pyrro|o[2,3-d]pyrim idinecarbony|)- min; m/z 387 [M+H]+.

Pyridinyl]—amide Prep HPLC (method 5) -Ch|oro-N-[5-(7-isopropy|-7H-pyrro|o[2,3- LCMS (system 8): Rt = 1.62 d]pyrimidinecarbony|)-pyridiny|]- min; m/z 421 [M+H]+. nicotinamide Prep HPLC (method 5) 4H-Furo[3,2-b]pyrro|ecarboxy|ic acid [5- LCMS (system 8): R = 1.59 (7-isopropyI-7H-pyrrolo1[2,3-d]pyrimidine min; m/z 415 [M+H]+. carbony|)-pyrid |]-am ide Prep HPLC (method 5) LCMS (system 8): R: 1.34 min; |midazo[1,2-a]pyridinecarboxylicacid [5- m/z 426 [M+H]+. (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.52 min; 1-EthyI-1H-pyrazoIecarboxylic acid [5-(7- m/z 404 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid |]-am ide LCMS (system 8): R = 1.58 1-|sopropy|-1H-imidazoIecarboxylic acid min; m/z 418 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide (Acid :WO2010/009062 LCMS (system 8): R = 1.62 8—Methoxy—imidazo[1 ,2-a]pyrazine min; m/z 457 [M+H]+. carboxylic acid [5-(7-isopropyI-7H- Prep HPLC (method 5) pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- (Acid can be prepared by 3-y|]-amide carbonylation of the bromide e.g. /078408) LCMS m 8): R = 1.55 1H-Pyrro|o[2,3-b]pyridinecarboxylic acid min; m/z 426 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) ony|)-pyrid |]-am ide LCMS (system 8): R: 1.69 min; 2-Methy|propy|-2H-pyrazoIecarboxylic m/z 432 [M+H]+. acid [5-(7-isopropyI-7H-pyrro|o[2,3- Prep HPLC (method 5) d]pyrim idinecarbony|)-pyridiny|]-am ide LCMS (system 8): R: 1.79 min; 4-|sopropy|-thiazoIecarboxylic acid [5-(7- m/z 435 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide (Acid: WO2007/017144 LCMS (system 8): R: 1.77 min; 3-MethyI-furo[2,3-c]pyridinecarboxylic acid m/z 441 [M+H]+. isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide (Acid: WOO4052348) LCMS m 8): R: 1.69 min; 6-MethyI-pyridinecarboxylic acid[5-(7- m/z 401 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide -Chloromethy|trif|uoromethyl-1H- LCMS (system 8): R = 1.63 pyrazoIecarboxylic acid [5-(7-isopropyl- min; m/z 492 [M+H]+. 7H-pyrro|o[2,3-d]pyrim idinecarbony|)- Prep HPLC (method 5) pyridiny|]-amide LCMS (system 8): R: 1.63 min; oxy—1H-benzimidazole-2—carboxylic m/z 456 [M+H]+. acid [5-(7-isopropyI-7H-pyrro|o[2,3- Prep HPLC (method 5) d]pyrim idinecarbony|)-pyridiny|]-am ide (Acid: /017144) 4-Chloro—1,5-dimethyI-1H-pyrazoIe LCMS (system 8): R: 1.65 min; carboxylic acid [5-(7-isopropyI-7H- m/z 438 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC (method 5) amide LCMS (system 8): R, = 1.58 1H-Pyrro|o[3,2-c]pyridinecarboxylic acid min; m/z 426 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.76 min; 4-EthyI-pyridinecarboxylic acid [5-(7- m/z 415 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide (Acid: JOC, 1990, 55, 738-741) 2,3-Dihydro-1,4-dioxino[2,3-b]pyridine LCMS (system 8): R, = 1.54 carboxylic acid [5-(7-isopropyI-7H- min; m/z 445 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC (method 5) 3-y|]-amide LCMS (system 8): R: 1.58 min; ro|o[3,2-b]pyridinecarboxylic acid m/z 426 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide LCMS (system 8): R, = 1.59 min; m/z 426 [M+H]+.

Pyrazo|o[1,5-a]pyridinecarboxylic acid [5- Prep HPLC d 5) (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine (Acid: J. Med. Chem. (2007), carbony|)-pyrid iny|]-am ide 45(21), 4594-4597) LCMS m 8): R, = 1.68 6-Methoxy—quinolinecarboxylic acid [5-(7- min; m/z 467 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC d 5) carbony|)-pyridiny|]-amide -MethyI(2,2,2-trif|uoro-ethy|)-2H- LCMS (system 8): R: 1.66 min; pyrazoIecarboxylic acid [5-(7-isopropyl- m/z 472 [M+H]+. 7H-pyrro|o[2,3-d]pyrim idinecarbony|)- Prep HPLC (method 5) pyridiny|]-amide (Acid: ) LCMS (system 8): R = 1.58 N-[5-(7-|sopropy|-7H-pyrro|o[2,3- min; m/z 455 [M+H]+. midinecarbony|)-pyridiny|] Prep HPLC (method 5) trifluoromethyI-nicotinamide LCMS (system 8): R: 1.46 min; 1-(2-Cyano-ethy|)-1H-pyrazoIecarboxylic m/z 429 . acid [5-(7-isopropyI-7H-pyrro|o[2,3- Prep HPLC (method 5) d]pyrim idinecarbony|)-pyridiny|]-am ide LCMS (system 8): R = 1.45 min; m/z 427 [M+H]+.

Furo[3,2-c]pyridinecarboxylic acid [5-(7- Prep HPLC (method 5) isopropy|-7H-pyrro|o[2,3-d]pyrimidine (Acid: J.Het.Chem. carbony|)-pyrid iny|]-am ide ,24(2), 373-6) LCMS (system 8): R: 1.32 min; 1H-Pyrro|o[3,2-c]pyridinecarboxylic acid m/z 426 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide LCMS (system 8): R = 1.70 Furo[3,2-c]pyridinecarboxylic acid [5-(7- min; m/z 427 . isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R = 1.58 2,4-Dimethyl-oxazolecarboxylic acid [5-(7- min; m/z 405 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R = 1.32 yI-1H-pyrro|o[2,3-c]pyridine min; m/z 440 [M+H]+. carboxylic acid [5-(7-isopropyI-7H- Prep HPLC (method 5) pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- (Acid: 7144) 3-y|]-amide ,6-Dihydro-4H-pyrro|o[1,2-b]pyrazo|e LCMS (system 8): R = 1.59 carboxylic acid [5-(7-isopropyI-7H- min; m/z 416 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC (method 5) 3-y|]-amide LCMS (system 8): R: 1.79 min; 2-CyclobutyI-thiazoIecarboxylic acid [5-(7- m/z 447 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide (Acid: WO2009098448) LCMS (system 8): R: 1.53 min; 3-FIuoro-N-[5-(7-isopropyI-7H-pyrro|o[2,3- m/z 405 [M+H]+. d]pyrimidinecarbony|)-pyridiny|]- Prep HPLC (method 5) isonicotinamide yI-imidazo[1,2-a]pyrimidine LCMS (system 8): R: 1.52 min; carboxylic acid [5-(7-isopropyI-7H- m/z 441 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC (method 5) 3-y|]-amide LCMS m 8): R: 1.57 min; -Methy|-isoxazoIecarboxylic acid [5-(7- m/z 391 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R = 1.62 methoxy—pyrimidinecarboxylic acid min; m/z 448 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.58 min; yI-pyrazinecarboxylic acid[5-(7- m/z 402 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R = 1.49 yI-1H-imidazoIecarboxylic acid [5- min; m/z 390 [M+H]+. (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine Prep HPLC carbony|)-pyrid iny|]-am ide (method 5) LCMS (system 8): R: 1.71 min; -Chloro—pyridinecarboxylic acid[5-(7- m/z 421 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.68 min; 1,8—Naphthyridinecarboxylic acid[5-(7- m/z 438 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.59 min; yI-1H-imidazoIecarboxylic acid [5- m/z 390 [M+H]+. (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine Prep HPLC d 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.56 min; -Methoxymethyl-isoxazolecarboxylic acid m/z 421 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.67 min; azinecarboxylic acid [5-(7- m/z 438 [M+H]+. py|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide ,6-Dihydro-4H-pyrro|o[1,2-b]pyrazo|e LCMS (system 8): R: 1.55 min; carboxylic acid [5-(7-isopropyI-7H- m/z 416 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC d 5) 3-y|]-amide LCMS (system 8): R: 1.58 min; -Bromo—pyrimidinecarboxylic acid [5-(7- m/z 467 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.55 min; 6-Cyano-N-[5-(7-isopropy|-7H-pyrro|o[2,3- m/z 412 . d]pyrimidinecarbony|)-pyridiny|]- Prep HPLC (method 5) nicotinamide LCMS (system 8): R: 1.58 min; Pyrazo|o[1,5-a]pyrimidinecarboxylic acid m/z 427 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC d 5) -carbony|)-pyrid iny|]-am ide 3-MethyI-1H-pyrazo|o[3,4-b]pyridine LCMS (system 8): R: 1.53 min; carboxylic acid [5-(7-isopropyI-7H- m/z 441 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC (method 5) 3-y|]-amide LCMS (system 8): R: 1.73 min; 7-MethyI-pyrazo|o[1,5-a]pyridinecarboxylic m/z 440 [M+H]+. acid [5-(7-isopropyI-7H-pyrro|o[2,3- Prep HPLC (method 5) d]pyrim idinecarbony|)-pyridiny|]-am ide LCMS (system 8): R: 1.59 min; -MethyI-oxazolecarboxylic acid [5-(7- m/z 391 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.74 min; Thieno[3,4-c]pyridinecarboxylic acid [5-(7- m/z 443 [M+H]+. py|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide (Acid: WO 2002100857) LCMS (system 8): R: 1.65 min; 2,6-DimethyI-pyrimidinecarboxylic acid [5- m/z 416 [M+H]+. (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.62 min; 4-Cyano—pyridinecarboxylic acid [5-(7- m/z 412 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5). carbony|)-pyrid iny|]-am ide -MethoxymethyImethy|-1H-pyrazoIe LCMS (system 8): R: 1.56 min; carboxylic acid [5-(7-isopropyI-7H- m/z 434 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC d 5). 3-y|]-amide (Acid: Prep 299) LCMS (system 8): R: 1.68 min; m/z 444 [M+H]+. 4,5-Dichloro-1H-imidazoIecarboxylic acid Prep HPLC (method 5). isopropyI-7H-pyrro|o[2,3-d]pyrim idine- (Acid: Angewandte Chemie, -carbony|)-pyrid iny|]-am ide 417-1418) LCMS (system 8): R: 1.78 min; m/z 482 [M+H]+. 4-Methoxy—8-methyI-1,7-naphthyridine Prep HPLC (method 5) carboxylic acid [5-(7-isopropyI-7H- (Acid: can be ed using pyrro|o[2,3-d]pyrimidinecarbony|)-pyridinchemistry outlined in 3-y|]-amide WOO7011811) LCMS (system 8): R: 1.63 min; 2-EthyImethyl-oxazolecarboxylic acid m/z 419 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.57 min; N-[5-(7-|sopropy|-7H-pyrro|o[2,3- m/z 417 [M+H]+. d]pyrimidinecarbony|)-pyridiny|] Prep HPLC (method 5) methoxy—nicotinamide LCMS m 8): R: 1.49 min; azo|o[3,4-b]pyridinecarboxylic acid m/z 427 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide 109 2012/051363 LCMS (system 8): R: 1.44 min; 3H-Imidazo[4,5-b]pyridinecarboxylic acid m/z 427 [M+H]+. isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.61 min; m/z 457 [M+H]+. 8—Methoxy—imidazo[1 ,2-a]pyrazine Prep HPLC (method 5) carboxylic acid [5-(7-isopropyI-7H- (Acid: can be made from the pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- appropriate halo derivative e.g. 3-y|]-amide WOO7028051) LCMS m 8): R = 1.51 N-[5-(7-|sopropy|-7H-pyrro|o[2,3- min; m/z 387 [M+H]+. d]pyrimidinecarbony|)-pyridiny|]- Prep HPLC (method 5) otinamide LCMS (system 8): R: 1.70 min; 3-MethyI-pyridinecarboxylic acid[5-(7- m/z 401 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.59 min; Furo[2,3-b]pyridinecarboxylic acid [5-(7- m/z 427 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide (Acid: WO 8) 3-IsopropyI-1,2,4-triazo|o[4,3-a]pyridine LCMS (system 8): R: 1.57 min; ylic acid [5-(7-isopropyI-7H- m/z 469 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC (method 5) 3-y|]-amide LCMS (system 8): R: 1.50 min; OxazoIecarboxylic acid [5-(7-isopropyl- m/z 377 [M+H]+. 7H-pyrro|o[2,3-d]pyrim idinecarbony|)- Prep HPLC (method 5) PyridinyI]-amide LCMS (system 8): R: 1.62 min; 3-Chloro-pyridinecarboxylic acid[5-(7- m/z 421 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.44 min; |midazo[1,2-a]pyrimidinecarboxylic acid m/z 427 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) ony|)-pyrid iny|]-am ide (Acid — Prep 300) LCMS (system 8): R: 1.67 min; -CyclopropyI-isoxazolecarboxylic acid [5- m/z 417 [M+H]+. (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.58 min; -Cyclopropy|-2H-pyrazoIecarboxylic acid m/z 416 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC d 5) -carbony|)-pyrid iny|]-am ide 4,7-DimethyI-pyrazo|o[5,1-c][1,2,4]triazine LCMS (system 8): R: 1.69 min; carboxylic acid [5-(7-isopropyI-7H- m/z 456 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC (method 5) 3-y|]-amide N-[5-(7-|sopropy|-7H-pyrro|o[2,3- LCMS (system 8): R: 1.51 min; d]pyrimidinecarbony|)-pyridiny|] m/z 401 [M+H]+. methyl-nicotinamide Prep HPLC (method 5) LCMS m 8): R = 1.64 1-CyclobutyI-1H-imidazoIecarboxylic acid min; m/z 430 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide (Acid — Prep 288) Pyrazo|o[1,5-a]pyridinecarboxylic acid [5- LCMS (system 8): R = 1.65 (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine min; m/z 426 [M+H]+. carbony|)-pyrid iny|]-am ide Prep HPLC (method 5) LCMS (system 8): R: 1.51 min; o|o[1,5-a]pyridinecarboxylic acid [5- m/z 428 [M+H]+. (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide Commercial 8-Tetrahydro-1,2,4-triazo|o[4,3- LCMS (system 8): R: 1.60 min; a]pyridinecarboxylic acid [5-(7-isopropyl- m/z 431 [M+H]+. 7H-pyrro|o[2,3-d]pyrim 5-carbony|)- Prep HPLC (method 5) pyridiny|]-amide Commercial 2-MethyItrifluoromethyI-oxazole LCMS (system 8): R: 1.69 min; ylic acid [5-(7-isopropyI-7H- m/z 459 [M+H]+. pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC d 5) 3-y|]-amide LCMS (system 8): R: 1.36 min; 1H-Pyrro|o[3,2-b]pyridinecarboxylic acid m/z 426 [M+H]+. [5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC d 5) -carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.57 min; Pyrazo|o[3,4-b]pyridinecarboxylic acid [5- m/z 427 [M+H]+. (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide azolecarboxylic acid [5-(7- LCMS (system 8): R = 1.65 isopropy|-7H-pyrro|o[2,3-d]pyrimidine min; m/z 426 [M+H]+. carbony|)-pyrid iny|]-am ide Prep HPLC d 5) LCMS (system 8): R: 1.58 min; 3-Methy|-isoxazo|o[5,4-b]pyridine m/z 442 [M+H]+. carboxylic acid [5-(7-isopropyI-7H- Prep HPLC (method 5) pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- (Acid - sis, 2009, 1858- amide 1864) LCMS (system 8): R: 1.45 min; Pyridazinecarboxylic acid [5-(7-isopropyl- m/z 388 [M+H]+. 7H-pyrro|o[2,3-d]pyrim idinecarbony|)- Prep HPLC (method 5) Pyridinyl]—amide LCMS (system 8): R: 1.66 min; 2,3-Dihydro-1,4-dioxino[2,3-c]pyridine m/z 445 [M+H]+. carboxylic acid [5-(7-isopropyI-7H- Prep HPLC (method 5) pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- (Acid: ) 3-y|]-amide LCMS (system 8): R: 1.58 min; 1H-Pyrazo|o[3,4-b]pyridinecarboxylic acid m/z 427 [M+H]+. isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide (Acid: ) LCMS (system 8): R: 1.68 min; -Fluoro-1H-indazoIecarboxylic acid [5-(7- m/z 444 [M+H]+. isopropy|-7H-pyrro|o[2,3-d]pyrimidine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide LCMS (system 8): R: 1.59 min; 2,5-Dimethyl-2H-pyrazoIecarboxylic acid m/z 404 [M+H]+. isopropyI-7H-pyrro|o[2,3-d]pyrim idine- Prep HPLC (method 5) -carbony|)-pyrid iny|]-am ide W0 2012/137089 112 LCMS m 8): R: 1.56 min; Thiazo|o[4,5-b]pyridinecarboxylic acid [5- m/z 444 [M+H]+. (7-isopropyI-7H-pyrro|o[2,3-d]pyrim idine Prep HPLC (method 5) carbony|)-pyrid iny|]-am ide 6-Chloro—imidazo[1,2-b]pyridazine LCMS (system 8): R: 1.68 min; carboxylic acid [5-(7-isopropyI-7H- m/z 461 . pyrro|o[2,3-d]pyrimidinecarbony|)-pyridin- Prep HPLC (method 5) 3-y|]-amide Example 517: 2-(5,8-Dihydro-6H-[1,7]naphthyridiny|)-N-[5-(7-isopropy|-7H-pyrro|o[2,3-d]pyrimidine carbonyl)-pyridiny|]-acetamide \/JJ\/NO \ \ N To a DMF solution of (5,8-Dihydro-6H-[1,7]naphthyridiny|)-acetic acid hydrochloride (Preparation 235) (34.2 mg, 0.18 mmol) were added (5-Amino-pyridiny|)-(7-isopropy|-7H-pyrroIo[2,3-d]pyrimidiny|)- methanone (Preparation 95) (50 mg, 0.18 mmo|), HATU (136.4 mg, 0.36 mmol) and Hunig’s base (0.092 ml, 0.54 mmo|). 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 purified over ative TLC e|uting with 5% MeOH/EtOAc to afford the title compound as off white solid in 26% yield, 21 mg. 1H NMR (400 MHz, DMSO-D6) 6: 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, 1H), 9.45 (s, 1H), 10.31 (s, 1H); LCMS m 9): R = 1.77 min; m/z 456 [M+H]+.

Example 518: 2-Hydroxy—N-[5-(7-isopropyI-7H-pyrro|o[2,3-d]pyrimidinecarbony|)-pyridiny|]pheny|- acetamide \ / O N'k\ N \ HW N/ K HO To stirred solution of N-[5-(7-Isopropy|-7H-pyrro|o[2,3-d]pyrimidinecarbony|)-pyridiny|]pheny| (tetrahydro-pyranyloxy)-acetamide (60 mg, 0.12 mmol) ration 237) in e (1 mL) was added dioxane-HCI (1 mL of a 4N solution) at 0°C. The mixture was stirred at room temperature for 2 hours. All 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.

W0 2012/137089 113 1H NMR (400 MHz, DMSO-D6) 6: 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, 1H), 8.63 (s, 1H), 8.76 (br s, 1H), 9.05 (s, 1H), 9.17 (br s, 1H), 9.48 (br s, 1H), 10.56 (s, 1H); LCMS (system 10): R = 2.81 min; m/z416 [M+H]+.

Example 519: N-[2-Ethoxy—5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinecarbonyl)-pyridiny|](5- methyltrifluoromethyl-pyrazoly|)-acetamide NJk/N‘H _ o O FF \ [(1 \/Me N \ \ KN/ N >‘Me The title compound was prepared according to the method described for Example 1 using (5-Amino—6- ethoxy—pyridinyl)-(7-isopropy|-7H-pyrro|o[2,3-d]pyrimidiny|)-methanone (Preparation 242) and (5- trifluoromethyl-pyrazoly|)-acetic acid to afford the title compound as off white solid in 50% yield, 40 mg. 1H NMR (400 MHz, CDCI3) 6: 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+H]+.

Example 520: N-[5-(2-Aminotert-butyl-7H-pyrrolo[2,3-d]pyrimidinecarbonyl)—pyridiny|](4-cyano- pheny|)-acetamide The title compound was prepared according to the method described for Example 1 using (2-amino tert-butyl-7H-pyrro|o[2,3-d]pyrimidiny|)-(5-amino-pyridinyl)—methanone (see ation 65) and 4- cyano phenyl acetic acid to afford the title compound as off white solid in 58%, 23 mg.

LCMS m 10): R = 2.78 min; m/z 454 .

Example 521: 2-(4-Chloro-phenyl)—3-hydroxy—N-[5-(7-isopropyl-7H-pyrro|o[2,3-d]pyrimidinecarbonyl)— pyridinyl]-propionamide \ / 0 Z/ IZ )‘Me OH W0 2012/137089 114 2-(4-Chloro-phenyl)hydroxy—propionic acid (570 mg, 2.84 mmol) (Preparation 244) was added to a solution of (5-Amino-pyridinyl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)—methanone (200 mg, 0.71 mmol) (Preparation 95) in THF (5 mL). Di-isopropyl ethylamine (0.64 mL, 3.56 mmol), EDC|.HC| (273 mg, 1.42 mmol) and HOBT (193 mg, 1.42 mmol) were added and the mixture was d at 25°C for 48 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layer was washed with water (5mL), brine (5 mL), dried over sodium te and evaporated in vacuo. The crude material was purified by preparative TLC (dichloromethane: methanol 93:7) to afford the title compound as a yellow solid in 3% yield, 10 mg. 1H NMR (400 MHz, 6) 6: 1.55 (d, 6H), 3.58-3.61 (m, 1H), 3.88-3.91 (m, 1H), 4.04 (t, 1H), 5.07- .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 = 2.99 min; m/z 464 [M+H]+. e 522: 2-(4-Cyano-phenyl)—N-{5-[7-(1-hydroxymethyl-cyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine carbonyl]—pyridinyl}-acetam ide (4-Cyano-phenyl)—acetic acid (6.1 mg, 0.04 mmol) was added to a solution of (5-Amino-pyridinyl)—{7-[1- (tetrahydro-pyranyloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidinyl}-methanone (15 mg, 0.04 mmol) ration 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 (3 x 5 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 temperature for 16 hours. The reaction mixture was ed with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with dichloromethane (5 x 5 mL). The combined organic layer was washed with brine (5 mL), dried over sodium sulphate and ated in vacuo. The crude material was purified by preparative TLC oromethane: methanol 95:5) to afford the title compound as a white solid in 58% yield, 10 mg. 1H NMR (400 MHz, DMSO-D6) 6: 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+H]+.

The following Examples were prepared ing to the method described above for Example 522 starting from (5-Amino-pyridinyl)-[7-(3-methyl-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidinyl]—methanone (Preparation 251) and the appropriate acids.

W0 2012/137089 115 2-(5-Chloro-pyridiny|)-N-{5-[7-(1-hydroxymethy|- cyclopropyl)-7H-pyrro|o[2,3-d]pyrimidinecarbony|]- LCMS m 10): Rt = pyridiny|}-acetamide 2.53 min; m/z 463 [M+H]+ N-{5-[7-(1-HydroxymethyI-cyclopropyl)-7H-pyrro|o[2,3- LCMS (system 10): R = d]pyrimidinecarbony|]-pyridiny|}(4-trif|uoromethyl- 2.89 min; m/z 496 [M+H]+. pheny|)-acetamide 7-(1-HydroxymethyI-cyclopropyl)-7H-pyrro|o[2,3- LCMS (system 9): R = 2.71 d]pyrimidinecarbony|]-pyridiny|}(3-trif|uoromethyl- min; m/z 486 [M+H]+. pyrazoIy|)-acetamide Example 526: 1-(3-CyclopropyI-1'-methy|-1'H-[1,4']bipyrazo|y|y|)[5-(7-isopropy|-7H-pyrro|o[2,3- d]pyrim idinecarbony|)-pyridiny|]-urea Phenyl chloroformate (0.03 mL, 0.24 mmol) was added slowly to a solution of 3-CyclopropyI-1'-methy|- 1'H-[1,4']bipyrazo|y|y|amine (Preparation 297, 40 mg, 0.19 mmol) and ne (0.03 mL) in THF (2 mL) at 0°C and the mixture was stirred at room temperature for 4 hours. A on of (5-Amino-pyridiny|)-(7- isopropyI-7H-pyrro|o[2,3-d]pyrimidiny|)-methanone (Preparation 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 e (15 mL), and washed with aqueous saturated NaHCO3 solution (2 x 10 mL), water (10 mL), brine (10 mL), dried over sodium te and evaporated to dryness in vacuo. The crude material was purified over preparative TLC plate (e|uting 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) 6: 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, 1H), 8.05 (s, 1H), 8.36 (s, 1H), 8.52 (s, 1H), 8.61 (br s, 1H), 8.65 (s, 1H), 8.78 (s, 1H), 8.99 (s, 1H), 9.45 (s, 2H); LCMS (system 10): R = 2.75 min; m/z 511 [M+H]+.

Example 527: 1-(3-tert-ButyI-1'-methy|-1'H-[1,4']bipyrazonIyl)[5-(7-isopropy|-7H-pyrro|o[2,3- d]pyrimidinecarbony|)-pyridiny|]-urea The title compound was prepared according to the method described for Example 526 using (5-Amino- pyridiny|)-(7-isopropy|-7H-pyrro|o[2,3-d]pyrimidiny|)-methanone (Preparation 95) and 3-tert-ButyI-1'- methyl-1'H-[1,4']bipyrazonIylamine (Preparation 296) to afford the title compound as yellow solid in % yield, 17 mg.LCMS (system 10): R = 3.01 min; m/z 527 [M+H]+.

W0 2012/137089 116 The following Examples were prepared according to the method described above for Example 1, starting from (2-aminotert—butyl-7H—pyrrolo[2,3-d]pyrimidinyl)(5-aminopyridinyl)methanone (Preparation 65) and the appropriate acids. 2-Am inotert-butyl-7H-pyrrolo[2,3-d]pyrim idine LCMS (system 10): Rt = 2.79 carbonyl)-pyridinyl]—2-(1H-benzoimidazolyl)— min; m/z 469 [M+H]+. acetamide LCMS (system 10): R = 2.94 N-[5-(2-Aminotert-butyl-7H-pyrrolo[2,3-d]pyrimidine min; m/z 508 [M+H]+ carbonyl)-pyrid inyl]—2-(5-bromo-pyridinyl)-acetam ide LCMS (system 10): R = 2.78 min; m/z 455 [M+H]+ (acid N-[5-(2-Am inotert-butyl-7H-pyrrolo[2,3-d]pyrim idine can be ed by carbonyl)-pyrid inyl]—2-(5-cyano-pyridinyl)-acetam ide cyanation of an appropriate bromo derivative The following Examples were prepared according to the method described for Example 522 using (5- Amino-pyridinyl)—{7-[(S)—1-methyl(tetrahydro-pyranyloxy)—ethyl]—7H-pyrrolo[2,3-d]pyrimidinyl}- one (Preparation 33) and the appropriate acid. 2-(4-Difluoromethoxy—phenyl)-N-{5-[7-((S) LCMS (system 9): R = 2.80 min; hydroxymethyl-ethyl)-7H-pyrrolo[2,3- m/z 482 [M+H]+ d]pyrim idinecarbonyl]-pyridinyl}-acetam ide N-{5-[7-((S)Hydroxy—1-methyl-ethyl)—7H- LCMS (system 9): Rt = 2.58 min; pyrrolo[2,3-d]pyrim 5-carbonyl]-pyridinyl} m/z 456 [M+H]+ lyl-acetam ide 2-(1H-Benzoimidazolyl)-N-{5-[7-((S)hydroxy- LCMS (system 10): Rt = 2.42 min; 1-methyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine m/z 456 [M+H]+. carbonyl]-pyridinyl}-acetam ide N-{5-[7-((S)Hydroxy—1-methyl-ethyl)—7H- LCMS (system 9): Rt = 2.99 min; pyrrolo[2,3-d]pyrim idinecarbonyl]-pyridinyl} m/z 500 [M+H]+ (4-trifluoromethoxy—phenyl)—acetam ide -Difluoro-phenyl)-N-{5-[7-((S)hydroxy—1 - LCMS (system 9): Rt = 2.75 min; methyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine m/z 452 [M+H]+ carbonyl]-pyridinyl}-acetam ide The following Examples were prepared according to the Method described for d]pyrimidinyl]methanone ration 186) and the appropriate acid.

W0 2012/137089 117 LCMS (system 10): R = 2-(5-Chloro-pyridiny|)-N-{5-[7-(2-m ethoxy—1 ,1- 2.92 min; m/z 479 dimethyl-ethyl)-7H-pyrro|o[2,3-d]pyrim idinecarbony|]- [|V|+H]+ pyridinyI}-acetam ide LCMS (system 10): R = 2-(5-FIuoro-pyridiny|)-N-{5-[7-(2-methoxy-1 ,1- 2.79 min; m/z 463 dimethyl-ethyl)-7H-pyrro|o[2,3-d]pyrimidinecarbony|]- [M+H]+. pyridinyI}-acetamide LCMS m 10): R = 2-(3-CyclopropyI-pyrazoly|)-N-{5-[7-(2-methoxy—1 ,1- 2.89 min; m/z 474 dimethyl-ethyl)-7H-pyrro|o[2,3-d]pyrimidinecarbony|]- [M+H]+. pyridinyI}-acetamide LCMS (system 10): R = 2-(4-FIuoro-pheny|)-N-{5-[7-(2-methoxy—1,1-dimethy|- 3.03 min; m/z 462 -7H-pyrro|o[2,3-d]pyrimidinecarbony|]-pyridin [M+H]+. y|}-acetamide e 540: N-[5—(7-tert—Buty|-7H-pyrro|o[2,3-d]pyrimidinecarbony|)-pyridiny|](4-f|uoro-pheny|)- N-methyl-acetamide N|\\ )PMe Me Me To a stirred solution of N-[5—(7-tert—Buty|-7H-pyrro|o[2,3-d]pyrimidinecarbony|)-pyridiny|](4-f|uoro- pheny|)-acetamide (Example 546, 115 mg, 0.27 mmol) in anhydrous THF (4.5 mL), was added NaH (60% in paraffin OH, 10.7 mg, 0.27 mmol) at 0°C under en 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 temperature for 1 hour. Aqueous saturated ammonium chloride (5 mL) was added and the mixture extracted with ethyl e (2 x 10 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 al was purified via preparative TLC (e|uting 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) 6: 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+H]+.

Example 541: [5—(7-tert—ButyI-7H-pyrro|o[2,3-d]pyrimidinecarbony|)-pyridiny|]-carbamic acid tert- butyl ester W0 2012/137089 118 N N Me Me To a d solution of (5-Amino-pyridinyl)—(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidinyl)—methanone (Preparation 31) (200 mg, 0.68 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 on mixture was stirred at room ature for 16 hours. It was diluted with DCM (15 mL) and washed with water (2 x 10 mL), brine (10 mL), dried over sodium sulphate and evaporated to dryness in vacuo. The crude al was purified by column chromatography on silica gel (Methanol:DCM 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+H]+.

Example 542: [5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidinecarbonyl)—pyridinyl]—methyl-carbamic acid tert-butyl ester The title compound was prepared according to the method described for Example 540 using [5-(7-tert- Butyl-7H-pyrrolo[2,3-d]pyrimidinecarbonyl)-pyridinyl]-carbamic acid tert-butyl ester (Example 541) to afford the title compound as yellow solid in 79% yield, 90 mg. LCMS (system 10): R = 3.83 min; m/z 410 [M+H]+.

Example 543: N-[5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidinecarbonyl)—pyridinyl]—2-(5-chloro-pyridin- 2-yl)-N-methyl-acetamide N \ / CI o /\ “W \ kN/ N)r Me Mil/'9 The title compound was prepared according to the method described for e 1 using (7-tert-butyl- 7H-pyrrolo[2,3-d]pyrimidinyl)—(5-methylamino-pyridinyl)—methanone (Preparation 187) and (5-chloro— pyridinyl)-acetic ee Preparation 90) to afford the title compound as off white solid in 21% yield, mg. 1H NMR (400 MHz, DMSO-D6) 6: 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, 1H), 9.02 (s, 1H), 9.51 (s, 1H); LCMS (system 10): R = 3.29 min; m/z 463.2 [M+H]+.

Example 544: N-[5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidinecarbonyl)—pyridinyl]—2-(4-chloro-phenyl)- N-methyl-acetamide W0 2012/137089 119 The title compound was prepared according to the method described for Example 1 using (7-tert—Butyl- 7H-pyrrolo[2,3-d]pyrimidinyl)-(5-methylamino-pyridinyl)-methanone ration 187) and (4-chlorophenyl )-acetic acid to afford the title compound as off white solid in 45% yield, 21 mg.

LCMS m 10): R = 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-aminopyridinyl)(7-tert—butyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 31) and the appropriate acids.

LCMS (system 10): R = 3.18 N-[5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidine-5— min; m/z 448 [M+H]+. carbonyl)-pyridinyl](4-chloro-phenyl)— acetam ide LCMS m 10): R = 3.08 N-[5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrImIdIne min; m/z 432 [M+H]+. carbonyl)-pyridinyl](4-fluoro-phenyl)— acetam ide The following Examples were prepared according to the method described for Example 1 starting from [2- 7-(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]-(5-amino-pyridinyl)-methanone (Preparation 261) and the appropriate acid.

LCMS (system 10): R = 2.85 N-{5—[2-Amino(2-m ethoxy-1 ,1-dimethyl-ethyl)—7H- min; m/z 494 [M+H]+. pyrrolo[2,3-d]pyrim idinecarbonyl]-pyridinyl} (Acid: Prep 90) (5-chloro-pyridinyl)-acetamide LCMS (system 10): R = 2.77 N-{5—[2-Amino(2-m ethoxy-1 ,1-dimethyl-ethyl)—7H- min; m/z 478 . o[2,3-d]pyrim idinecarbonyl]-pyridinyl} (Acid Prep 92) oro-pyridinyl)-acetam ide LCMS (system 10): R = 3.02 N-{5—[2-Amino(2-m ethoxy-1 ,1-dimethyl-ethyl)—7H- min; m/z 517 [M+H]+. pyrrolo[2,3-d]pyrim idinecarbonyl]-pyridinyl} (Acid Prep 85) (3-trifluoromethyl-pyrazoly|)-acetamide LCMS (system 10): R = 2.93 N-{5—[2-Amino(2-m ethoxy-1 ,1-dimethyl-ethyl)—7H- min; m/z 518 [M+H]+. o[2,3-d]pyrim idinecarbonyl]-pyridinyl} (Acid Prep 81) (4-trifluoromethyl-[1 ,2,3]triazoly|)-acetamide LCMS (system 10): R = 3.01 N-{5—[2-Amino(2-m -1 ,1-dimethyl-ethyl)—7H- min; m/z 517 [M+H]+. pyrrolo[2,3-d]pyrim idinecarbonyl]-pyridinyl} (Acid Prep 85) (4-trifluoromethyl-pyrazoly|)-acetamide LCMS (system 10): R = 2.69 N-{5—[2-Amino(2-m ethoxy-1 ,1-dimethyl-ethyl)—7H- min; m/z 490 [M+H]+. pyrrolo[2,3-d]pyrim idinecarbonyl]-pyridinyl} (Acid Prep 83) (4-cyclopropyl-[1,2,3]triazoly|)-acetamide W0 2012/137089 120 The following Examples were prepared according to the method described for Example 522 using (5- Amino-pyridiny|)-{7-[(S)methy|(tetrahydro-pyrany|oxy)-ethy|]-7H-pyrro|o[2,3-d]pyrimidiny|}- methanone (Preparation 49) and the appropriate acid.

N-{5-[2-Amino(2-hydroxy-1 ethyI-ethy|)- LCMS (system 10): R = 2.67 min; 7H-pyrro|o[2,3-d]pyrim idinecarbony|]-pyridin m/z 485 [M+H]+. y|}indazoIyI-acetam ide LCMS (system 10): R = 2.52 min; N-{5-[2-Amino(2-hydroxy-1 ,1-dimethyI-ethy|)- m/z 513 [M+H]+. 7H-pyrro|o[2,3-d]pyrim idinecarbony|]-pyridin y|}(4-oxo-4H-q uinazolinyl)—acetam ide LCMS (system 9): R = 2.07 min; N-{5-[2-Amino(2-hydroxy-1 ,1-dimethyI-ethy|)- m/z 482 [M+H]+. 7H-pyrro|o[2,3-d]pyrim idinecarbony|]-pyridin y|}(3,5-difluoro-pyridiny|)-acetamide Acid Prep 265) LCMS (system 9): R = 1.36 min; N-{5-[2-Amino(2-hydroxy-1 ,1-dimethyI-ethy|)- m/z 460 [M+H]+. 7H-pyrro|o[2,3-d]pyrim idinecarbony|]-pyridin y|}(5-methyl-pyridiny|)-acetam ide Acid Prep 274 N-(5-{[2-amino(2-hydroxy-1,1-dimethylethy|)-7H- LCMS (system 9): R = 2.19 min; pyrro|o[2,3-d]pyrimidiny|]carbony|}pyrid iny|)- m/z 552 [M+H]+. m ethy|(methy|su|fony|)am ino]pheny|}- Acid Prep 271 acetam ide LCMS (system 9): R = 1.42 min; N-{5-[2-Amino(2-hydroxy-1 ,1-dimethyI-ethy|)- m/z 485 [M+H]+. ro|o[2,3-d]pyrim 5-carbony|]-pyridin y|}(1H-benzoimidazoIy|)-acetamide N-{5-[2-Amino(2-hydroxy-1 ,1-dimethyI-ethy|)- LCMS (system 9): R = 2.18 min; 7H-pyrro|o[2,3-d]pyrim idinecarbony|]-pyridin m/z 530 [M+H]+. y|}(2-oxotrif|uorom ethy|-2H-pyridiny|)- acetam ide LCMS (system 9): R = 2.23 min; N-{5-[2-Amino(2-hydroxy-1 ,1-dimethyI-ethy|)- m/z 498 [M+H]+. 7H-pyrro|o[2,3-d]pyrim 5-carbony|]-pyridin y|}(5-ch|orofluoro-pyridiny|)-acetamide LCMS (system 10): R = 2.64 min; m/z 490 [M+H]+ (acid can be N-{5-[2-Amino(2-hydroxy-1 ,1-dimethyI-ethy|)- prepared from the riate 7H-pyrro|o[2,3-d]pyrim 5-carbony|]-pyridin bromide using the method in y|}(5-ethoxy-pyridiny|)-acetamide /114271) LCMS (system 9): R = 2.40 min; 2-Amino(2-hydroxy-1 ,1-dimethyI-ethy|)- m/z 514 [M+H]+. 7H-pyrro|o[2,3-d]pyrim idinecarbony|]-pyridin y|}(5-trif|uoromethyl-pyrid iny|)-acetam ide LCMS (system 9): R = 2.39 min; N-{5-[2-Amino(2-hydroxy-1 ,1-dimethyI-ethy|)- m/z 503 [M+H]+. 7H-pyrro|o[2,3-d]pyrimidinecarbony|]-pyridin Acid prep 85 y|}(4-trif|uoromethyl-pyrazoly|)-acetamide 2-Amino(2-hydroxy-1 ,1-dimethyI-ethy|)- LCMS (system 9) R = 4.47 min (12 7H-p rro|o[2,3-d]p rimidinecarbon |]-p ridin min run ; m/z 538 [M+H]+.

W0 2012/137089 121 -yl}(4-methanesulfonylamino-phenyl)—acetamide— The following Examples were prepared according to the method described for Examples 73-87 using (5- pyridinyl)-{7-[(S)methyl(tetrahydro-pyranyloxy)—ethyl]—7H-pyrrolo[2,3-d]pyrimidinyl}- methanone (Preparation 49) and the appropriate acid.

N-{5-[2-Amino(2-hydroxy-1,1-dimethyl-ethyl)-7H- LCMS (system 9): R = 2.56 pyrrolo[2,3-d]pyrimidinecarbonyl]—pyridinyl}(4- min; m/z 511 [M+H]+. difluoromethoxy-phenyl)-acetamide LCMS (system 9): R = 2.74 N-{5-[2-Am ino(2-hydroxy-1 ,1-dimethyl-ethyl)-7H- min; m/z 529 [M+H]+. pyrrolo[2,3-d]pyrimidinecarbonyl]—pyridinyl}(4- trifluoromethoxy-phenyl)-acetamide N-{5-[2-Amino(2-hydroxy-1,1-dimethyl-ethyl)-7H- LCMS (system 9): R = 2.50 pyrrolo[2,3-d]pyrimidinecarbonyl]—pyridinyl}(3,4- min; m/z 481 [m+H]+_ difluoro-phenyl)—acetamide LCMS (system 10): R = 2.35 min; m/z 481 [M+H]+ 2-Amino(2-hydroxy-1,1-dimethyl-ethyl)-7H- (acid can be ed by pyrrolo[2,3-d]pyrimidinecarbonyl]—pyridinyl}(5- oxidation of the appropriate chloro-pyrimidinyl)-acetamide aldehyde WOO4110453) Example 570: 2-(4-Cyano-phenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidinecarbonyl)—pyridinyl]-acetamide \ / o “t \ N \ H N N The title compound was prepared according to the method described for Example 343 using 2-(4-Cyano- phenyl)-N-{5-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidinecarbonyl]-pyridinyl}- acetamide (Preparation 277) to afford the title compound as a white solid in 99% yield, 1H NMR (400 MHz, DMSO-d6) 6: 3.87 (s, 2H), 7.55 (d, 2H), 7.81 (d, 2H), 8.36 (s, 1H), 8.47 (s, 1H), 8.72 (s, 1H), 8.97 (m, 2H), 9.47 (s, 1H), 10.66 (s, 1H), 13.14 (s, 1H); LCMS (System 10): R = 2.48 min; m/z 383 [M+H]+.

The following es were prepared according to the method described above for e 1, starting from (5-Amino-pyridinyl)-[7-(3-methyl-oxetanyl)—7H-pyrrolo[2,3-d]pyrimidinyl]-methanone (Preparation 222) and the appropriate acid.

N-{5-[7-(3-Methyl-oxetanyl)—7H-pyrrolo[2,3-d]pyrImIdIne- LCMS m 10): Rt: 302 -carbonyl]-pyridinyl}(4-trifluoromethyl-pheny|)- . + mIn, m/z 496 [M+H]_ acetamide W0 2012/137089 122 N-{5-[7-(3-Methyl-oxetanyl)—7H-pyrrolo[2,3-d]pyrim idine- LCMS (System 10): Rt = 2.98 -carbonyl]-pyridinyl}(3-trifluoromethyl-pheny|)- min; m/z 496 [M+H]+. acetamide 2-(3-F|uorotrifluoromethyl-phenyl)-N-{5-[7-(3-methyl- LCMS (System 10): Rt = 3.01 oxetanyl)—7H-pyrrolo[2,3-d]pyrimidinecarbonyl]- min; m/z 514 [M+H]+. pyridinyl}-acetamide N-{5-[7-(3-Methyl-oxetanyl)—7H-pyrrolo[2,3-d]pyrimidine- LCMS (System 10): Rt = 3.00 -carbonyl]-pyridinyl}trifluoromethyl-benzamide min; m/z 482 [M+H]+ .

N-{5-[7-(3-Methyl-oxetanyl)—7H-pyrrolo[2,3-d]pyrimidine- LCMS (System 10): Rt = 3.05 -carbonyl]-pyridinyl}trifluoromethoxy—benzamide min; m/z 498 [M+H]+ Example 576: N-{5-[2-Amino(2-hydroxy-1,1-dimethyl-ethyl)—7H-pyrrolo[2,3-d]pyrimidinecarbonyl]- pyridinyl}(4-cyclopropyl-pyrazoly|)-acetamide The title nd was prepared according to the method described for Example 1 using {2-amino [1 ,1-dimethy|(tetrahydro-pyranyloxy)—ethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}-(5-amino-pyridinyl)— methanone (Preparation 49) and lopropyl-pyrazoly|)-acetic acid to afford the title nd as a white solid in 72 % yield, 16.5 mg.

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

Example 577: N-[5-(2-Aminotert-butyl-7H-pyrrolo[2,3-d]pyrimidinecarbonyl)—pyridinyl](4- cyclopropyl-pyrazoly|)-acetamide The title compound was prepared ing to the method described for Example 1 using (2-Amino—7- tert-butyl-7H-pyrrolo[2,3-d]pyrimidinyl)—(5-amino-pyridinyl)—methanone (see Preparation 65) and (4- cyclopropyl-pyrazoly|)-acetic acid to afford the title compound as a pale yellow solid in 16 % yield, 12 mg.LCMS m 10): R = 2.80 min; m/z 459 [M+H]+.

Example 578: N-[5-(2-Aminobicyclo[1.1.1]penty|-7H-pyrro|o[2,3-d]pyrimidinecarbonyl)—pyridin yl](5-fluoro-pyridiny|)-acetamide \ / O N \ \ H JL \ / H2N N N W0 2012/137089 123 To a solution of (5-amino-pyridinyl)-[7-bicyclo[1.1.1]penty|(4-methoxy-benzylamino)-7H- pyrrolo[2,3-d]pyrimidinyl]-methanone ration 287) (50 mg, 0.11 mmol) in THF (5 mL) at room temperature was added 5-fluoro neyl acetic acid (27 mg, 0.17 mmol), TEA (0.08 mL, 0.56 mmol) and 1-propylphosphonic acid cyclic ide (50% solution in EtOAc, 0.20 mL, 0.34 mmol). The resulting mixture was before stirred for 18 hours. The mixture was trated under reduced pressure and the residue was partitioned between saturated sodium bicarbonate solution (10 mL) and ethyl acetate (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 ature for 18 hours. The mixture was concentrated under d 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 ed by Preparative TLC (MeOH:DCM 5: 95) to afford the title compound as off white solid in 31% yield, 16 mg. 1H NMR (400 MHz, DMSO-d6) 6: 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, 1H), 8.96 (d, 1H), 10.67 (s, 1H); LCMS (System 10): R = 2.85 min; m/z 458 .

The following Examples were prepared according to the method described above for Example 578 starting from ((5-Amino-pyridinyl)-[7-bicyclo[1.1.1]pent—1-y|(4-methoxy-benzylamino)-7H-pyrrolo[2,3- d]pyrimidinyl]-methanone (Preparation 287) and the appropriate acid.

N-[5-(2-Aminobicyclo[1.1.1]pentyl-7H-pyrrolo[2,3- LCMS (System 10): Rt = 2.87 d]pyrimidinecarbonyl)—pyridinyl](3- min; m/z 517 [M+H]+. methanesulfonyl-phenyl)-acetamide LCMS (System 10): Rt = 2.92 N-[5-(2-Aminobicyclo[1.1.1]pentyl-7H-pyrrolo[2,3- min; m/z 497 [M+H]+. d]pyrimidinecarbonyl)—pyridinyl](3- trifluoromethyl-pyrazoly|)-acetamide N-[5-(2-Aminobicyclo[1.1.1]pentyl-7H-pyrrolo[2,3- LCMS (System 10): Rt = 2.89 d]pyrimidinecarbonyl)—pyridinyl](4- min; m/z 498 [M+H]+. trifluoromethyl-[1,2,3]triazoly|)-acetamide (Acid : Prep 81) LCMS (System 10): Rt = 2.94 N-[5-(2-Aminobicyclo[1.1.1]pentyl-7H-pyrrolo[2,3- min; m/z 464 [M+H]+. d]pyrimidinecarbonyl)-pyridinyl](4-cyano- phenyl)-acetamide LCMS m 9) : Rt = 6.28 2-Aminobicyclo[1.1.1]pentyl-7H-pyrrolo[2,3- min; m/z 474 [M+H]+. d]pyrimidinecarbonyl)—pyridinyl](5-chloro-pyridin- (ACid Prep 90) 2-yl)-acetamide Examples 584-5923 illustrate compounds of general formula : that fall into general formula (I) by virtue of pyridone tautomerism. 584 2-(4-cyanophenyl)-N-(2-oxo{[7-(propanyl)—7H-pyrrolo[2,3- LCMS Rt = 5.25 min; d]pyrimidinyl]carbonyl}-1,2-dihydropyridinyl)acetamide m/z 441 [M+H]+ 585 N-(2-oxo{[7-(propanyl)-7H-pyrrolo[2,3-d]pyrim idin y|]carbonyl}-1,2-dihydropyridinyl)—2-[2- LCMS Rt = 4.04 min; (trifluoromethoxy)phenoxy]acetamide m/z 516 [M+H]+ 586 2-(2-cyclopropyl-1 ,3-oxazolyl)-N-(2-oxo{[7-(propanyl)—7H- LCMS Rt = 3.39 min; o[2,3-d]pyrimidinyl]carbonyl}-1,2-dihydropyridin m/z 447 [M+H]+ l acetamide 587 2-[5-methyl(trifluoromethyl)-1H-pyrazolyl]-N-(2-oxo{[7- LCMS Rt = 3.51 min; nyl)—7H-pyrrolo[2,3-d]pyrimidinyl]carbonyl}-1,2- m/z 433 [M+H]+ dih drop ridin lacetamide 588 N-(2-oxo{[7-(propanyl)-7H-pyrrolo[2,3-d]pyrim idin LCMS Rt = 3.51 min; y|]carbonyl}-1,2-dihydropyridinyl)—2-(quinolinyl)acetamide m/z 435 [M+H]+ 589 2-(4-chlorophenyl)-N-(2-oxo{[7-(propanyl)—7H-pyrrolo[2,3- d]pyrimidinyl]carbonyl}-1,2-dihydropyridinyl)acetamide LCMS Rt = 3.82 min; m/z 450 [M+H]+ 590 2-(5-chloropyridinyl)-N-(2-oxo{[7-(propanyl)—7H- LCMS Rt = 3.22 min; o[2,3-d]pyrimidinyl]carbonyl}-1,2-dihydropyridin m/z 451 [M+H]+ l acetamide 591 N-(2-oxo{[7-(propanyl)-7H-pyrrolo[2,3-d]pyrimidin LCMS Rt = 3.31 min; y|]carbonyl}-1 ,2-dihydropyridinyl)[4-(trifluoromethyl)—1H- m/z 475 [M+H]+ 1,2,3-triazol |]acetamide 592 [2-Amino(2-hydroxy-1,1-dimethylethyl)—7H-pyrrolo[2,3- d]pyrimidinyl]carbonyl}oxo—pyridinyl)—2-(5-chloropyridin l acetamide 593 N-[5-({7-[(1S)—2-Hydroxy—1-methylethyl]—7H-pyrrolo[2,3- m/Z 500, RT 4.94 d]pyrimidinyl}carbonyl)—2-oxo—pyridinyl]—2-[4- trifluorometh Iphen |]acetamide Preparation 1: 7-[(1S)—2-{[tert—Butyl(dimethyl)silyl]oxy}methylethyl]—4-chloro-7H-pyrrolo[2,3- d]pyrimidine (S)—2-tert—Butyldimethylsilyloxy—1-methylethylamine (120 g, 636 mmol) was added to (4,6- dichloropyrimidinyl)acetaldehyde (52.8 g, 276 mmol) in ethanol (500 mL). The mixture was heated to W0 2012/137089 125 reflux for 45 minutes. The reaction mixture was evaporated in vacuo then the residue was diluted with water (400 mL) and ted with ethyl acetate (600 mL). The organic extract was evaporated in vacuo and the crude material was purified by column tography 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) 5: -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).

Preparation 2: 7-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)chloro-7H-pyrrolo[2,3-d]pyrimidine The title compound was prepared ing to the method described for Preparation 1 using (4,6- dichloropyrimidinyl)acetaldehyde and 1-{[tert-butyl(dimethyl)silyl]oxy}methylpropanamine to afford the title nd as a yellow oil in 38% yield, 377 mg. 1H NMR (400 MHz, CDCI3) 6: 0.00 (s, 6H), 0.94 (s, 9H), 1.97 (s, 6H), 4.28 (s, 2H), 6.78 (d, 1H), 7.66 (d, 1H), 8.83 (s, 1H).

Preparation 3: (2R)—2-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidinyl)propano| ”C ' \ \N N Ho\)'"lVIe The title compound was prepared according to the method described for Preparation 1 using (4,6- dichloropyrimidinyl)acetaldehyde and (R)—2-aminopropanol to afford the title compound as a yellow solid in 100% yield, 11.12 g.

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

Preparation DL3: (R,S) 7-[2-{[tert-Butyl(dimethyl)silyl]oxy}methylethyl]-4—chloro-7H-pyrrolo[2,3- d]pyrimidine W0 2012/137089 126 The title compound was prepared according to the method described for Preparation 1 using (4,6- dichloropyrimidinyl)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) 6: -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).

Preparation 4: (2S)—2-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidinyl)propano| ”C I \ \N N Ho\)‘lVIe The title compound was prepared according to the method described for Preparation 1 using (4,6- dichloropyrimidinyl)acetaldehyde and (S)—2-amino—1-propanol to afford the title nd as a cream solid in 98% yield, 10.9 g. 1H NMR (400 MHz, DMSO-D6) 6: 1.42 (d, 3H), 3.72 (m, 2H), 4.89 (m, 1H), 6.63 (d, 1H), 7.83 (d, 1H), 8.59 (s, 1H).

Preparation 5: 7-tert-Butylchloro-7H-pyrrolo[2,3-d]pyrimidine k\N | )VMe Me Me The title compound was ed according to the method described for Preparation 1 using (4,6- dichloropyrimidinyl)acetaldehyde and tert—butylamine to afford the title compound as a yellow liquid in 77% yield, 1.61 g. 1H NMR (400 MHz, 6) 6: 1.75 (s, 9H), 6.60 (d, 1H), 7.79 (d, 1H), 8.63 (s, 1H).

Preparation 6: 4-Chloro—7-[(1R)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]—7H-pyrrolo[2,3- midine ”C I \ \N N 2,3-Dihydropyran (25.0 mL, 270 mmol) was added to (2R)—2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin yl)propanol (11.00 g, 51.97 mmol) (see Preparation 3) and pyridinium toluenesulphonate (3.92 g, W0 2012/137089 127 .6 mmol) in DCM (150 mL). The reaction mixture was washed with water (200 mL) and the aqueous phase was extracted with DCM (2 x 150 mL). The combined c phases were dried over magnesium sulfate and evaporated in vacuo. The crude material was ed by column chromatography on silica gel (gradient of heptane:EtOAc 100:0 to 70:30) to afford the title nd as a yellow oil in 100% yield, .65 g.

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

Preparation 7: 4-Chloro[(1S)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3- d]pyrimidine ”C I \ \N N The title compound was prepared according to the method described for Preparation 6 using (2S)—2-(4- -7H-pyrrolo[2,3-d]pyrimidinyl)propano| (see Preparation 4) to afford the title compound as a yellow oil in 87% yield, 11.5 g. 1H NMR (400 MHz, CDCI3) 6: 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, 1H), 8.61 (s, 1H).

Preparation 8: 7-[(1S)—2-{[tert—Butyl(dimethyl)silyl]oxy}methylethyl]-7H-pyrrolo[2,3-d]pyrimidine Palladium (10% on carbon, 18 g) was added to 7-[(1S)—2-{[tert—butyl(dimethyl)silyl]oxy}methylethyl] chloro-7H-pyrrolo[2,3-d]pyrimidine (182 g, 558 mmol) (see Preparation 1) in ethanol (900 mL) and concentrated ammonia solution (100 mL) and hydrogenated (60 psi, 20°C) for 18 hours. The reaction mixture was filtered through ArbocelTM 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 title compound as an orange oil in 94% yield, 162.7 g. 1H NMR (400 MHz, CDCI3) 6: -0.90 (s, 3H), 0.80 (s, 9H), 1.58 (d, 3H), 3.86 (m, 2H), 5.06 (m, 1H), 6.53 (d, 1H), 7.40 (d, 1H), 8.83 (s, 1H), 8.96 (s, 1H).

W0 37089 128 Preparation 9: 7-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidine The title nd was prepared according to the method described for Preparation 8 using 7-(2-{[tert- butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)chloro-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 2) to afford the title compound as a white solid in 97% yield, 327 mg. 1H NMR (400 MHz, CDCI3) 6: 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, 1H), 9.21 (s,1H).

Preparation 10: (R,S) 7-(2-{[tert-Butyl(dimethyl)silyl]oxy}methylethyl)-7H-pyrrolo[2,3-d]pyrimidine The title compound was prepared according to the method described for Preparation 8 using (R,S) 7-(2- {[tert—butyl(dimethyl)silyl]oxy}methylethyl)chloro-7H-pyrrolo[2,3-d]pyrimidine (see Preparation DL3) to afford the title compound as a brown liquid in 78% yield, 1.12 g. 1H NMR (400 MHz, DMSO-D6) 6: 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).

Preparation 11: 7-[(1R)—1-Methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine ”C I \ OJ'HIMe The title compound was ed according to the method described for Preparation 8 using 4-chloro [(1R)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 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+H]+.

W0 2012/137089 129 Preparation 12: 7-[(1S)—1-Methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine ' \ KN N O\)‘Me The title compound was prepared according to the method described for Preparation 8 using ro [(1S)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (see ation 7) to afford the title compound as a colourless oil in 90% yield, 9.18 g. 1H NMR (400 MHz, coc13) 5: 1.44-1.69 (m, 9H), 3.42 (m, 1H), 3.57 (m, 1H), 3.69 (m, 1H), 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).

Preparation 13: 7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidine Me Me The title compound was prepared according to the method described for ation 8 using 7-tert-butyl- 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 5) to afford the title compound as a yellow liquid in 94% yield, 1.27 g. 1H 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).

Preparation 14: 7-[(1S)—2-{[tert—Butyl(dimethyl)silyl]oxy}methylethyl]iodo-7H-pyrrolo[2,3-d]pyrimidine N-lodosuccinimide (124 g, 553 mmol) was added to )—2-{[tert—butyl(dimethyl)silyl]oxy} methylethyl]-7H-pyrrolo[2,3-d]pyrimidine (153.4 g, 526 mmol) (see Preparation 8) in acetonitrile (700 mL).

The e was stirred at room temperature 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 magnesium 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. 1H NMR (400 MHz, CDCI3) 6: -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).

W0 2012/137089 130 Preparation 15: 7-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)iodo-7H-pyrrolo[2,3-d]pyrimidine The title compound was prepared according to the method described for Preparation 14 using 7-(2-{[tert- dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 9) to afford the title compound as a brown oil in 59% yield, 270 mg. 1H NMR (400 MHz, CDCI3) 6: 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).

Preparation 16: (R,S) [tert-Butyl(dimethyl)silyl]oxy}methylethyl)iodo-7H-pyrrolo[2,3- d]pyrimidine The title compound was prepared according to the method described for Preparation 14 using (R,S) 7-(2- {[tert—butyl(dimethyl)silyl]oxy}methylethyl)-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 10) to afford the title compound as a yellow liquid in 74% yield, 1.18 g.

LCMS (system 1): R = 4.03 min; m/z 418 [M+H]+.

Preparation 17: 5-lodo[(1R)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3- d]pyrimidine The title compound was prepared according to the method described for ation 14 using 7-[(1R)—1- methyl(tetrahydro-2H-pyranyloxy)ethyl]—7H-pyrrolo[2,3-d]pyrimidine (see Preparation 11) to afford the title compound as a brown oil in 34% yield, 7.50 g. 1H NMR (400 MHz, CDCI3) 6: 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).

W0 2012/137089 131 Preparation 18: 5-lodo[(1S)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3- d]pyrimidine The title compound was prepared according to the method described for Preparation 14 using 7-[(1S)—1- methyl(tetrahydro-2H-pyranyloxy)ethyl]—7H-pyrrolo[2,3-d]pyrimidine (see Preparation 12) to afford the title compound as a brown oil in 71% yield, 9.68 g. 1H NMR (400 MHz, CDCI3) 6: 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, 1H), 5.24 (m, 1H), 7.51 (s, 1H), 8.76 (s, 1H), 8.89 (s, 1H). ation 19: 7-tert-Butyliodo-7H-pyrrolo[2,3-d]pyrimidine Me The title compound was prepared according to the method described for Preparation 14 using 7-tert- butyl-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 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 .

Preparation 20: (R,S) Methyl 2-(5-iodo-7H-pyrrolo[2,3-d]pyrimidinyl)propanoate KN N Me>\’(OO Methylbromopropionate (6.83 mL, 61.2 mmol) was added to a mixture of -7H-pyrrolo[2,3- d]pyrimidine (15.0 g, 61.0 mmol) and cesium carbonate (35.9 g, 110.0 mmol) in DMF (75 mL). The mixture was stirred at room temperature for 4 hours. The reaction mixture was d with water (250 mL) and extracted with diethyl ether (100 mL). The organic layer was washed with brine (70 mL), dried over magnesium sulfate and ated in vacuo to afford the title compound as an off-white solid in 83% yield, 16.87 g. 1H NMR (400 MHz, CDCI3) 6: 1.82 (d, 3H), 3.76 (s, 3H), 5.72 (q, 1H), 7.48 (s, 1H), 8.76 (s, 1H), 8.89 (s, 1H).

W0 2012/137089 132 Preparation 21: Methyl 2-(5-iodo-7H-pyrrolo[2,3-d]pyrimidinyl)methylpropanoate Potassium t—butoxide (71.3 mL, 71.3 mmol, 1.0 M in THF) was added to (R,S) methyl 2-(5-iodo-7H- pyrrolo[2,3-d]pyrimidinyl)propanoate (16.9 g, 50.9 mmol) (see Preparation 20) and iodomethane (4.44 mL, 71.3 mmol) in THF (100 mL). The mixture was stirred at room temperature for 15 s then water (20 mL) and aqueous HCI (0.3 mL, 2M) was added. THF was d by evaporation in vacuo then the aqueous residue was extracted with EtOAc (250 mL). The organic phase was dried over magnesium sulfate and evaporated in vacuo. The crude solid was purified by column chromatography on silica gel (80:20 pentane:EtOAc) to afford the title nd as a white solid in 51% yield, 8.92 g. 1H NMR (400 MHz, CDCI3) 6: 1.93 (s, 6H), 3.68 (s, 3H), 7.43 (s, 1H), 8.75 (s, 1H), 8.85 (s, 1H).

Preparation 22: 2-(5-lodo-7H-pyrrolo[2,3-d]pyrimidinyl)methylpropanol Lithium borohydride (32.3 mL, 64.6 mmol, 2.0 M in THF) was added to methyl 2-(5-iodo-7H-pyrrolo[2,3- d]pyrimidinyl)methylpropanoate (8.92 g, 25.9 mmol) (see ation 21) in ethanol (70 mL). The mixture was stirred at room temperature 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 ium e 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) 6: 1.65 (s, 6H), 3.16 (d, 2H), 7.77 (s, 1H), 8.67 (s, 1H), 8.80 (s, 1H).

Preparation 23: 5-[(Diphenylmethylene)amino]-N-methoxy—N-methylnicotinamide N/l \ Me\l?l 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-butylphosphino— W0 2012/137089 133 2012/051363 2',4',6'-triisopropylbiphenyl (34.7 g, 82.0 mmol) and freshly ground ium phosphate tribasic (541 g, 2.55 mol) in 1,2-dimethoxyethane (2500 mL). The mixture was stirred at 50°C for 17 hours. The reaction mixture was filtered h ArbocelTM 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) 6: 3.19 (s, 3H), 3.37 (s, 3H), .23 (m, 2H), 7.29 (m, 1H), 7.32-7.39 (m, 3H), 7.46-7.53 (m, 2H), 7.57 (m, 1H), 7.67-7.73 (m, 2H), 8.09 (d, 1H), 8.27 (d, 1H).

Preparation 24: {7-[(1S)—2-{[tert—Butyl(dimethyl)silyl]oxy}methylethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}{5- [(diphenylmethylene)amino]pyridinyl}methanone lsopropyl magnesium chloride (68.8 mL, 138 mmol, 2.0 M in THF) was added to 7-[(1S)—2-{[tert— butyl(dimethyl)silyl]oxy}methylethyl]iodo-7H-pyrrolo[2,3-d]pyrimidine (52.2 g, 125 mmol) (see Preparation 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 Preparation 23) in THF (100 mL) was added dropwise at 0°C. The mixture was warmed to room temperature and stirred at this temperature 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 tography on silica gel (gradient of EtOAc:pentane 10:90 to 60:40) to afford the title nd as a less gum in 88% yield, 63.2 g.

R = 7.94 min; m/z 576 [M+H]+.

Preparation 25: [7-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]{5- [(diphenylmethylene)amino]pyridinyl}methanone W0 2012/137089 134 2012/051363 The title compound was prepared according to the method described for Preparation 24 using 7-(2-{[tert- butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)iodo-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 15) and -[(diphenylmethylene)amino]-N-methoxy—N-methylnicotinamide (see Preparation 23) to afford the title compound as a colourless gum in 56% yield, 1.49 g. 1H NMR (400 MHz, CDCI3) 6: 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, 1H), 7.79 (d, 2H), 7.89 (s, 1H), 8.18 (d, 1H), 8.58 (d, 1H), 9.01 (s, 1H), 9.60 (s, 1H).

Preparation 26: (5-Bromopyridinyl){7-[(1R)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]—7H- pyrrolo[2,3-d]pyrimidinyl}methanone The title compound was prepared according to the method described for Preparation 24 using 5-iodo [(1R)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 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]+.

Preparation 27: (5-Bromopyridinyl){7-[(1S)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H- pyrrolo[2,3-d]pyrimidinyl}methanone N/ Br KN I \ of'v'e The title nd was prepared ing to the method described for Preparation 24 using 5-iodo [(1S)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (see ation 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+H]+.

Preparation 28: (R,S) {7-[2-{[tert—Butyl(dimethyl)silyl]oxy}methylethyl]-7H-pyrrolo[2,3-d]pyrimidin yl}{5-[(diphenylmethylene)amino]pyridinyl}methanone W0 2012/137089 135 nButyllithium (0.57 mL, 1.31 mmol, 2.3 M in s) was added to (R,S) 7-(2-{[tert— butyl(dimethyl)silyl]oxy}methylethyl)iodo-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.19 mmol) (see Preparation 16) in dry ether (20 mL) at -78°C and the reaction mixture was stirred for 30 minutes. Then -[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (372 mg, 1.07 mmol) (see Preparation 23) in dry ether (25mL) was added drop wise at the same temperature. After 15 s the mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (70 mL).

The organic t 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 = 4.53 min; m/z 576 [M+H]+.

Preparation 29: (R,S) (5-Bromopyridinyl)(7-tert-butyl-7H—pyrrolo[2,3-d]pyrimidinyl)methanol l \ Me Me The title compound was prepared according to the method bed for Preparation 28 using 7-tert- butyliodo-7H-pyrrolo[2,3-d]pyrimidine (see ation 19) and 5-bromo—pyridinecarbaldehyde 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]+.

Preparation 30: (5-Bromopyridinyl)(7-tert—butyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone W0 2012/137089 136 2-lodoxybenzoic acid (909 mg, 3.25 mmol) was added to (R,S) (5-bromopyridinyl)(7-tert-butyl-7H- pyrrolo[2,3-d]pyrimidinyl)methanol (405 mg, 1.34 mmol) (see Preparation 29) in ethyl e (30mL) and the mixture was refluxed for 4 hours. The mixture was filtered and the filtrate was ated in vacuo to afford the title compound as a white solid in 95% yield, 554 mg.

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

Preparation 31: (5-Aminopyridinyl)(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone K | N Me Me Copper sulfate pentahydrate (55 mg, 0.24 mmol) was added to (5-bromopyridinyl)(7-tert-butyl-7H- pyrrolo[2,3-d]pyrimidinyl)methanone (292 mg, 0.81 mmol) (see Preparation 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 temperature for 17 hours. The reaction mixture was basified to pH 9 using ted s sodium carbonate then extracted with DCM (3 x 20 mL). The combined organic ts were dried over magnesium sulfate and evaporated in vacuo to afford the title compound as a white solid in 49% yield, 240 mg.

LCMS (System 4): R, = 2.68 min; m/z 296 [M+H]+. ation 32: (5-Aminopyridinyl){7—[(1S)—2-hydroxymethylethyl]-7H-pyrrolo[2,3-d]pyrimidin yl}methanone The title compound was prepared according to the method described for Preparation 31 using (5- bromopyridinyl){7-[(1S)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]—7H-pyrrolo[2,3-d]pyrimidin yl}methanone (see Preparation 27) to afford the title compound as a white solid in 10% yield, 134 mg.

LCMS (system 2): R, = 0.59 min; m/z 298 [M+H]+.

W0 2012/137089 137 Preparation 33: (5-Aminopyridinyl){7-[(1S)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H- pyrrolo[2,3-d]pyrimidinyl}methanone N/ NH2 KN ' \ O\)‘Me Benzophenone imine (0.40 mL, 2.4 mmol) was added to (5-bromopyridinyl){7-[(1S)—1-methyl (tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}methanone (891 mg, 2.0 mmol) (see Preparation 27), tris(dibenzylideneacetone)dipalladium (55 mg, 0.06 mmol), 2-di-tert—butylphosphino- 2',4',6'-triisopropylbiphenyl (68 mg, 0.16 mmol) and freshly ground potassium phosphate tribasic (1.06 g, .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 ArbocelTM 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 ature for 16 hours. Water (40 mL) was added then sodium hydroxide was added to basify the mixture. The e was extracted with EtOAc (3 x 40 mL) and the combined c extracts were dried over magnesium sulfate and evaporated in vacuo. The e was purified by column chromatography on silica gel ent 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 = 3.27 min; m/z 382 [M+H]+.

Preparation 34: 2-(2H-Benzotriazolyl)-N-[5-({7-[(1S)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]- 7H-pyrrolo[2,3-d]pyrimidinyl}carbonyl)pyridinyl]acetamide The title compound was prepared according to the method described for Example 1 using (5- aminopyridinyl){7-[(1S)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin yl}methanone (see Preparation 33) and benzotriazolyl-acetic acid to afford the title compound as a yellow solid in 72% yield, 70 mg.

LCMS (system 5): R = n, m/z 541 [M+H]+.

Preparation 35: 2-(2,4-Difluorophenyl)—N-[5-({7-[(1S)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H- pyrrolo[2,3-d]pyrimidin-5—yl}carbonyl)pyridinyl]acetamide W0 2012/137089 138 The title compound was prepared according to the method bed for Example 1 using (5- aminopyridinyl){7-[(1S)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin y|}methanone (see Preparation 33) and 2,5-difluorophenylacetic acid to afford the title compound as a yellow solid in 75% yield, 75 mg.

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

Preparation 36: (5-Aminopyridinyl){7-[(1R)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H- pyrrolo[2,3-d]pyrimidinyl}methanone Copper (l) oxide (9.2 mg, 0.06 mmol) was added to (5-bromopyridinyl){7-[(1R)—1-methyl(tetrahydro- 2H-pyranyloxy)ethyl]—7H-pyrrolo[2,3-d]pyrimidinyl}methanone (285 mg, 0.64 mmol) (see Preparation 26) and trated ammonia solution (2 mL) in 1-methylpyrrolidinone (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 magnesium e 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 m 2): R = 0.78 min; m/z 382 [M+H]+.

Preparation 37: (5-Aminopyridinyl){7-[(1S)—2-{[tert—butyl(dimethyl)silyl]oxy}methylethyl]-7H- pyrrolo[2,3-d]pyrimidinyl}methanone W0 2012/137089 139 2012/051363 s citric acid (120 mL, 2.0 M) was added to {7-[(1S)—2-{[tert—butyl(dimethyl)silyl]oxy}methylethyl]- 7H-pyrrolo[2,3-d]pyrimidinyl}{5-[(diphenylmethylene)amino]pyridinyl}methanone (63.2 g, 110 mmol) (see Preparation 24) in THF (274 mL) and the mixture was stirred at room temperature for 17 hours. The mixture was cooled to 0°C, water (200 mL) added and the e was basified using sodium hydroxide (28 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 title compound as a semi-solid in tative yield, 45.2 g.

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

Preparation 38: (5-Aminopyridinyl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H- pyrrolo[2,3-d]pyrim idinyl]methanone N/ NH2 l \ Me“aMeO Me‘sf—Me lVIe‘é‘Me The title compound was prepared according to the method described for Preparation 37 using [7-(2-{[tert- butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]{5- [(diphenylmethylene)amino]pyridinyl}methanone (see Preparation 25) to afford the title compound as a white solid in 81% yield, 872 mg. 1H NMR (400 MHz, DMSO-d6) 6: 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).

W0 2012/137089 140 Preparation 39: (R,S) (5-Aminopyridinyl){7-[2-{[tert-butyl(dimethyl)silyl]oxy}methylethyl]-7H- pyrrolo[2,3-d]pyrimidinyl}metha none N/ NH2 I \ MeNH Me\s{—Me M9+Me The title nd was prepared according to the method described for Preparation 37 using (R,S) {7- ert-butyl(dimethyl)silyl]oxy}methylethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}{5- [(diphenylmethylene)amino]pyridinyl}methanone (see Preparation 28) to afford the title compound as a white solid in 89% yield, 86 mg.

LCMS (System 4): R =1.37 min; m/z 412 .

Preparation 40: 2-Chloroiodo-7H—pyrrolo[2,3-d]pyrimidine CI N N H N-lodosuccinimide (742 g, 3.30 mol) was added to 2-chloro-7H—pyrrolo[2,3-d]pyrimidine (482.5 g, 3.14 mol) in acetonitrile (2500 mL) at 12°C. The mixture was stirred at room temperature 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. 1H NMR (400 MHz, DMSO-D6)6: 7.83 (s, 1H), 8.63 (s, 1H), 12.73 (s, 1H).

Preparation 41: Methyl 2-(2-chloro—5-iodo-7H-pyrrolo[2,3-d]pyrimidinyl)methylpropanoate Methyl 2-bromomethylpropanoate (663 mL, 5.13 mmol) was added to 2-chloroiodo-7H—pyrrolo[2,3- d]pyrimidine (358.1 g, 1.28 mol) (see Preparation 40), potassium iodide (21.3 g, 128 mmol) and cesium carbonate (1670 g, 5.13 mol) in DMF (7162 mL). The e was heated at 60°C for 19 hours. The reaction mixture was diluted with water (7000 mL) and stirred at room temperature 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.

W0 2012/137089 141 1H NMR (400 MHz, coc13) 6: 1.89 (s, 6H), 3.65 (s, 3H), 7.39 (s, 1H), 8.56 (s, 1H).

Preparation 42: 2-(2-Chloro—5-iodo-7H-pyrrolo[2,3-d]pyrimidinyl)methylpropanoic acid Lithium hydroxide monohydrate (4.08 g, 97.5 mmol) was added to methyl 2-(2-chloroiodo-7H- pyrrolo[2,3-d]pyrimidinyl)methylpropanoate (18.5 g, 48.7 mmol) (see Preparation 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 evaporation in vacuo. The aqueous residue was acidified using aqueous HCI (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: 2.24 min; m/z 366 [M+H]+.

Preparation 43: 2-(2-Chloroiodo-7H-pyrrolo[2,3-d]pyrimidinyl)methylpropanol Cl N MeMeOH Route a lsobutyl formate (6.6 mL, 50.02 mmol) was added to hloro—5-iodo-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)methylpropanoic acid (16.6 g, 45.48 mmol) (see Preparation 42) and triethylamine (12.64 mL, 90.9 mmol) in THF (300 mL) at 0°C under en. The mixture was stirred at room temperature for 3 hours then filtered through a short plug of Celite TM. 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 ated with hexane to afford the title nd as a white solid in 63% yield, 10.0 g. 1H NMR (400 MHz, DMSO-Dg) 6: 1.64 (s, 6H), 3.85 (d, 2H), 4.99 (t, 1H), 7.82 (s, 1H), 8.63 (s, 1H).

W0 2012/137089 142 Route b Diisobutylaluminium hydride (300 mL, 300 mmol, 1M in THF) was added dropwise to methyl 2-(2-chloro- -iodo-7H-pyrrolo[2,3-d]pyrimidinyl)methylpropanoate (51.8 g, 136 mmol) (see Preparation 41) in THF (150 mL) at 0°C. The mixture was stirred for 90 minutes then methanol (27.9 mL) and aqueous HCI (20 mL, 2M) was added. Water (100 mL), aqueous HCI (280 mL, 2M) and EtOAc (150 mL) were added and the mixture was stirred at room temperature 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: 4.88 min; m/z 352 [M+H]+. ation 44: 7-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)chloroiodo-7H-pyrrolo[2,3- d]pyrimidine t—Butyldimethylsilyl chloride (78.8 g, 518 mmol) was added to 2-(2-chloroiodo-7H-pyrrolo[2,3- d]pyrimidinyl)methylpropano| (140 g, 398 mmol) (see Preparation 43) and imidazole (67.8 g, 996 mmol) in DMF (996 mL) at 0°C. The mixture was stirred at room temperature 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 magnesium e and ated in vacuo to afford the title nd as a brown gum in 96% yield, 178.2 g.

LCMS (System 1) R: 8.32 min; m/z 466 [M+H]+.

Preparation 45: 2-Chloro—7-[1,1-dimethyl(tetrahydro-2H-pyranyloxy)ethyl]iodo-7H-pyrrolo[2,3- d]pyrimidine CIkN | N MemeO The title compound was prepared according to the method described for Preparation 6 using 2-(2-chloro- 5-iodo-7H-pyrrolo[2,3-d]pyrimidinyl)methylpropano| (see ation 43) to afford the title nd as a yellow oil in 74% yield, 7.3 g.

LCMS (system 5) R: 4.01 min; m/z 436 [M+H]+.

W0 2012/137089 143 Preparation 46: (5-Bromopyridinyl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)—2-chloro-7H- pyrrolo[2,3-d]pyrim idinyl] methanone Cl N ‘ Me Me/ISI—K Me Me Me The title compound was prepared according to the method described for Preparation 28 using 7-(2-{[tert- butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)chloro—5-iodo-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 44) and 5-bromo-N-methoxy—N-methylnicotinamide to afford the title nd as a yellow solid in 42% yield, 1.40 g. 1H NMR (400 MHz, CDCI3) 6: -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, 1H), 8.95 (s, 1H), 8.99 (d, 1H), 9.36 (s, 1H). ation 47: (5-Bromopyridinyl){2-chloro[1,1-dimethyl(tetrahydro-2H-pyranyloxy)ethyl]-7H- o[2,3-d]pyrimidin-5—yl}methanone The title compound was prepared according to the method described for Preparation 28 using 2-chloro [1,1-dimethyl(tetrahydro-2H-pyranyloxy)ethyl]iodo-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 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) 6: 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).

Preparation 48: [2-Amino—7-(2-hydroxy-1,1-dimethylethyl)—7H-pyrrolo[2,3-d]pyrimidinyl](5- aminopyridinyl)methanone N/ NHZ | \ H2N)\\N N MeweOH The title compound was prepared according to the method described for Preparation 36 W0 2012/137089 144 using (5-bromopyridinyl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)chloro-7H-pyrrolo[2,3- midinyl]methanone (see Preparation 46) to afford the title compound as a yellow solid in 48% yield, 300 mg. 1H NMR (400 MHz, DMSO-D6) 6: 1.64 (s, 6H), 3.90 (d, 2H), 5.07 (t, 1H), 5.60 (s, 2H), 6.50 (s, 2H), 7.23 (s, 1H), 7.61 (s, 1H), 8.11 (m, 2H), 8.93 (s, 1H). [7-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1 ,1-dimethylethyl)amino-7H-pyrrolo[2,3-d]pyrimidinyl]{5- aminopyridinyl}methanone (Preparation 48a) was also ed from the reaction mixture. 1H NMR (400 MHz, DMSO) 6: -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, 1H), 7.57 (s, 1H), 8.07 (s, 1H), 8.10 (s, 1H), 8.93 (s, 1H).

Preparation 49: {2-Amino[1,1-dimethyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3- d]pyrimidinyl}(5-aminopyridinyl)methanone N/ NHZ | \ H2NJ§N N MeweO The title compound was prepared according to the method described for Preparation 36 using (5-bromopyridinyl){2-chloro[1,1-dimethyl(tetrahydro-2H-pyranyloxy)ethyl]—7H-pyrrolo[2,3- d]pyrimidinyl}methanone (see Preparation 47) to afford the title compound as a yellow solid in 52% yield, 1.3 g.

LCMS (system 5) R: 2.72 min; m/z 411 .

Preparation 50: [7-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)chloro-7H-pyrrolo[2,3- d]pyrimidinyl]{5-[(diphenylmethylene)amino]pyridinyl}methanone I \ C'AN\ O MeN):Me0‘ Me/ISI+ Me Me Me pyl magnesium chloride (105 mL, 210 mmol, 2.0 M in THF) was added to 7-(2-{[tert- butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)chloroiodo-7H-pyrrolo[2,3-d]pyrimidine (89.0 g, 190 mmol) (see Preparation 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) W0 2012/137089 145 (see Preparation 23) in THF (200 mL) was added dropwise at 0°C. The mixture was warmed to room temperature and stirred at this temperature for 16 hours. The on mixture was quenched with 10% aqueous um chloride (500 mL) and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (2 x 300 mL). The combined organic extracts were washed with brine (400 mL), dried over sodium e, evaporated in vacuo and the crude al was purified by column chromatography on silica gel ent 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: 8.60 min; m/z 624 [M+H]+.

Preparation 51: (5-Aminopyridinyl){7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)[(2,4- oxybenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidinyl}methanone Me\O/©:O\HJ%N/|Me>§——O Me |e Me/ISi—K Me Me Me 2,4-Dimethoxybenzylamine (99.4 g, 594 mmol) was added to [7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1- dimethylethyl)chloro-7H-pyrrolo[2,3-d]pyrimidinyl]{5-[(diphenylmethylene)amino]pyridin yl}methanone (53.0 g, 85 mmol) (see Preparation 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 temperature 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 magnesium sulfate and evaporated in vacuo.

The crude e was dissolved in THF (200 mL) and aqueous citric acid (200 mL, 2M) was added. The mixture was stirred at room temperature 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 c phase was dried over magnesium 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 less oil in 78% yield, 39.0 g.

LCMS (System 1) R: 5.97 min; m/z 591 [M+H]+.

Preparation 52: N-[5-({2-Amino[1,1-dimethyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3- d]pyrimidinyl}carbonyl)pyridinyl]—2-(4-cyclopropyl-1H-1,2,3-triazolyl)acetamide W0 2012/137089 146 2012/051363 The title compound was prepared according to the method described for Example 1 using {2-amino [1 ,1-dimethyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}(5-aminopyridin y|)methanone (see Preparation 49) and (4-cyclopropyl-1H-1,2,3-triazolyl)acetic acid (see Preparation 83) to afford the title compound as a yellow solid in 86% yield, 70 mg.

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

Preparation 53: (R,S) Methyl 2-(2-chloroiodo-7H-pyrrolo[2,3-d]pyrimidinyl)propanoate CI N H0 Me The title compound was prepared according to the method described for Preparation 20 using 2-chloro iodo-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 40) to afford the title compound as a brown solid in 62% yield, 18.0 g. 1H NMR (400 MHz, CDCI3) 6: 1.77 (d, 3H), 3.75 (s, 3H), 5.67 (q, 1H), 7.46 (s, 1H), 8.58 (s, 1H).

Preparation 54: (R,S) 2-(2-Chloroiodo-7H—pyrrolo[2,3-d]pyrimidinyl)propano| The title nd was prepared according to the method described for Preparation 22 using (R,S) methyl 2-(2-chloroiodo-7H-pyrrolo[2,3-d]pyrimidinyl)propanoate (see Preparation 53) to afford the title nd as a yellow solid in 75% yield, 11.0 g. 1H NMR (400 MHz, DMSO-D6) 6: 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).

W0 2012/137089 147 Preparation 55: 7-(2-{[tert-Butyl(dimethyl)silyl]oxy}methylethyl)chloroiodo—7H-pyrrolo[2,3- d]pyrimidine The title compound was prepared ing to the method described for Preparation 44 using 2-(2- chloro—5—iodo-7H—pyrrolo[2,3-d]pyrimidinyl)propanol (see Preparation 54) to afford the title compound as a yellow solid in 89% yield, 12.50 g. 1H NMR (400 MHz, CDCI3) 6: -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:lPA:diethylamine (flow rate — 18.0 ute).

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) Preparation 56: (5-Bromopyridinyl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}methylethyl)chloro-7H- pyrrolo[2,3-d]pyrimidinyl]methanone (enantiomer 1) >\\ Me 0‘81 The title compound was ed according to the method described for Preparation 28 using [tert- butyl(dimethyl)silyl]oxy}methylethyl)chloroiodo-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 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) 6: -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).

W0 2012/137089 148 Preparation 57: [2-Amino—7-(2-hydroxy—1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5—yl](5-aminopyridin y|)methanone (enantiomer 1) 1" \ 2 H2N \N N)\\ The title compound was ed ing to the method described for Preparation 36 using (5-bromopyridinyl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}methylethyl)chloro-7H-pyrrolo[2,3- d]pyrimidinyl]methanone (see Preparation 56) to afford the title compound as a yellow solid in 51% yield, 450 mg. 1H NMR (400 MHz, DMSO-D6) 6: 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 = 1.72 min; m/z 313 [M+H]+.

Preparation 58 : (5-Bromopyridinyl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}methylethyl)chloro-7H- pyrrolo[2,3-d]pyrimidinyl]methanone (enantiomer 2) o \ / I' \ CI \N N)\\ Me ,M9 O‘ISi Me lVIe>4Me The title compound was prepared ing to the method described for Preparation 28 using 7-(2-{[tert- butyl(dimethyl)silyl]oxy}methylethyl)chloroiodo-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 55, enantiomer 2) and 5-bromo-N-methoxy—N-methylnicotinamide to afford the title compound as a yellow solid in 30% yield, 1.4 g. 1H NMR (400 MHz, DMSO-D6) 6: -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).

W0 2012/137089 149 Preparation 59: [2-Amino—7-(2-hydroxymethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5—yl](5-aminopyridin hanone (enantiomer 2) H2N \N N)\\ The title compound was prepared according to the method described for Preparation 36 using (5-bromopyridinyl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}methylethyl)chloro-7H-pyrrolo[2,3- d]pyrimidinyl]methanone (see Preparation 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]+.

Preparation 60: 5-Bromo-N-tert—butylchloropyrimidinamine kN%/|VI\BFN Me Cl N Me)LMe utylamine (5.28 g, 72 mmol) was added to o-2,4-dichloropyrimidine (15 g, 66 mmol) and triethylamine (19.9 g, 197 mmol) in acetonitrile (450 mL) at room temperature and the mixture was stirred at room temperature 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 c 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 = 3.46 min; m/z 265 [M+H]+.

Preparation 61: N-tert—Butylchloro[(E)ethoxyvinyl]pyrimidinamine ANNf/OV\ NH Cl Me 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 d for 2 hours at room temperature then heated at 70°C for 2 hours. The e was then cooled to room temperature and a solution of 5-bromo-N-tert—butylchloropyrimidinamine (10 g, 37.8 mmol) (see Preparation 60) in THF (50 mL) was added. The solution was degassed with argon for about 25 minutes W0 2012/137089 150 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 temperature. EtOAc (200 mL) was added and the e was filtered through a CeliteTM 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 90:10) to afford the title compound as a yellow oil in 55% yield, 5.3 g.

LCMS m 5): R = 3.65 min; m/z 256 [M+H]+. ation 62: 7-tert-Butylchloro-7H-pyrrolo[2,3-d]pyrimidine C|)\\N N Me'é‘Me Concentrated HCI (25 mL) was added to N-tert—butyl-2—chloro[(E)ethoxyvinyl]pyrimidinamine (5.3 g, 20.72 mmol) (see Preparation 61) in panol (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 title nd as a yellow oil in 85% yield, 3.7 g.

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

Preparation 63: 7-tert-Butylchloroiodo-7H—pyrrolo[2,3-d]pyrimidine Ax N CI N M99\Me The title compound was ed according to the method described for Preparation 14 using 7-tert- butylchloro-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 62) to afford the title compound as a brown solid in 87% yield, 4.7 g. 1H NMR (400 MHz, CDCI3) 6: 1.55 (s, 9H), 7.39 (s, 1H), 8.54 (s, 1H).

Preparation 64: (5-Bromopyridinyl)(7-tert-butylchloro-7H-pyrrolo[2,3-d]pyrimidinyl)methanone W0 2012/137089 151 The title compound was prepared according to the method described for Preparation 28 using 7-tert- butylchloroiodo-7H-pyrrolo[2,3-d]pyrimidine (see ation 63) and 5-bromo-N-methoxy—N- methylnicotinamide to afford the title compound as a brown oil in 36% yield, 2.1 g. 1H NMR (400 MHz, CDCI3) 6: 1.82 (s, 9H), 7.78 (s, 1H), 8.25 (s, 1H), 8.88 (s, 1H), 8.92 (s, 1H), 9.44 (s, 1H).

Preparation 65: (2-Aminotert-butyl-7H—pyrrolo[2,3-d]pyrimidinyl)(5-aminopyridinyl)methanone H2N N N lVIe9‘Me The title compound was ed according to the method described for Preparation 36 using (5- bromopyridinyl)(7-tert-butylchloro-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (see Preparation 64) to afford the title compound as a white solid in 55% yield, 870 mg.

LCMS (system 5): R = 2.42 min; m/z 311 [M+H]+.

Preparations 66 to 70 were prepared according to Example 1, ng from (5-aminopyridinyl){7-[(1S)- 2-{[tert-butyl(dimethyl)silyl]oxy}methylethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}methanone (see Preparation 37) and the appropriate acids of formula : W0 2012/137089 152 LCMS (system 4). R: 3.51min, m/z 589 [M+H] LCMS(system 4): R: 3.55min, m/z 565 [M+H] Preparations 71 to78 were prepared according to the method described above for Example 1, starting from (5-aminopyridiny|)[7-(2-{[tert—buty|(dimethy|)si|y|]oxy}-1,1-dimethylethy|)-7H-pyrro|o[2,3- d]pyrimidiny|]methanone (see Preparation 38) and the appropriate acids of formula : (system 4): R: 3.88 min; m/z 616 [M+H] LCMS m 4): R: 4.09 min; m/z 612 [M+H] :- LCMS(system 4): R = 4.07 min; m/z 578 [M+H]+ LCMS(system 4): R: 3. 81 min; m/z 579 [M+H] LCMS(system 4): R: 3.79 min; m/z 602 [M+H] LCMS(system 4): R: 3.58 min; m/z 575 [M+H] LCMS(system 4): R: 3.74 min; m/z 603 [M+H] W0 2012/137089 153 LCMS (system 4): R = 3.78 min; m/z 573 [M+H]+ Potassium carbonate (7.67 g, 55.56 mmol) was added to 3-cyclopropyl-1H-pyrazole (2.0 g, 18.52 mmol) 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 ature. The reaction e was neutralized with aqueous HCI (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 in 42% yield, 1.50 g. 1H NMR (400 MHz, DMSO) 6: 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, 1H), 7.54 (d, 1H).

Preparation 80: (3-Cyclopropyl-1H-pyrazolyl)acetic acid The title compound was prepared according to the method described for Preparation 42 using ethyl (3- cyclopropyl-1H-pyrazolyl) acetate (see Preparation 79) to afford the title compound as a white solid in 83% yield, 4.06 g.

LCMS(system 4): R = 1.16 min; m/z167[M+H]+. ation 81: [4-(Trifluoromethyl)-1H-1,2,3-triazolyl]acetic acid F N=N\ F lOH 0 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 W0 2012/137089 154 2012/051363 (105 mL). The mixture was stirred at room temperature for 240 hours then evaporated in vacuo. The residue was extracted with EtOAc (500 mL) and the organic phase was dried over ium sulfate then ated 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 temperature 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 ed 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) 6: 5.40 (s, 2H), 8.85 (s, 1H), 13.50 (br s, 1H).

Preparation 82: Ethyl (4-cyclopropyl-1H—1,2,3-triazolyl)acetate N=l\{ Vg/NClo 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 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) 6: 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).

Preparation 83: (4-Cyclopropyl-1H—1,2,3-triazolyl)acetic acid N=l\{ The title compound was prepared according to the method described for Preparation 42 using ethyl (4- cyclopropyl-1H—1,2,3-triazolyl)acetate (see Preparation 82) to afford the title nd as a yellow solid in 63% yield, 13.0 g.

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

Preparation 84: tert—Butyl [4-(trifluoromethyl)-1H-pyrazolyl]acetate W3”...Me)40Me W0 2012/137089 155 The title compound was prepared according to the method bed for Preparation 79 using 4- (trifluoromethyl)—1H-pyrazole and tert butyl cetate to afford the title compound as a yellow solid in 24% yield, 1.32 g.

LCMS(system 4): Rt=3.64min; m/z 251 [M+H]+.

Preparation 85: [4-(Trifluoromethyl)-1H-pyrazolyl]acetic acid 01..

Trifluoroacetic acid (10 mL) was added to tert-butyl [4-(trifluoromethyl)-1H-pyrazolyl]acetate (1.3 g, 5.2 mmol) (see Preparation 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 pentane (1 :9, 2 mL) to afford the title compound as a white solid in 79% yield, 800 mg.

LCMS(system 4): R: n; m/z 193 [M+H]+.

Preparation 86: utyl [4-bromo-1H-pyrazolyl]acetate BrQNl—N\ o OMe Me The title compound was prepared according to the method described for Preparation 79 using 4-bromo- 1H-pyrazole and tert butyl bromoacetate to afford the title compound as a yellow solid in 34% yield, 48.0 1H NMR (400 MHz, CDCI3) 6: 1.42 (s, 9H), 4.70 (s, 2H), 7.40 (s, 2H).

Preparation 87: tert—Butyl (4-cyclopropyl-1H-pyrazolyl)acetate 0 Me Palladium acetate (215 mg, 0.957 mmol) was added to tert-butyl mo-1H-pyrazolyl]acetate (5 g, 19.14 mmol) (see Preparation 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 CeliteTM, 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): Rt=3.17min; m/z 223[M+H]+.

W0 2012/137089 156 Preparation 88: (4-Cyclopropyl-1H-pyrazolyl)acetic acid \NNl0H The title compound was prepared according to the method described for Preparation 85 using tert-butyl (4-cyclopropyl-1H-pyrazolyl)acetate (see Preparation 87) to afford the title compound as a yellow solid in 75% yield, 1.0 g.

LCMS m 4): R min; m/z 165[M+H]+.

Preparation 89: Ethyl (5-chloropyridinyl)acetate OAMe Cesium carbonate (71 g, 218 mmol) was added to 2-bromochloropyridine (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 minutes. Then copper (l) oxide (2.8 g, 14.55 mmol) and picolinic acid (3.6 g, 29 mmol) were added and the mixture was stirred in a sealed vessel at 130°C for 24 hours. The mixture was cooled to room temperature, ed 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: 8) to afford the title compound as a yellow oil in 54% yield, 8.0 g. 1H NMR (400 MHz, DMSO-d6) 6: 1.17 (t, 3H), 3.85 (s, 2H), 4.08 (q, 2H), 7.42 (d, 1H), 7.90 (dd, 1H), 8.54 (d, 1H).

Preparation 90: (5-Chloropyridinyl)acetic acid The title compound was prepared according to the method described for Preparation 42 using ethyl (5- pyridinyl)acetate (see Preparation 89) to afford the title compound as a brown solid in 51% yield, 3.5 g.

LCMS (system 4): R: 1.00 min; m/z 172 .

Preparation 91: Ethyl (5-fluoropyridinyl)acetate OAMe W0 2012/137089 157 The title nd was prepared according to the method described for Preparation 89 using 2-bromo- ropyridine to afford the title compound as a yellow oil in 20% yield, 5 g. 1H NMR (400 MHz, DMSO-d6) 6: 1.17 (t, 3H), 3.84 (s, 2H), 4.08 (q, 2H), 7.42-7.45 (m, 1H), 7.67-7.72 (m, 1H), 8.48 (d, 1H).

Preparation 92: (5-Fluoropyridinyl)acetic acid F /{\j The title compound was prepared ing to the method described for Preparation 42 using ethyl (5- fluoropyridinyl)acetate (see Preparation 91) to afford the title nd as a brown solid in 57% yield, 2.4 g. 1H NMR (400 MHz, DMSO-d6) 6: 3.75 (s, 2H), 7.41-7.44 (m, 1H), 7.65-7.70 (m, 1H), 8.47 (d, 1H), 12.50 (br s, 1H). ation 93: 5-lodoisopropyl-7H-pyrrolo[2,3-d]pyrimidine “C I \ >‘Me To a mixture of 5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 201, 2.90 g, 12.0 mmol) and cesium carbonate (5.78 g, 17.8 mmol) in DMF (45 mL) was added propane (1.78 mL, 17.8 mmol). The mixture was stirred at room temperature 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. 1H NMR (400 MHz, CDCI3) 6: 1.53 (d, 6H), 5.15 (m, 1H), 7.40 (s, 1H), 8.73 (s, 1H), 8.88 (s, 1H); LCMS (system 2): R = 1.02 min; m/z 288 [M+H]+.

Preparation 94: (5-Bromopyridinyl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone To a stirred solution of 5-iodoisopropyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 93, 4.85 g, 16.9 mmol) in THF (90 mL) at 0°C, under nitrogen was added isopropyl magnesium chloride (9.28 mL, 18.6 W0 2012/137089 158 mmol, 2.0 M in diethyl ether). The mixture was stirred at 0 °C for 1 hour then a solution of 5-bromo-N- methoxy-N-methylnicotinamide (Preparation 227, 4.55 g, 18.6 mmol) in THF (10 mL) was added dropwise at 0 °C. The mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous um de (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organics were concentrated under reduced re and purified by silica gel column chromatography eluting with gradient of 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, CDCI3) 6: 1.60 (d, 6H), 5.20 (m, 1H), 7.79 (s, 1H), 8.28 (dd, 1H), 8.90 (d, 1H), 8.95 (d, 1H), 9.03 (s, 1H), 9.59 (s, 1H); LCMS (system 2): R = 1.36 min; m/z 346 .

Preparation 95: (5-Aminopyridinyl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone The title compound was prepared according to the method described for Preparation 31 using (5- bromopyridinyl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 94) to afford the title compound as a white solid in 69% yield, 1.20 g. 1H NMR (400 MHz, CDCI3) 6: 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 (br s, 1H), 9.01 (s, 1H), 9.59 (s, 1H); LCMS (system 2): R = 0.50 min; m/z 282 [M+H]+.

Preparation 96: 4-Chlorooxetanyl-7H-pyrrolo[2,3-d]pyrimidine I \ KN N The title compound was prepared according to the method described for Preparation 1 using (4,6- dichloropyrimidinyl)acetaldehyde (Preparation 208) and oxetanamine to afford the title compound as a yellow solid in 67% yield, 2.81 g.

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

W0 2012/137089 159 Preparation 97: 7-Oxetanyl-7H-pyrrolo[2,3-d]pyrimidine The title nd was prepared according to the method described for Preparation 8 using 4-chloro oxetanyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 96) to afford the title compound as a white solid in 90% yield, 1.20 g. 1H NMR (400 MHz, DMSO-d6) 6: 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).

Preparation 98: —7-oxetanyl-7H-pyrrolo[2,3-d]pyrimidine “%RN The title compound was prepared according to the method described for Preparation 14 using an- 3-yl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 97) to afford the title compound as a white solid in 49% yield, 999 mg. 1H NMR (400 MHz, DMSO-d6) 6: .08 (m, 4H), 5.94 (m, 1H), 8.28 (s, 1H), 8.75 (s, 1H), 8.85 (s, 1H).

Preparation 99: {5-[(Diphenylmethylene)amino]pyridinyl}(7-oxetanyl-7H-pyrrolo[2,3-d]pyrimidin yl)methanone The title compound was prepared according to the method described for Preparation 94 using 5-iodo oxetanyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 98) and 5-[(diphenylmethylene)amino]-N-methoxy— N-methylnicotinamide (Preparation 23) to afford the title compound as a yellow solid in 55% yield, 253 mg. 1H NMR (400 MHz, DMSO-d6) 6: 4.95-5.06 (m, 2H), 5.15-5.24 (m, 2H), 5.96 (m, 1H), 7.21-7.80 (m, 11H), 8.22 (d, 1H), 8.52 (s, 1H), 8.62 (m, 1H), 9.01 (s, 1H), 9.44 (s, 1H).

W0 2012/137089 160 Preparation 100: (5-Aminopyridinyl)(7-oxetanyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone The title compound was prepared according to the method described for Preparation 37 using {5- [(diphenylmethylene)amino]pyridinyl}(7-oxetanyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 99) to afford the title compound as a yellow solid in 96% yield, 128 mg. 1H NMR (400 MHz, DMSO-d6) 6: 4.95-5.04 (m, 2H), 5.14-5.22 (m, 2H), 5.66 (br s, 2H), 5.97 (m, 1H), 7.33 (m, 1H), 8.19 (d, 1H), 8.25 (d, 1H), 8.62 (s, 1H), 9.00 (s, 1H), 9.46 (s, 1H).

Preparation 101: 5-lodo{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine | \ K N Me-jSi~|\/|e To a stirred solution of 5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 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 temperature for 30 s, cooled to -20 °C and 2-(trimethylsilyl)ethoxymethyl chloride (0.58 mL, 3.30 mmol) added. The reaction e was stirred at -20°C for 3 hours then water (30 mL) was added.

The mixture was ted with EtOAc (2 x 50 mL) and the combined c phases were dried over magnesium 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) 6: -0.11 (s, 9H), 0.81 (t, 2H), 3.51 (t, 2H), 5.61 (s, 2H), 8.01 (s, 1H), 8.77 (s, 1H), 8.89 (s, 1H).

W0 2012/137089 161 Preparation 102: {5-[(Diphenylmethylene)amino]pyridinyl}(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H- pyrrolo[2,3-d]pyrimidinyl)methanone I \ KN O Me‘ZSi‘Me The title compound was prepared according to the method described for Preparation 28 using 5-iodo {[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (Preparation 101) and 5- [(diphenylmethylene)amino]-N-methoxy—N-methylnicotinamide (Preparation 23) to afford the title compound as a yellow oil in 32% yield, 460 mg. 1H NMR (400 MHz, DMSO-d6) 6: -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), 9.45 (s, 1H); LCMS (system 9): R = 2.36 min; m/z 534 [M+H]+.

Preparation 103: (5-Aminopyridinyl)(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin yl)methanone /\/o\/Z MeTSi‘Me The title compound was prepared according to the method described for Preparation 37 using {5- [(diphenylmethylene)amino]pyridinyl}(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin yl)methanone (Preparation 102) to afford the title compound as a less oil in 73% yield, 2.10 g. 1H NMR (400 MHz, 6) 6: 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, 1H), 9.47 (s, 1H); ystem 9): R = 3.25 min; m/z 370 [M+H]+. ation 104: 2-(4-chlorophenyl)-N-(5-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidinecarbonyl)pyridinyl)acetamide W0 2012/137089 162 K | \ N O) Me—jSi-Me The title compound was prepared according to the method described for Examples 73-87 using (5- aminopyridinyl)(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidinyl)methanone ration 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) 6: -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 = 3.50 min; m/z 522 [M+H]+.

Preparation 105: N-[5—({7-[(1S)—2-{[tert—butyl(dimethyl)silyl]oxy}methylethyl]-7H-pyrrolo[2,3- d]pyrimidin--y)|}carbonylpyridin--y-|]-[3-(trifluoromethyl)phenyl]acetamide TBSOx)‘élokd Prepared according to Example 1, using (8) (5-aminopyridinyl){2-{[tert-butyl(dimethyl)silyl]oxy} methylethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}methanone (Preparation 37) and 3- trifluoromethylphenylacetic acid with DIPEA as base. 1H NMR (400 MHz, DMSO) 6: -0.24 (s, 3H), -0.18 (s, 3H), 0.56 (s, 9H), 1.52 (d, 3H), 3.86 (m,3H), 3.94 (m, 1H), 5.06 (m, 1H), 7.58 (t, 1H), 7.63 (t,2H), 7.72 (s, 1H), 8.45 (s, 1H), 8.50 (s, 1H), 8.67 (d, 1H), 8.93 (d, 1H), 8.98 (s,1H), 9.45 (s,1H), 10.73 (s,1H).

LCMS (System 9): R = n; m/z 598 [M+H]+.

Preparation 106: 5-[(Diphenylmethylene)amino]nicotinaldehyde / H To a stirred solution of phenylmethylene)amino]-N-methoxy—N-methylnicotinamide (Preparation 23, 7.50 g, 0.021 mol) in THF (150 mL) at -70°C was added diisopropylaluminium hydride (42 mL, 0.042 mol, W0 2012/137089 163 1.0 M in THF) and the resulting mixture stirred at -70°C for 2 hours. Water (20 mL) and ethyl e (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]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 cooling to room temperature, the reaction was diluted with DCM (50 mL) and the mixture filtered h a pad of arbocel. The filter cake was washed with DCM (50 mL) and the filtrate concentrated under reduced pressure. The crude material was tallized from ethyl acetate/heptane to give the desired compound as a solid in 78% yield, 3341 mg. 1H NMR (400 MHz, DMSO-d6) 6: 7.18-7.26 (m, 2H), .39 (m, 3H), 7.47-7.54 (m, 2H), 7.55-7.62 (m, 2H), 7.68-7.75 (m, 2H), 8.25 (d, 1H), 8.63 (d, 1H), 10.00 (s, 1H).

Preparation 107: 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecanol \/K/OTBDMS To a stirred solution of glycerol (4.01 mL, 55 mmol) and ole (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 on e was allowed to warm to room temperature 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 ed 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-d6) 6: 0.03 (s, 12H), 0.86 (s, 18H), 3.40-3.59 (m, 5H), 4.58 (d, 1H).

Preparation 108: 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecanyl trifluoromethanesulfonate FTe/oF (3,ng TBDMSO\)\/OTBDMS To a stirred solution of 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecanol (Preparation 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 on 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 (Preparation 196) without r purification.

W0 2012/137089 164 Preparation 109: 4-Chloro-[7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl]{5- [(diphenylmethylene)amino]pyridinyl}methanone CI \ / N/ \ RN I N\ 0 The title compound was prepared according to the method described for Preparation 28 followed by Preparation 30 using roiodomethyl-7H—pyrrolo[2,3-d]pyrimidine (Preparation 226) and 5- [(diphenylmethylene)amino]nicotinaldehyde (Preparation 106) to afford the title compound as a yellow solid (11.0 g, 48%). 1H NMR (400 MHz, c0013) 6: 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, 1H), 8.49 (d, 1H), 8.69 (s, 1H).

Preparation 110 :(5-Aminopyridinyl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone “(H 2 N N Citric acid (2 M, 200 mL) was added to 4-chloro-[7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl]{5- [(diphenylmethylene)amino]pyridinyl}methanone (Preparation 109, 30 g, 0.066 mol) in THF (200 mL) and the mixture was stirred at room temperature 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-aminopyridinyl)(4-chloro—7-methyl- 7H-pyrrolo[2,3-d]pyrimidinyl)methanone as a brown solid, 18 g, 95% Methanethiol sodium salt (15.5 g, 0.22 mol) was added to 5-aminopyridinyl)(4-chloromethyl-7H- pyrrolo[2,3-d]pyrimidinyl)methanone (21 g, 0.073 mol) in methanol (300 mL) and the e was stirred at room temperature for 7 hours. The reaction e 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-aminopyridinyl)[7-methyl(methylthio)-7H-pyrrolo[2,3-d]pyrimidinyl]methanone as a brown solid, 15 g, 69% Raney nickel (10 g) was added to (5-aminopyridinyl)[7-methyl(methylthio)-7H-pyrrolo[2,3- midinyl]methanone (1.5 g, 5.0 mmol) and conc ammonia (150 mL) in 1,4 dioxane (150 mL). The mixture was ed for 6 hours then filtered. The te 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-DG) 6: 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, 1H), 9.42 (s, 1H).

W0 2012/137089 165 Preparation 111: 2,2,3,3,6,9,9,10,10-Nonamethyl-4,8-dioxa-3,9-disilaundecanamine Me NH TBDMSOQQ/OTBDMS2 The title compound was prepared according to the method described for Preparation 44 using 2-amino methyl-1,3-propanediol to afford the title compound as a colourless oil in 100% yield, 23.0 g. 1H NMR (400 MHz, CDCI3) 6: 0.05 (s, 12H), .99 (m, 21H), 3.36-3.42 (m, 4H).

Preparation 112: 7-[2-{[tert—Butyl(dimethyl)silyl]oxy}({[tert-butyl(dimethyl)silyl]oxy}methyl)—1- methylethyl]chloro-7H-pyrrolo[2,3-d]pyrimidine The title compound was prepared ing to the method described for ation 1 using 2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecanamine (Preparation 111) to afford the title compound as a colourless gum in 75% yield, 8.91 g. 1H NMR (400 MHz, CDCI3) 6: 0.09-0.11 (m, 12H), .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).

Preparation 113: 7-[2-{[tert—Butyl(dimethyl)silyl]oxy}({[tert-butyl(dimethyl)silyl]oxy}methyl)—1- methylethyl]-7H-pyrrolo[2,3-d]pyrimidine N%\/IE\>K N 8%OTBDMS OTBDMS The title compound was prepared according to the method described for Preparation 8 using 7-[2-{[tert- butyl(dimethyl)silyl]oxy}({[tert-butyl(dimethyl)silyl]oxy}methyl)—1-methylethyl]chloro-7H-pyrrolo[2,3- d]pyrimidine (Preparation 112) to afford the title compound as a yellow oil in 99% yield, 8.14 g. 1H NMR (400 MHz, CDCI3) 6: -0.13 (s,6H), -0.10 (s,6H), 0.78 ), 1.75 (s, 3H), 4.11 (d, 2H), 4.33 (d, 2H), 6.45 (d, 1H), 7.41 (d, 1H), 8.78 (s,1H), 8.90 (s, 1H).

W0 2012/137089 166 Preparation 114: 7-[2-{[tert—Butyl(dimethyl)silyl]oxy}({[tert-butyl(dimethyl)silyl]oxy}methyl)—1- methylethyl]iodo-7H-pyrrolo[2,3-d]pyrimidine TBDMSO The title compound was prepared according to the method described for Preparation 14 using 7-[2-{[tert- butyl(dimethyl)silyl]oxy}({[tert-butyl(dimethyl)silyl]oxy}methyl)—1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidine (Preparation 113) to afford the title compound as a yellow oil in 88% yield, 7.98 g. 1H NMR (400 MHz, CDCI3) 0 (s, 12H), 0.79 (s, 18H), 1.75 (s, 3H), 4.07 (d, 2H), 4.27 (d, 2H), 7.49 (s, 1H), 8.70 (s, 1H), 8.82 (s, 1H).

Preparation 115: {[tert—Butyl(dimethyl)silyl]oxy}({[tert-butyl(dimethyl)silyl]oxy}methyl)—1- methylethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}{5-[(diphenylmethylene)amino]pyridinyl}methanone The title compound was ed according to the method described for Preparation 28 using 7-[2-{[tert- butyl(dimethyl)silyl]oxy}({[tert-butyl(dimethyl)silyl]oxy}methyl)—1-methylethyl]iodo-7H-pyrrolo[2,3- d]pyrimidine (Preparation 114) and 5-[(diphenylmethylene)amino]—N-methoxy—N-methylnicotinamide (Preparation 23) to afford the title nd as a yellow foam in 69% yield, 1.76 g. 1H NMR (400 MHz, CDCI3) 6: 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).

W0 2012/137089 167 Preparation 116: (5-Aminopyridinyl){7-[2-{[tert-butyl(dimethyl)silyl]oxy}({[tertbutyl (dimethyl)silyl]oxy}methyl)methylethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}methanone N/ NH2 K | \ 8V.OTBDMS TBDMSO The title compound was prepared ing to the method described for Preparation 37 using {7-[2-{[tert- butyl(dimethyl)silyl]oxy}({[tert-butyl(dimethyl)silyl]oxy}methyl)methylethyl]-7H-pyrrolo[2,3-d]pyrimidin- -yl}{5-[(diphenylmethylene)amino]pyridinyl}methanone ration 115) to afford the title compound as a yellow foam in 85% yield, 1.15 g.

LCMS (System 1): R = 4.01 min; m/z 556 [M+H]+.

Preparation 117: 1-lsopropyltrifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester Me/kN . \ FF F Me To a suspension of 5-trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester (13 g, 62.5 mmol) and cesium carbonate (61.1 g, 187.5 mmol) in DMF (70 mL) was added -propane (6.86 mL, 68.75 mmol) and the resulting mixture allowed to stir at room ature 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. 1H NMR (400 MHz, CDCI3) 6: 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: 3.55 min; m/z 251 [M+H]+.

Preparation 118: propyltrifluoromethyl-1H-pyrazolyl)—methanol Me/k'?J \ The title compound was prepared according to the method described for Preparation 183 using 1- isopropyltrifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester (Preparation 117) to afford the title compound an off-white solid in 97% yield, 8.3 g.

W0 2012/137089 168 1H NMR (400 MHz, CDCI3) 6: 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: 2.77 min; m/z 209 [M+H]+.

Preparation 119: (1-|sopropyltrifluoromethyl-1H-pyrazolyl)-acetonitrile Me/k The title compound was prepared ing to the method described for Preparation 184 using (1- pyltrifluoromethyl-1H-pyrazolyl)—methanol (Preparation 118) to afford the title compound as an off-white solid in 58% yield, 5 g. 1H NMR (400 MHz, DMSO-d6) 6: 1.42 (d, 6H), 3.92 (s, 2H), 4.56-4.63 (m, 1H), 8.06 (s, 1H).

Preparation 120: 2-Chloroiodoisopropyl-7H-pyrrolo[2,3-d]pyrimidine fl?N / \ >‘Me The title compound was prepared according to the method described for Preparation 93 using ro iodoisopropyl-7H—pyrrolo[2,3-d]pyrimidine (Preparation 40) to afford the title compound as a white solid in 87% yield, 5.5 g. 1H NMR (400 MHz, CDCI3) 5: 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]+.

Preparation 121: (5-Bromopyridinyl)(2-chloroisopropyl-7H—pyrrolo[2,3-d]pyrimidinyl)methanone The title compound was prepared according to the method described for Preparation 28 using 2-chloro-5— iodoisopropyl-7H—pyrrolo[2,3-d]pyrimidine (Preparation 120) and 5-bromo-N-methoxy—N- methylnicotinamide to afford the title compound as a yellow solid in 41% yield, 1.2 g. 1H NMR (400 MHz, DMSO-D6) 6: 1.54 (d, 6H), 5.02 (m, 1H), 8.41 (d, 1H), 8.63 (s, 1H), 9.0 (m, 2H), 9.33 (s, 1H).

Preparation 122: (2-Aminoisopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)(5-aminopyridinyl)methanone W0 2012/137089 169 The title compound was prepared ing to the method described for Preparation 31 using (5- bromopyridinyl)(2-chloroisopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 121) to afford the title compound as a yellow solid in 58% yield, 500 mg. 1H NMR (400 MHz, DMSO-D6) 6: 1.47 (d, 6H), 4.82-4.86 (m, 1H), 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-|sopropyltrifluoromethyl-1H-pyrazolyl)—acetic acid Me Me “l/ OH F F F O The title nd was prepared according to the method described for Preparation 185 using (1- isopropyltrifluoromethyl-1H-pyrazolyl)-acetonitrile (Preparation 119) to afford the title compound as off-white solid in 82% yield, 4.5 g. 1H NMR (400 MHz, DMSO-d6) 6: 1.41 (d, 6H), 3.50 (s, 2H), 4.52-4.58 (m, 1H), 7.89 (s, 1H), 12.35 (br, 1H); LCMS (system 10): R: 1.56 min; m/z 235 [M-H]'.

Preparation 124: (3-Cyclopropylmethyl-1H-pyrazolyl)-acetonitrile To a suspension of potassium tert-butoxide (8.95 g, 79.9 mmol) in DME (250 mL) -78 0C under nitrogen was added a solution of 1-(isocyanomethyl yl)methyl benzene (9.36 g, 47.94 mmol) in DME (50 ml). After stirring for 10 minutes, a solution of 3-cyclopropylmethyl-1H-pyrazolecarbaldehyde (6 g, 39.95 mmol) in DME (100 mL) was added. The resulting mixture was allowed to stir at -78 0C for 1 hour and then at room temperature for 1hour. ol (50 mL) was added and the resulting mixture refluxed for 1 hour. The on e 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.

W0 2012/137089 170 1H NMR (400 MHz, DMSO-d6) 6: 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/z162[M+H]+.

Preparation 125: (3-Cyclopropylmethyl-1H-pyrazolyl)-acetic acid l\|/|e 0 \/ The title compound was prepared according to the method described for Preparation 141 using (3- ropylmethyl-1H-pyrazolyl)—acetonitrile (Preparation 124) to afford the title nd as solid in 83% yield, 4 g. 1H NMR (400 MHz, DMSO-d6) 6: 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+H]+.

Preparation 126: (3-Cyano—4-fluoro-phenyl)-acetic acid N\\\/(>/erH0 To a solution of (3-bromo—4-fluoro—phenyl)—acetic acid (10 g, 42.9 mmol) in DMF (65 mL) was added copper (l) e (7.7 g, 85.8 mmol) and heated at 130 °C for 24 hrs. The reaction mixture was cooled to room temperature and diluted with ethyl e (250 mL). The organic layer was washed with water (5 x 50 mL), brine (50 mL), dried over sodium filtered and trated 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. 1H NMR (400 MHz, DMSO-d6) 6: 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: 1.39 min; m/z178[M-H]'.

Preparation 127: (3-Cyano—4-fluoro-phenyl)-acetic acid ethyl ester Ora;/N To a suspension of (3-cyano—4-fluoro-phenyl)—acetic acid (500 mg, 2.79 mmol) (Preparation 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 temperature for 4 hours. The crude on 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 sulphate, 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) 6: 1.26 (t, 3H), 3.61 (s, 2H), 4.16 (q, 2H), 7.17 (t, 1H), 7.49-7.55 (m, 2H).

Preparation 128: (3-Amino-benzo[d]isoxazol-5—yl)—acetic acid ethyl ester W0 2012/137089 171 r0 0 To a solution of (3-cyanofluoro-phenyl)—acetic acid ethyl ester (Preparation 127, 400 mg, 1.93 mmol) and acetohydroxamic acid (362 mg, 4.83 mmol) in DMF (40 mL) and water (15 mL) was added ium carbonate (1.6 g, 11.58 mmol) and the reaction mixture stirred at room temperature for 12 hours. The on 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 nt 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: 2.87 min; m/z 221 [M+H]+.

Preparation 129: (3-Amino-benzo[d]isoxazolyl)—acetic acid OH / The title compound was prepared according to the method described for Preparation 141 using (3-amino- benzo[d]isoxazolyl)-acetic acid ethyl ester ration 128) to afford the title compound as an off- white solid in 69% yield, 30 mg. 1H NMR (400 MHz, DMSO-de) 6: 3.65 (s, 2H), 6.36 (br s, 2H), 7.36-7.42 (m, 2H), 7.69 (s, 1H), 12.37 (br s, 1 H); LCMS (system 10): R: 1.65 min; m/z193[M+H]+.

Preparation 130: o[1,2-a]pyridinyl-acetic acid ethyl ester Me/\Ow\ \N 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 cesium carbonate (3 gm, 9.1 mmol). Argon was bubbled through the mixture for 10 minutes and then copper (l) iodide (116 mg, 0.61 mmol) and picolinic acid (150 mg, 1.22 mmol) were added. The ant mixture was heated in a sealed tube at 130 0C for 24 hours. The reaction mixture was cooled to room temperature, quenched with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), brine (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude al 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: 2.61 min; m/z 205 [M+H]+.

Preparation 131: N-(5-{[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl]carbonyl}pyridinyl)(4-cyanophenyl)acetamide W0 2012/137089 172 2012/051363 Prepared according to the method described for Example 1 using (5-aminopyridinyl)[7-(2-{[tert- butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]methanone (Preparation 38), and ophenylacetic acid with DIPEA. 1H NMR (400 MHz, DMSO) 6: -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, 1H), 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]+.

Preparation 132: |midazo[1,2-a]pyridinyl-acetic acid 0 /N/\> HO \N To a solution of imidazo[1,2-a]pyridinyl-acetic acid ethyl ester (180 mg, 0.65 mmol) (Preparation 130) in dioxane (4 mL) at 0 0C was added 2 N aqueous sodium hydroxide solution (4 mL). Then reaction mixture was heated at 900C for 6 hours. After cooling to 0 0C, the e was acidified to pH 4 with with 2 N aqueous hydrochoric acid and extracted with 20% isopropanol in dichoromethane (8 x 10 mL). The combined organics were dried over sodium e and concentrated under reduced re to afford the title compound as an off-white solid in 70% yield, 80 mg.

LCMS (system 10): R: 1.40 min; m/z177[M+H]+.

Preparation 133: Pyrazolo[3,4-b]pyridinyl-acetic acid ethyl ester N N 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 temperature and d with ethyl acetate (20 mL). The organic layer was washed with water (2 x 5 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.

W0 2012/137089 173 1H NMR (400 MHz, DMSO-d6) 6: 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).

Preparation 134: Pyrazolo[3,4-b]pyridinyl-acetic acid N N To a stirred solution of pyrazolo[3,4-b]pyridinyl-acetic acid ethyl ester (210 mg, 1.02 mmol) (Preparation 133) in THF (4 mL) and water (1 mL) at 0 0C was added LiOH.H20 (129 mg, 3.06 mmol).

The on mixture was stirred at room temperature 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 (8 x 5 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 1H NMR (400 MHz, DMSO-d6) 6: 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: 1.93 min; m/z178[M+H]+.

Preparation 135: 1-Cyclopropyltrifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester N/ O V/ O/\Me 4,4,4-Trifluoro—3-oxo-butyric acid ethyl ester (16 g, 86.4 mmol) was dissolved in acetic ide (33.6 g, 329.6 mmol) and yl orthoformate (38.4 g, 260 mmol) was added to the mixture. The resultant mixture was refluxed for 18 hours. The e was concentrated under reduced pressure to obtain 20 g of 2-[1- Ethoxy—meth-(E)-ylidene]-4,4,4-trifluorooxo—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 resultant mixture was slowly warmed to room temperature and stirred for 16 hours. The mixture was concentrated under reduced pressure and residue formed was partitioned n EtOAc (50 mL) and water (50 mL). The organic layer was washed with 2N HCl (25 mL), water (25 mL), brine (25 mL), dried 4) and evaporated in vacuo. The crude al 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) 6: 1.10-1.21 (m, 4H), 1.26 (t, 3H), 3.90 (m, 1H), 4.26 (q, 2H), 7.98 (s, 1H).

Preparation 136: N-(5-{[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl]carbonyl}pyridinyl)[3-(trifluoromethyl)phenyl]acetamide W0 2012/137089 174 Prepared according to the method described for Example 1 using (5-aminopyridinyl)[7-(2-{[tert- buty|(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrro|o[2,3-d]pyrimidinyl]methanone (Preparation 38), and luoromethylphenylacetic acid with DIPEA. 1H NMR (400 MHz, DMSO) 6: -0.27 (s, 6H), 0.56 (s, 9H), 1.75 (s, 6H), 3.87 (s, 2H), 4.09 (s, 2H), 7.57- 7.64 Preparation 137: lopropyltrifluoromethyl-1H-pyrazolyl)—methanol V OH A on of 1-Cyclopropyltrifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester (Preparation 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 HCI (10 mL). This was d for a further 4 hours at room temperature followed by extraction with EtOAc (2 x 25 mL) and the combined organic layers were washed with water (2 x 10 mL), brine (10 mL) dried 4) and evaporated in vacuo to afford the title compound as off white solid in 100% yield, 1.2 g. 1H NMR (400 MHz, DMSO-D6) 6: 1.03-1.17 (m, 4H), 3.68-3.73 (m, 1H), 4.42 (d, 2H), 5.15 (t, 1H), 7.51 (s, 1H); LCMS (system 10): R: 2.68 min; m/z 207 [M+H]+ Preparation 138: N-(5-{[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)—7H-pyrrolo[2,3-d]pyrimidin- 5-yl]carbonyl}pyridinyl)—2-(4-isopropyl-1H-1,2,3-triazolyl)acetamide.

Prepared according to the method described for Example 1 using (5-aminopyridinyl)[7-(2-{[tert— butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)—7H-pyrrolo[2,3-d]pyrimidinyl]methanone (Preparation 38), and [4-(trifluoromethyl)-1H-pyrazolyl]acetic acid (Preparation 85) with DIPEA as base.

LCMS (System 9): R = 3.67 min; m/z 577 [M+H]+.

Preparation 139: (1-Cyclopropyltrifluoromethyl-1H-pyrazolyl)-acetonitrile W0 2012/137089 175 A solution of lopropyltrifluoromethyl-1H-pyrazolyl)—methanol (Preparation 137, 1.2 g, 5.82 mmol) in DCM (15 mL) was cooled to 0°C and thionyl de (0.85 mL, 11.7 mmol) was added. The reaction e was stirred at 0°C for 2 hours and diluted with DCM. The organic layer was washed with water, brine and dried (Na2804) 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 reaction mixture was stirred for 10 mins ed by the on of KCN (1.28 g, 19.82 mmol) and resultant mixture was stirred for a further 16 hours at room temperature. The e was diluted with EtOAc (50 mL) and washed with water (1 x 10 mL), brine (1 x 10 mL), dried (Na2804) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (Hexane:EtOAc 10:90) to afford the title compound as light yellow solid in 56% yield, 700 mg. 1H NMR (400 MHz, CDCI3) 6: 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).

Preparation 140: N-(5-{[7-(2-{[tert—butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl]carbonyl}pyridinyl)quinolinylacetamide KIN \N/ Prepared according to the method described for Example 1 using (5-aminopyridinyl)[7-(2-{[tert- butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]methanone (Preparation 38), and 2-quinolinylacetic acid with DIPEA as base. 1H NMR (400 MHz, DMSO) 6: -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, 1H), 9.47 (s, 1H), 10.77 (s, 1H); LCMS (System 9): R = 3.72 min; m/z 595 [M+H]+.

Preparation 141: (1-Cyclopropyltrifluoromethyl-1H-pyrazolyl)—acetic acid K 7 OH F O To a solution of (1-Cyclopropyltrifluoromethyl-1H-pyrazolyl)-acetonitrile (Preparation 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 W0 2012/137089 176 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 (Na2804) and evaporated in vacuo to afford the title compound as a solid in 85% yield, 650 mg. 1H NMR (400 MHz, DMSO-DG) 6: 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: 1.50 min; m/z 233 [M-H]+.

Preparation 142 N-[5-({7-[(1R)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]—7H-pyrrolo[2,3-d]pyrimidin- -yl}carbonyl)pyridinyl][3-(trifluoromethyl)phenyl]acetamide O CF3 \ / ° KN' \ H THPO Prepared according to the method bed above for Example 1, using nopyridinyl){7-[(1R)—1- methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}methanone ration 36) and 3-trifluoromethylphenylacetic acid with DIPEA as base. 1H NMR (400 MHz, DMSO-d6) 6: 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, 1H); LCMS (System 9): R = 3.56 min; m/z 568 [M+H]+.

Preparation 143: 5-Trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester .N’ 0 H,N / F Me To a suspension of hydrazine hydrochloride (10 g, 147 mmol) in EtOH (500 mL), DIPEA (45.3 mL, 267 mmol) was added slowly at -200C and stirred for 10 mins. Then 2-[1-Ethoxy-meth-(E)-ylidene]-4,4,4- trifluorooxo-butyric acid ethyl ester (Preparation 135, 32 g, 133.33 mmol) was added to above solution and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and residue was ioned between EtOAc (200 mL) and water (50 mL). The organic layer was washed with water (25 mL), dried (Na2804) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (Hexane:EtOAc 90:10) to afford the title nd as off white solid in 43% yield, 13 g. 1H NMR (400 MHz, DMSO-DG) 6: 1.26 (t, 3H), 4.25 (q, 2H), 8.57 (s, 1H), 14.10 (br s, 1H).

Preparation 144: N-[5-({7-[(1R)- 1-methyl(tetrahydro-2H-pyranyloxy)ethyl]—7H-pyrrolo[2,3- d]pyrimidinyl}carbonyl)pyridinyl]—2-(4-isopropyl-1H-1,2,3-triazolyl)acetamide /N Me \ / 0 Me N/ \ ”kw ¢N k ' N \N N THPO Prepared according to the method described above for e 1, using (5-aminopyridinyl){7-[(1R)—1- methyl(tetrahydro-2H-pyranyloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}methanone (Preparation 36) and (4-isopropyl-1H-1,2,3-triazolyl)acetic acid with DIPEA as base. 1H NMR (400 MHz, DMSO-de) 6: 1.22 (6H, d), 1.23-1.30 (m, 5H), 1.54(d, 3H), 3.4 (1H, m), 3.72 (m, 1H), 3.88 (m, 1H), 3.95 (m, 1H), 4.10 (m, 1H), 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, 1H), 8.75 (s, 1H), 8.97 (m, 2H), 9.45 (s, 1H), 10.96 (s, 1H); LCMS (System 9): R = 2.86 min; m/z 533 [M+H]+.

Preparation 145: 1-Cyclopropyltrifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester it \ O FF F Me Cyclopropyl boronic acid (11 g, 127 mmol), Copper e (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-Trifluoromethyl- 1H-pyrazole—4-carboxylic acid ethyl ester (Preparation 143, 6.63 g, 31.9 mmol) in THF (70 mL) and the ing mixture was allowed to stir at 600C 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 HCI (1 x 25 mL), brine (1 x 25 mL) and dried (Na2804) 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) 6: 1.08-1.14 (m, 2H), 1.17-1.21 (m, 2H), 1.33 (t, 3H), .67 (m, 1H), 4.30 (q, 2H), 8.01 (s, 1H); LCMS (system 10): R: 3.39 min; m/z 249 [M+H]+.

Preparation 146: lopropyltrifluoromethyl-1H-pyrazolyl)—methanol A solution of 1-Cyclopropyltrifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester (Preparation 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 HCI (25 mL) followed by r stirring for 2 hours at room temperature. The mixture W0 2012/137089 178 was extracted with EtOAc (2 x 50 mL) and the combined organic layers were washed with water (2 x 15 mL), brine (15 mL) and dried (NaZSO4) and evaporated in vacuo to afford the title compound as off white solid in 100% yield, 3 g. 1H NMR (400 MHz, CDCI3) 6: 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: 2.57 min; m/z 207 .

Preparation 147: (1-Cyclopropyltrifluoromethyl-1H-pyrazolyl)-acetonitrile The title compound was prepared according to the method described for Preparation 139 using (1- Cyclopropyltrifluoromethyl-1H-pyrazolyl)—methanol (Preparation 146) to afford the title compound as yellow solid in 70% yield, 2.2 g. 1H NMR (400 MHz, DMSO-DG) 6: 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: 3.10 min; m/z 216 [M+H]+.

Preparation 148: (1-Cyclopropyltrifluoromethyl-1H-pyrazolyl)—acetic acid N\ / OH F F F O The title nd was prepared according to the method described for ation 141 using (1- Cyclopropyltrifluoromethyl-1H-pyrazolyl)-acetonitrile (Preparation 147) to afford the title compound as a solid in 79% yield, 1.9 g. 1H NMR (400 MHz, DMSO-DG) 6: 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]+.

Preparation 149: (7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)[5-(methylamino)pyridinyl]methanone HaMe W0 2012/137089 179 The title compound was prepared according to the method bed for Preparation 31 using (5- bromopyridinyl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 94) and methylamine (20 mL) in 13% yield, 78 mg.

LCMS (system 2). R: 0.91 min; m/z 296 [M+H] The following Preparations were prepared according to the method described above for Example 1, using (5-aminopyridinyl){7-[(1R)—1-methyl(tetrahydro-2H-pyranyloxy)ethyl]—7H-pyrrolo[2,3-d]pyrimidin yl}methanone ration 36) and the corresponding carboxylic acid with DIPEA. All carboxylic acids are commercially available unless othenNise mentioned.

O / o ”’K/R102 ——-ii-— ({7-[(1R)— 1--m-ethy|2-- LCMS (System 9). R: 3.24 min; m/z 600 (tetrahydro-2H-pyran [M+H]+ yloxy)ethyl]-7H-pyrrolo[2,3- Using (Prep 185). d]pyrimidinyl}carbonyl)pyridin y|][1-isopropyl (trifluoromethyl)—1H-pyrazol yl]acetamide 2-(4-cyanophenyl)-N-[5-({7-[(1R)- LCMS (System 9): R = 2.94 min; m/z 525 1-methyl(tetrahyd ro-2H-pyran . yloxy)ethyl]-7H-pyrrolo[2,3- d]pyrimidinyl}carbonyl)pyridin yl]acetamide N-[5-({7-[(1R)- 1-methyI LCMS (System 9): R = 2.82 min; m/z 578 (tetrahydro-2H-pyran [M+H]+ yloxy)ethyl]-7H-pyrrolo[2,3- d]pyrimidinyl}carbonyl)pyridin y|][3- (methylsulfonyl)phenyl]acetamide {7-[(1R)- 1-methyI LCMS (System 9): R = 2.97 min; m/z 551 hydro-2H-pyran [M+H]+. yloxy)ethyl]-7H-pyrrolo[2,3- d]pyrimidinyl}carbonyl)pyridin y|]quinolinylacetamide W0 2012/137089 180 Preparation 154: Ethyl (2-cyclopropyl-1,3-oxazolyl)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 then evaporated in vacuo. The crude solid was purified by column chromatography on silica gel (80:20 petroleum ether: EtOAc) to afford the title nd as a white solid in 50% yield, 4.00 g. 1H NMR (300 MHz, DMSO-de) 6: 0.80-1.00 (m, 4H), 1.20 (t, 3H), 2.10 (m, 1H), 3.50 (s, 2H), 4.10 (q, 2H), 7.80 (s, 1H).

Preparation 155: lopropyl-1,3-oxazoly|)acetic acid Lithium hydroxide monohydrate (7.83 g, 186.7 mmol) was added to ethyl (2-cyclopropyl-1,3-oxazol yl)acetate (Preparation 154, 7.00 g, 35.9 mmol) in THF (200 mL) and water (100 mL). The mixture was stirred at room temperature for 2 hours then the reaction e volume was reduced to one third by evaporation in vacuo. The aqueous residue was ied using aqueous HCl (1.0 M) then extracted with EtOAc (200 mL). The organic phase was evaporated in vacuo and the crude material was ated with diethyl ether (100 mL) to afford the title compound as a white solid in 66% yield, 4.00 g. 1H NMR (300 MHz, CDCI3) 6: 1.05 (m, 4H), 2.10 (m, 1H), 3.60 (s, 2H), 7.40 (s, 1H), 10.00 (brs, 1H).

Preparation 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), cesium carbonate (2.55 g, 7.82 mmol) and methyl 2-hydroxyphenyl acetate (1.30 g, 7.82 mmol) were added and the mixture d at room temperature 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 magnesium 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 subsequent steps.

W0 2012/137089 181 1H NMR (400 MHz, CDCI3) 6: 3.67 (s, 2H), 3.39 (s, 3H), 4.40 (dd, 1H), 4.69 (dd, 1H), 6.59 (dd, 1H), 6.97- 7.08 (m, 2H), 7.23-7.28 (m, 2H).

Preparation 157: Methyl [4-(vinyloxy)phenyl]acetate H2C=\0% The title compound was prepared according to the method described for ation 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) 6: 3.58 (s, 2H), 3.39 (s, 3H), 4.42 (m, 1H), 4.75 (m, 1H), 6.62 (m, 1H), 6.94- 6.97 (m, 2H), 7.21-7.24 (m, 2H).

Preparation 158: Methyl [3-(vinyloxy)phenyl]acetate The title compound was prepared according to the method described for Preparation 156 using methyl 3- hydroxyphenyl acetate to afford the title compound as a colourless oil in 56% yield, 835 mg. 1H NMR (400 MHz, CDCI3) 6: 3.61 (s, 2H), 3.70 (s, 3H), 4.44 (m, 1H), 4.78 (m, 1H), 6.63 (m, 1H), 6.89- 6.94 (m, 2H), 7.00 (m, 1H), 7.27 (m, 1H).

Preparation 159: Methyl [5-(vinyloxy)pyridinyl]acetate The title compound was prepared ing to the method described for Preparation 156 using methyl (5-hydroxypyridinyl)acetate to afford the title compound as a yellow oil in 25% yield, 76 mg.

LCMS m 2): R = 0.85 min; m/z 194 [M+H]+.

W0 2012/137089 182 Preparation 160: [2-(Cyclopropyloxy)phenyl]acetic acid Diethyl zinc (2.34 mL, 2.34 mmol, 1M in e) was cooled to 0°C under nitrogen then chloroiodomethane (0.35 mL, 4.68 mmol) in DOE (1 mL) was added drop-wise. The mixture was stirred under nitrogen at 0°C for 20 minutes then methyl [2-(vinyloxy)phenyl]acetate (Preparation 156, 150 mg, 0.78 mmol) in DOE (1 mL) was added. The reaction mixture was stirred at 0°C for 30 minutes then stirred at room temperature for 17 hours. Saturated aqueous ammonium chloride (10 mL) was added and the mixture was extracted with DCM (4 x 8 mL). The ed organic phases were dried over magnesium 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 ated 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. 1H NMR (400 MHz, CDCI3) 6: 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).

Preparation 161: [4-(Cyclopropyloxy)phenyl]acetic acid ed according to the method described for Preparation 160 using methyl [4- (vinyloxy)phenyl]acetate (Preparation 157) to afford the title compound as a colourless oil in 44% yield, 360 mg. 1H NMR (400 MHz, CDCI3) 6: 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).

W0 2012/137089 183 Preparation 162: [3-(Cyclopropyloxy)phenyl]acetic acid The title compound was prepared according to the method described for ation 160 using methyl [3-(vinyloxy)phenyl]acetate (Preparation 158) to afford the title compound as a colourless oil in 33% yield, 50 mg. 1H NMR (400 MHz, CDCI3) 6:0.74—0.81 (m, 4H), 3.57—3.67 (m, 2H), 3.72 (m, 1H), 6.74-7.03 (m, 3H), 7.22 (m, 1H).

Preparation 163: clopropyloxy)pyridinyl]acetic acid The title compound was prepared according to the method described for Preparation 160 using methyl nyloxy)pyridinyl]acetate (Preparation 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]+. ation 164: [4-Cyano(trifluoromethyl)phenyl]acetic acid Lithium diisopropylamide (13.8 mL, 24.8 mmol, 1.8M in THF) was added to 4-methyl (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 temperature for 17 hours. Saturated aqueous ammonium chloride (10.5 mL) and EtOAc (20 mL) were added then the W0 2012/137089 184 aqueous layer was acidified with HCI acid on (1 M). This was extracted with EtOAc (3 x 15 mL) and the ed 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) 6: 3.81 (s, 2H), 7.62 (d, 1H), 7.73 (s, 1H), 7.83 (d, 1H).

Preparation 165: (2-Methquuinolinyl)acetic acid N Me ic aldehyde (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 ed with chloroform (900 mL) and methanol (100 mL) then the solution was decanted and purified by column chromatography on silica gel (gradient of chloroform:MeOH 9:1 to 4:1) to afford a mixture of isomeric acids. This was purified by fractional crystallisation using isopropanol to afford the title compound as a white solid in 12% yield, 4.90 g. 1H NMR (400 MHz, DMSO-d6) 6: 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).

Preparation 166: Ethyl (3-isopropylmethyl-1H-pyrazolyl)acetate Mew\,N N Me 1 o O\\ Ethyl bromoacetate (1.00 mL, 9.03 mmol) was added to 5-isopropylmethyl-1H-pyrazole (1.07 g, 8.60 mmol) and potassium carbonate (3.57 g, 25.9 mol) in DMF (10 mL). The mixture was d at room temperature for 17 hours then EtOAc (20 mL) and s HCI (20 mL, 1 M) were added. The organic phase was dried over magnesium 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) 6: 1.26 (m, 9H), 2.03 (s, 3H), 2.96 (m, 1H), 4.21 (q, 2H), 4.78 (s, 2H), 7.13 (s, 1H).

W0 2012/137089 185 Preparation 167: (3-lsopropylmethyl-1H-pyrazolyl)acetic acid Mew\ /NN Lithium hydroxide (342 mg, 8.15 mmol) in water (4 mL) was added to ethyl (3-isopropylmethyl-1H- pyrazolyl)acetate (Preparation 166, 571 mg, 2.72 mmol) in methanol (4 mL) and the mixture was stirred at room temperature for 30 minutes. Aqueous hloric acid (2 M) was added to acidify the mixture then the solution was extracted with EtOAc (10 mL). The c phase was dried over magnesium sulphate and evaporated in vacuo to afford the title compound as a cream solid in 66% yield, 328 mg. m/z 183 [M+H]+.

Preparation 168: Ethyl (6-chloro-1H-indazolyl)acetate \ f ’N Me Concentrated sulphuric acid (0.25 mL) was added to a on of 2-(6-chloro-1H-indazolyl)acetic 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 c 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) 6: 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).

Preparation 169: Ethyl (6-chloromethyl-1H-indazolyl)acetate N ( NI Me Sodium hydride (24 mg, 0.602 mmol, 60% in oil) was added to ethyl (6-chloro-1H-indazolyl)acetate (Preparation 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 temperature for 30 mins then water (4 mL) was added. The e was ated 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 W0 2012/137089 186 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) 6: 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 =3.48 min; m/z 253 [M+H]+.

Preparation 170: (6-Chloromethyl-1H-indazolyl)acetic acid CI "l Aqueous potasium hydroxide (5.93 mL, 10%) was added to ethyl (6-chloromethyl-1H-indazol yl)acetate (Preparation 169, 1.78 g, 0.704 mol) in MeOH (30 mL). The e was stirred for 1 hour at 25°C then the methanol was evaporated in vacuo. The aqueous residue was washed with l 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) 6: 3.79 (s, 2H), 4.14 (s, 3H), 7.12 (d, 1H), 7.73 (d, 1H), 7.83 (s, 1H). 12.51 (s, 1H).

Preparation 171: Ethyl (5-fluoro-1H-indazolyl)acetate QMN 4..

The title compound was ed according to the method bed for Preparation 93 using 5-fluoro- 1H-indazole and ethyl bromoacetate to afford the title compound as an off- white solid in 53% yield, 260 1H NMR (400 MHz, CDCI3) 6: 1.24 (t, 3H), 4.22 (q, 2H), 5.13 (s, 2H), 7.17 (m, 1H), 7.28 (m, 1H), 7.37 (d, 1H), 7.99 (s, 1H); LCMS (System 9): R: 3.14 min; m/z 223 .

Preparation 172: (5-Fluoro-1H-indazolyl)acetic acid W0 37089 187 The title compound was prepared according to the method described for Preparation 155 using ethyl (5- -1H-indazolyl)acetate (Preparation 171) to afford the title compound as a yellow solid in 62% yield, 140 mg. 1H NMR (400 MHz, DMSO-d6) 6: 5.26 (s, 2H), 7.28 (m, 1H), 7.54 (dd, 1H), 7.68 (dd, 1H), 8.06 (s, 1H), 13.11 (brs, 1H).

LCMS (System 9): R: 1.49 min; m/z193[M-H]' ation 173: Ethyl (5-fluoro-2H-indazolyl)acetate F —>/—O 0 \—Me The title compound was prepared according to the method described for Preparation 93 using 5-fluoro- 1H-indazole and ethyl bromoacetate to afford the title compound as an off- white solid in 27% yield, 130 1H NMR (400 MHz, CDCI3) 6: 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, 1H), 7.96 (s, 1H); LCMS (System 9): R: 3.04 min; m/z 223 [M+H]+ Preparation 174:(5-F|uoro-2H-indazolyl)acetic acid The title compound was prepared according to the method described for Preparation 155 using ethyl (5- fluoro-2H-indazolyl)acetate (Preparation 173) to afford the title compound as a yellow solid in 100% yield, 160 mg.

LCMS m 9): R: 1.49 min; m/z193[M-H]' ation 175: Ethyl (7-fluoro-1H-indazolyl)acetate The title compound was prepared according to the method described for Preparation 93 using 7-fluoro- 1H-indazole and ethyl bromoacetate to afford the title compound as an off- white solid in 41% yield, 200 1H NMR (400 MHz, CDCI3) 6: 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).

Preparation 176: (7-Fluoro—1H-indazolyl)acetic acid W0 2012/137089 188 The title compound was prepared according to the method described for Preparation 155 using ethyl (7- fluoro-1H-indazolyl)acetate (Preparation 175) to afford the title nd as a yellow solid in 68% yield, 120 mg. 1H NMR (400 MHz, DMSO-d6) 6: 5.27 (s, 2H), 7.12 (m, 1H), 7.23 (m, 1H), 7.60 (d, 1H), 8.17 (d, 1H), 13.18 (br s, 1H); LCMS (System 9): R: 1.38 min; m/z195[M+H]+ Preparation 177: Ethyl (7-fluoro-2H-indazolyl)acetate N_>—O 0 \—Me The title compound was prepared according to the method described for Preparation 93 using 7-fluoro- 1H-indazole and ethyl bromoacetate to afford the title compound as an off- white solid in 35% yield, 175 1H NMR (400 MHz, CDCI3) 6: 1.28 (t, 3H), 4.25 (q, 2H), 5.28 (s, 2H), 6.93 (m, 1H), 6.99 (m, 1H), 7.43 (d, 1H), 8.06 (d, 1H).

Preparation 178: (7-Fluoro-2H-indazolyl)acetic acid The title nd was prepared according to the method described for ation 155 using ethyl (7- fluoro-2H-indazolyl)acetate (Preparation 177) to afford the title compound as a yellow solid in 75% yield, 110 mg. 1H NMR (400 MHz, DMSO-d6) 6: 5.34 (s, 2H), 6.97-7.05 (m, 2H), 7.56 (d, 1H), 8.50 (d, 1H), 13.30 (br s, 1H); LCMS (System 9): R: 1.40 min; m/z195[M+H]+ ation 179: Ethyl 1H-pyrazolo[3,4-b]pyridinylacetate W0 37089 189 The title compound was prepared ing to the method described for Preparation 93 using 1H- pyrazolo[3,4-b]pyridine and ethyl bromoacetate to afford the title compound as an off- white solid in 49% yield, 210 mg. 1H NMR (400 MHz, DMSO-d6) 6: 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).

Preparation 180: 1H-Pyrazolo[3,4-b]pyridinylacetic acid ///<OH \ / The title compound was prepared according to the method described for Preparation 155 using ethyl 1H- pyrazolo[3,4-b]pyridinylacetate (see Preparation 179) to afford the title compound as a yellow solid in 40% yield, 70 mg. 1H NMR (400 MHz, DMSO-d6) 6: 5.22 (s, 2H), 7.25 (dd, 1H), 8.19 (s, 1H), 8.27 (dd, 1H), 8.55 (dd, 1H), 13.15 (brs, 1H).

Preparation 181: tert—Butyl 1H-indazolylacetate / 0 Me N 0JVMe H Me 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 for 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-t— butyl ine luoroborate (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 (2 x 10 mL), brine (10 mL) and dried over sodium te (Na2804). 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) 6: 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).

Preparation 182: 1H-lndazolylacetic acid / O N OH Hydrochloric acid (10 mL, 4 M in 1.4 dioxane) was added to tert—butyl 1H-indazolylacetate (Preparation 181, 1.00 g, 4.3 mmol) in 1,4 dioxane (5 mL) at 0°C and the mixture was stirred at room W0 2012/137089 190 temperature for 16 hours. The mixture was evaporated in vacuo and the residue was triturated with dry ether to afford the title compound as a white solid in 100% yield, 800 mg. 1H NMR (400 MHz, CDCI3) 6: 3.69 (s, 2H), 7.00 (d, 1H), 7.41 (s, 1H), 7.67 (d, 1H), 8.02 (s, 1H), 12.81 (br s, 1H).

Preparation 183: [1-lsopropyl(trifluoromethyl)-1H-pyrazolyl]methanol F N_'{' Diisobutylaluminium hydride (99 mL, 120 mmol, 1.2 M solution in e) was added to ethyl 1-isopropyl- -(trifluoromethyl)-1H-pyrazolecarboxylate (WO 2007071900, 12 g, 48 mmol) in toluene (220 mL) at - 78°C . The reaction e was stirred at -78°C for 2 hours then poured into s HCI (100 mL, 2 M).

The mixture was stirred for 4 hours at room temperature then extracted with EtOAc (400 mL). The organic phase was washed with water (200 mL), brine (200 mL) and dried over sodium te. The filtrate was ated in vacuo to afford the title compound as a colourless oil in 100% yield, 10.5 g. 1H NMR (400 MHz, CDCI3) 6: 1.51 (d, 6H), 4.57-4.66 (m, 3H), 7.58 (s, 1H). 1H NMR (400 MHz, CDCI3) 6: 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 = 1.67 min; m/z189.9[M+H]+.

Preparation 184: [1-lsopropyl(trifluoromethyl)-1H-pyrazolyl]acetonitrile Thionyl chloride (5.26 mL, 72 mmol) was added to [1-isopropyl(trifluoromethyl)-1H-pyrazol yl]methanol (Preparation 183, 7.5 g, 36 mmol) in DCM (75 mL) at 0 °C and the mixture was stirred for 2 hours. The mixture was d with DCM (30 mL) and the organic phase was washed with water (75 mL), brine (75 mL) and dried over sodium te. The filtrate was evaporated in vacuo to afford 4- (chloromethyl)isopropyl(trifluoromethyl)-1H-pyrazole in 86% yield, 7 g.

Tetrabutyl ammonium bromide (7.95 gm, 24.7 mmol) was added to 4-(chloromethyl)isopropyl (trifluoromethyl)—1H-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 temperature. 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 W0 2012/137089 191 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) 6: 1.43 (d, 6H), 3.99 (s, 2H), 4.61 (m, 1H), 7.71 (s,1H). ation 185: [1-lsopropyl(trifluoromethyl)-1H-pyrazolyl]acetic acid F \\ Aqueous sodium hydroxide (150 mL of a 1 M solution) was added to [1-isopropyl(trifluoromethyl)-1H- pyrazolyl]acetonitrile (Preparation 184, 6.2 g, 28.6 mmol) in EtOH (150 mL) and the e 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 ied to pH 5 using 1N HCI 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. 1H NMR (400 MHz, DMSO-de) 6: 1.42 (d, 6H), 3.56 (s, 2H), 4.58 (m, 1H), 7.57 (s, 1H), 12.28 (br s, 1H).

Preparation 186: no-pyridinyl)-[7-(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin yl]-methanone N \ \ lN/ N Me%\/OMe The title compound was prepared according to the method described for Preparation 65 using (5-Bromo— pyridinyl)-[7-(2-methoxy-1 ,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]-metha none (Preparation 263) to afford the title compound as off white solid in 41% yield, 650 mg. 1H NMR (400 MHz, DMSO-D6) 6 1.76 (s, 6H), 3.19 (s, 3H), 3.96 (s, 2H), 5.65 (s, 2H), 7.30 (s, 1H), 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+H]+.

Preparation 187: (7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidinyl)—(5-methylamino-pyridinyl)-methanone W0 2012/137089 192 N—Me o /\ N|\ \ kN/ N [5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidine-5—carbonyl)—pyridiny|]-methy|-carbamic acid tert-butyl ester (Example 542) was treated with 4N HCI in Dioxane at room temperature 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) 6: 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 m 10): R = 2.74 min; m/z 310 .

Preparation 188: 1,5—naphthyridinylacetic acid N\ \ 0 I / / A mixture of 3-bromo-1,5-naphthyridine (540 mg, 2.58 mmol), diethylmalonate (0.8 mL, 5.17 mmol) and cesium 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 temperature, 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 phthyridinylacetate.

Sodium hydroxide (10 mL, 2.0 M) was added to ethyl 1,5-naphthyridinylacetate in 1,4-dioxane (10 mL) and the mixture was heated at 100 °C for 6 hours. The reaction mixture was cooled to room temperature and acidified to pH 4 using aqueous 2M HCI and then evaporated in vacuo. The residue was azeotroped with toluene (2 x 15 mL) then dissolved in THF (50 mL) and d at 40 °C for 30 min. The mixture was filtered, the filtrate was evaporated in vacuo and the residue was triturated with diethyl ether to afford the title compound as an off white solid, 200 mg. 1H NMR (400 MHz, DMSO-da) 6: 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 m 10): R = 1.49 min; m/z187[M-H]+ Preparation 189: Tert-butyl 1H-pyrazo|o[4,3-b]pyridiny|acetate W0 2012/137089 193 / \ N\ | Me 0V Tert—butyl bromoacetate (0.55 mL, 3.69 mmol) was added to 1H-pyrazolo[4,3-b]pyridine (220 mg, 1.85 mmol) and Cs2CO3 (723mg, 2.22 mmol) in anhydrous DMF (7 mL). The e was stirred at room temperature 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-Da) 6: 1.39 (s, 9H), 5.32 (s, 2H), 7.42 (dd, 1H), 8.14 (d, 1H), 8.32 (s, 1H), 8.55 (d, 1H).

Preparation 190: 1H-Pyrazolo[4,3-b]pyridinylacetic acid / \ N\ I Tert—butyl azolo[4,3,b]pyridinylacetate (Preparation 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 temperature 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. 1H NMR (400 MHz, DMSO-Ds) 6: 5.36 (s, 2H), 7.51 (dd, 1H), 8.30 (d, 1H), 8.36 (s, 1H), 8.62 (d, 1H); LCMS m 10): R = 1.39 min; m/z176[M-H]+.

Preparation 192: 2-(3-formylphenyl)-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridin yl}acetamide Me’< Dess Martin Periodinane (392 mg, 0.93 mmol) was added to a solution of (2-[3-(hydroxymethyl)phenyl]—N- -isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}acetamide (Preparation 193, 265 mg, 0.62 mmol) in dichloromethane (15 mL) and the mixture was d at room temperature for 18 hours.

Water (10 mL) was added and the aqueous layer extracted with a 95:5 mixture of dichloromethane/methanol (3 x 10 mL). The combined organic layers were dried over magnesium sulfate W0 2012/137089 194 and concentrated in vacuo. The residue was purified by column tography 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 .

Preparation 193: 2-[3-(hydroxymethyl)phenyl]-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5— yl)carbonyl]pyridinyl}acetamide Me’< A mixture of (5-aminopyridinyl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)methanone ration 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 ature 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) 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 itate was filtered off and dried in vacuo to afford the title compound as a white solid, 412 mg, which was used crude in subsequent reactions.

LCMS (System 2): R = 1.33 min; m/z 430 .

Preparation 194: (5-((Diphenylmethylene)amino)pyridinyl)(7H-pyrrolo[2,3-d]pyrimidinyl)methanol /N O N \ N N N H O A mixture of 7H-pyrrolo[2,3-d]pyrimidine (Preparation 202, 953 mg, 8.0 mmol), 5- [(diphenylmethylene)amino]nicotinaldehyde ration 106, 3340 mg, 11.7 mmol) and KOH (1350 mg, 24 mmol) in MeOH (16 mL) was stirred for 16 hours at room temperature. 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.

W0 2012/137089 195 1H NMR (400 MHz, DMSO-d6) 6: 5.88-5.99 (m, 2H), .99 (m, 1H), 7.04-7.14 (m, 3H), .27 (m, 3H), 7.43-7.51 (m, 2H), 7.51-7.58 (m, 1H), .69 (m,2H), 7.89 (d, 1H), 8.21 (d, 1H), 8.72 (s, 1H), 8.73 (s, 1H), 11.92 (brs, 1H) Preparation 195: (5-((Diphenylmethylene)amino)pyridinyl)(7H-pyrrolo[2,3-d]pyrimidinyl)methanone N\ N WuI 0 To a stirred solution of (5-((Diphenylmethylene)amino)pyridinyl)(7H-pyrrolo[2,3-d]pyrimidin yl)methanol (Preparation 194, 1820 mg, 4.5 mmol) in MeCN (45 mL) was added Mn02 (1960 mg, 22.5 mmol) portionwise and the resulting mixture stirred at 50 °C overnight. Another n of Mn02 (1960 mg, 22.5 mmol) was added to the reaction and the mixture heated to reflux for 5 hr. After cooling to room temperature, 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 tography 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. 1H NMR (400 MHz, DMSO-d6) 6: 7.24-7.33 (m, 2H), 7.37-7.64 (m, 7H), .78 (m, 3H), 8.28 (d, 1H), 8.53 (d, 1H), 8.94 (s, 1H), 9.41 (s, 1H), 13.09 (brs, 1H) Preparation 196: (5-aminopyridinyl){7-[2-{[tert-butyl(dimethyl)silyl]oxy}({[tert- dimethyl)silyl]oxy}methyl)ethyl]—7H-pyrrolo[2,3-d]pyrimidinyl}methanone \\ / NC\ NH N/ N OTBDMS OTBDMS A mixture of (5-((Diphenylmethylene)amino)pyridinyl)(7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 195, 1120 mg, 2.77 mmol) and Cs2C03 (2710 mg, 8.31 mmol) in DMF (10 mL) was stirred at room temperature for 30 min. A solution of crude 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9- disilaundecanyl trifluoromethanesulfonate (Preparation 108) in DMF (3.8 mL) was then added to the reaction and the resulting mixture stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (100 mL) and the mixture extracted with EtOAc (100 W0 2012/137089 196 mLx3). The combined c layers were washed with water (200 mL), dried over sodium sulfate and concentrated in vacuo. The ing material was purified by column chromatography on silica gel (gradient of heptane:EtOAc 100:0 to 50:50) to provide (5-((diphenylmethylene)amino)pyridinyl)(7- (2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecanyl)-7H-pyrrolo[2,3-d]pyrimidin yl)methanone.

The above material was dissolved in THF (20 mL) and aqueous 1N citric acid (20 mL) was added to the solution. The reaction e was stirred for 4 hours at room temperature, 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 ons were dried over Na2804 and concentrated in vacuo. The resulting material was purified by column chromatography on silica gel ne: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) 6: -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).

Preparation 197: 3-(3-(trifluoromethyl)-3H-diazirinyl)benzoic acid 0 N~‘N F F Ethyl 3-(3-(trifluoromethyl)-3H-diazirinyl)benzoate (Preparation 198, 60 mg, 0.23 mmol) was stirred in a 2:1 e of THF:water (2mL). Lithium hydroxide (5 mg. 0.23 mmol) was added and the e stirred at 25° C for 18 hours. The reaction mixture was acidified to pH 1 using 6M aqueous hydrochloric acid and then extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over magnesium 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 t further purification.

Preparation 198 Methyl 3-(3-(trifluoromethyl)-3H-diazirinyl)benzoate MeAO o Ethyl 3-(3-(trifluoromethyl)diaziridinyl)benzoate (Preparation 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 e 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) 6: 1.40 (t, 3H), 4.38 (q, 2H), 7.46-7.51 (m, 2H), 7.83 (s, 1H), 8.08 (d, 1H).

Preparation 199: Ethyl 3-(3-(trifluoromethyl)diaziridinyl)benzoate W0 2012/137089 197 To a solution of ethyl 3-(2,2,2-trifluoroacetyl)benzoate (500 mg, 2.15 mmol) in ethanol was added pyridine (5 mL) and hydroxylamine hloride (500 mg, 7.2 mmol) and the resulting e stirred at 57°C for 3 hours. The reaction mixture was cooled and passed through an ion exhange column g with methanol (30 mL). The methanol solution was evaporated in vacuo to give (E)-ethyl 3-(2,2,2-trifluoro- 1-(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(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-methylbenzenesu|fony| chloride (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 temperature for 18 hours. The mixture was diluted with water (10 mL) and the organic layer separated, dried over magnesium sulfate and evaporated in vacuo to afford (E)-ethyl 3-(2,2,2-trifluoro ((tosyloxy)imino)ethyl)benzoate as an oil in 78% yield, 500 mg. This material was used in the next step without further purification. A e of hyl 3-(2,2,2-trifluoro((tosyloxy)imino)ethyl)benzoate (500 mg, 1.2 mmol) in diethylether (5 mL) in a 3-necked flask equipped with an internal thermometer and sor 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 to room temperature overnight with stirring. The mixture was evaporated in vacuo and the crude al purified by column chromatography on silica gel ent 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,CDCI3) 6: 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). ation 200: 3-(2,2,2-trifluoroacetyl)benzoic acid O OH The title compound was prepared according to the method described for Preparation 42 starting from ethyl 3-(2,2,2-trifluoroacetyl)benzoate to afford the title compound as a white solid in 26% yield, 23 mg. 1H NMR (400 MHz,CDCI3) 6: 7.71 (t, 1H), 8.32 (d, 1H), 8.45 (d, 1H), 8.80 (s, 1H).

W0 2012/137089 198 2012/051363 Preparation 201: 5-iodo—7H-pyrrolo[2,3-d]pyrimidine I \ K N A mixture of 7H-pyrrolo[2,3-d]pyrimidine (Preparation 202, 28.0 g, 235 mmol) and N-iodosuccinimide (55.4 g, 246 mmol) in acetonitrile (470 mL) was stirred at room temperature 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 en chloride solution until ~pH 9. The resulting precipitate was filtered, rinsed with water (300 mL), and dried in vacuo for 16 hours at 70 oC, ~10 mbar, to afford the title compound in 81% yield, 46.84 g. 1H NMR (400 MHz, a) 6: 7.82 (s, 1H), 8.73 (s, 1H), 8.80 (s, 1H), 12.56 (br s, 1H); LCMS (system 1): R = 0.87 min; m/z 246 [M+H]+.

Preparation 202: 7H-pyrrolo[2,3-d]pyrimidine k\N I \ In each of four separate reaction vessels, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (50.0 g, 260 mmol) was suspended in ethanol (1.4 L) and concentrated ammonium ide on (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 temperature overnight. Those reactions still ning starting material were charged with another 1 g of 10% palladium on carbon, pressurized to 20 psi hydrogen and stirred until the starting material had been consumed. The reaction mixture was ed over Arbocel, washed with ethanol, and the filtrate was evaporated to obtain a white solid. The four crude reaction ts were combined, suspended in 500 mL water and extracted with ethyl acetate (3 x 500 mL). The organic layers were ed, dried over magnesium 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% ol in ethyl acetate (3 x 500 mL), the organic layers combined, dried over magnesium 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. 1H NMR (400 MHz, CDCI3) 6: 6.63 (dd, 1H), 7.43 (dd, 1H), 8.96 (s, 1H), 9.07 (s, 1H), 11.65 (br. s., 1 H).

Preparation 203: N-(5-{7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-oxetanyl]-7H-pyrrolo[2,3- d]pyrimidinecarbonyl}-pyridinyl)(4-chloro—phenyl) acetamide: W0 2012/137089 199 (5-Amino-pyridinyl)-{7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-oxetanyl]-7H-pyrrolo[2,3-d]pyrimidin- methanone (Preparation 216, 30 mg, 0.068 mmol) was ved in dry pyridine (2 mL) under nitrogen and to this was added (4-chloro-phenyl)—acetic acid (17 mg, 0.102 mmol), ed by HATU (39 mg, 0.102 mmol). The on was heated to 50°C and stirred overnight. The reaction was cooled to room temperature, 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 trated to dryness to afford N-(5-{7-[3-(tert-butyl-dimethyl- silanyloxymethyl)-oxetanyl]-7H-pyrrolo[2,3-d]pyrimidinecarbonyl}-pyridinyl)(4-chloro-phenyl)- acetamide as a pale yellow solid 35 mg, 87% yield. 1H NMR (400 MHz, CDCI3) 65-023 (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) .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).

Preparation 204: N-(5-{7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-oxetanyl]-7H-pyrrolo[2,3- d]pyrimidinecarbonyl}-pyridinyl)(4-trifluoromethyl-phenyl)-acetamide: (5-Amino-pyridinyl)-{7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-oxetanyl]-7H-pyrrolo[2,3-d]pyrimidin- -yl}-methanone (Preparation 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 d overnight. The reaction was then cooled to room temperature, 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-silanyloxymethyl)-oxetanyl]-7H-pyrrolo[2,3-d]pyrimidinecarbonyl}-pyridinyl)- 2-(4-trifluoromethyl-phenyl)-acetamide as a pale yellow solid 39 mg, 92% yield. 1H NMR (400 MHz, DMSO-da) 63-029 (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).

W0 37089 200 Preparation 205: 2-Allyl-malonic acid diethyl ester H2C— o O > Malonic acid diethyl ester (100 g, 0.625 mol) was added dropwise at 0°C to a mixture of sodium de (46.8 g, 0.688 mol) in ethanol (1 L). The reaction mixture was d 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 temperature, 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.

Preparation 206: 5-Allylhydroxy-3H-pyrimidinone kx I N OH l-malonic acid diethyl ester (Preparation 205, 100 g, 0.5 mol) was added dropwise to a mixture of sodium methoxide (27 g, 0.5 mol) in l (1 L) at 0-5°C and the mixture was stirred at this temperature for 10 min. Formamidine acetate (51.9 g, 0.5 mol) was added and the e was stirred at room temperature 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-da) 6: 2.96 (d, 1H), 4.89 (m, 2H), 5.76 (m, 1H), 7.89 (s, 1H).

Preparation 207: 5-Allyl-4,6-dichloro-pyrimidine k\N Cl 5-Allylhydroxy—3H-pyrimidinone (Preparation 206, 40 g, 0.263 mol) was added to POCI3 (100 mL) at room temperature. 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 e (500 mL x 4), washed with brine (300 mL), dried over sodium sulfate and evaporated in vacuo to afford the title compound as a yellow oil in 59% yield, 31 g. 1H NMR (400 MHz,CDCI3 ) 6: 3.59 (m, 2H), 5.09 (m, 2H), 5.79 (m, 1H), 8.59 (s, 1H).

Preparation 208: (4,6-Dichloro-pyrimidinyl)-acetaldehyde W0 2012/137089 201 k\N | To a stirred on of 5-Allyl-4,6-dichloro-pyrimidine (Preparation 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 d 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 CI3) 6: 4.15 (s, 2H), 8.74 (s, 1H), 9.80 (s, 1H).

Preparation 209: 2-(4-Chloro-pyrrolo[2,3-d]pyrimidinyl)hydroxymethyl-propane-1,3-diol N \ \ KN/ N ine (1.27 g, 10.5 mmol) was added to 4,6-Dichloro-pyrimidinyl)-acetaldehyde (Preparation 208, 1.0 g, 5.2 mmol) in ethanol (40 mL) and stirred at reflux temperature 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 ted 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) 8 ppm 2.97 (br. s, 1H), 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, 1H); LCMS (System 2): R = 1.04 min; m/z 258 [M+H]+.

Preparation 210: esulfonic acid 2-(4-chloro-pyrrolo[2,3-d]pyrimidinyl)hydroxy hydroxymethyl-propyl ester NI \ \ kN/ N HO7‘ ,9 0‘8: OH 0 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]pyrimidinyl)hydroxymethyl-propane-1,3-diol (Preparation W0 2012/137089 202 209, 650 mg, 2.52 mmol) in dichloromethane (20 mL) at 0°C. The mixture was d portion-wise with tosyl chloride (505 mg, 2.65 mmol) and stirred at 0°C for 16 hours. The reaction e was treated with water and stirred for 10 min. The resulting mixture was washed with citric acid, ted aqueous sodium bicarbonate, and saturated brine, then ated in vacuo. The crude product was purified by column tography on silica gel ent of EtOAc:DCM 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]+.

Preparation 211: Chloro-pyrrolo[2,3-d]pyrimidinyl)-oxetanyl]-methanol nButyllithium (12.2 mL, 30.6 mmol, 2.5 M in hexanes) was added to toluenesulfonic acid 2-(4-chloro- pyrrolo[2,3-d]pyrimidinyl)hydroxyhydroxymethyl-propyl ester (Preparation 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 temperature and stirred for 16 hours, at which point it was quenched with saturated aqueous ammonium chloride. The ing 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) 6: 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).

Preparation 212: 7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-oxetanyl]chloro-7H-pyrrolo[2,3- d]pyrimidine NI \ \ kN/ N TBDMSO i’ lmidazole (277 mg, 4.07 mmol) was added to [3-(4-Chloro-pyrrolo[2,3-d]pyrimidinyl)-oxetanyl]- methanol (Preparation 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 temperature 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.

W0 2012/137089 203 1H NMR (400 MHz, CDCI3) 6: -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+H]+.

Preparation 213: 7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-oxetanyl]-7H-pyrrolo[2,3-d]pyrimidine N \ \ m/NN fiOTBDMS The title compound was prepared according to the method bed for Preparation 8 using tert- Butyl-dimethyl-silanyloxymethyl)-oxetanyl]chloro-7H-pyrrolo[2,3-d]pyrimidine (Preparation 212) to afford the title compound as a brown oil in 82% yield, 650 mg. 1H NMR (400 MHz, CDCI3) 6: -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+H]+.

Preparation 214: 7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-oxetanyl]—5-iodo-7H-pyrrolo[2,3- d]pyrimidine I S OTBDMS The title compound was prepared according to the method described for Preparation 14 using tert- Butyl-dimethyl-silanyloxymethyl)-oxetanyl]—7H-pyrrolo[2,3-d]pyrimidine (Preparation 213) and DMF to afford the title compound as a brown solid in 75% yield, 675 mg. 1H NMR (400 MHz, CDCI3) 6: -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, 1H), 8.77 (s, 1H), 8.81 (s, 1H); LCMS (system 2): R = 1.55 min; m/z 446 [M+H]+.

Preparation 215: (7-(3-(((tert-Butyldimethylsilyl)oxy)methyl)oxetanyl)-7H-pyrrolo[2,3-d]pyrimidin yl)(5-((diphenylmethylene)amino)pyridinyl)methanone fiOTBDMS The title compound was prepared according to the method described for Preparation 24 using 7-[3-(tert- butyl-dimethyl-silanyloxymethyl)-oxetanyl]—5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 214) and 5- W0 2012/137089 204 enylmethylene)amino]-N-methoxy-N-methylnicotinamide (Preparation 23) to afford the title compound as a purple solid in 51% yield, 240 mg. 1H NMR (400 MHz, CDCI3) 6: 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 Hz, 2H), 8.18 (d, J=2.54 Hz, 1H), 8.60 (d, J=1.95 Hz, 1H), 8.93 (s, 1H), 9.60 (s, 1H).

Preparation 216: (5-Amino-pyridinyl)-{7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-oxetanyl]-7H- pyrrolo[2,3-d]pyrimidinyl}-methanone fiomoms The title compound was prepared according to the method bed for ation 37 using (7-(3- (((tert-butyldimethylsilyl)oxy)methyl)oxetanyl)-7H-pyrrolo[2,3-d]pyrimidinyl)(5- ((diphenylmethylene)amino)pyridinyl)methanone (Preparation 215) to afford the title compound as a colourless solid in 76% yield, 132 mg. 1H NMR (400 MHz, CDCI3) 6: 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).

Preparation 217: 2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidinyl)methylpropane-1,3-diol N/g” How9 OH The title compound was prepared according to the method described for Preparation 1 using (4,6- dichloropyrimidinyl)acetaldehyde (Preparation 208) and 2-aminomethylpropane-1,3-diol to afford the title compound as a yellow liquid in 79% yield, 3.88 g. 1H NMR (400 MHz, DMSO-da) 6: 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).

Preparation 218: 4-chloro(3-methyloxetanyl)-7H-pyrrolo[2,3-d]pyrimidine N/ \ u | N N ZSMe W0 2012/137089 205 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-7H- pyrrolo[2,3-d]pyrimidinyl)methylpropane-1,3-diol (Preparation 217, 3.63 g, 15.0 mmol), in THF (80 mL) at -78 °C. The reaction mixture was allowed to warm to -50 °C in 2 hours and TsCl (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 temperature, the on was quenched by 50 mL of ted aqueous NH4C| solution and 100 mL of water, and the e was extracted with EtOAc (3x 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude e was purified by column chromatogranhy on silica gel ent of EtOAc:heptane 20:80 to 70:30) to give a solid in 55% yield, 1.87 mg. 1H NMR (400 MHz, DMSO-da) 6: 1.79 (s, 3H) 4.72 (d, 2H) 5.15 (d, 2H) 6.69 (d, 1H) 7.78 (d, 1H) 8.59 (s, 1H).

Preparation 219: 7-(3-methyloxetanyl)-7H-pyrrolo[2,3-d]pyrimidine NfiKN NZSMQ The title compound was prepared according to the method described for Preparation 8 using 4-chloro (3-methyloxetanyl)-7H-pyrrolo[2,3-d]pyrimidine (Preparation 218) to afford the title compound as a yellow liquid in 22% yield, 0.341 g. 1H NMR (400 MHz, DMSO-da) 6: 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, 1H), 9.02 (s, 1H).

The title compound may also be prepared ing 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 pyrrolo[2,3-d]pyrimidinyl-propane-1,3-diol (Preparation 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 TsCl (2.76 g, 14.5 mmol) as a solution in THF (50 mL) was slowly added. The mixture was d for another 1 hour at 0°C. TLC showed consumption of starting al and another equivalent of LiHMDS (14.5 mL, 14.5 mmol) was added to the mixture and it was heated at 60° for 16 hours. Sat. aq. NH4C| solution (200 mL) was then added and the mixture then extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na2804) 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 W0 37089 206 Preparation 220: 5-iodo(3-methyloxetanyl)-7H-pyrrolo[2,3-d]pyrimidine I \ K N N Me The title compound was prepared according to the method described for Preparation 14 using 7-(3- methyloxetanyl)-7H-pyrrolo[2,3-d]pyrimidine (Preparation 219) to afford the title compound as a yellow solid in 78% yield, 0.44 g. 1H NMR (400 MHz, DMSO-D6) 6: 1.80 (s, 3H), 4.71 (d, 2H), 5.18 (d, 2H), 7.94 (s, 1H), 8.76 (s, 1H), 8.82 (s, 1H).

Preparation 221: (5-((diphenylmethylene)amino)pyridinyl)(7-(3-methyloxetanyl)-7H-pyrrolo[2,3- d]pyrimidinyl)methanone The title compound was prepared according to the method described for Preparation 24 using 5-iodo (3-methyloxetanyl)-7H-pyrrolo[2,3-d]pyrimidine ration 220) to afford the title compound.

LCMS (system 2): R = 1.24 min; m/z 474 [M+H]+. ation 222: (5-aminopyridinyl)[7-(3-methyloxetanyl)-7H-pyrrolo[2,3-d]pyrimidinyl]methanone Nk/l NH2 \N NMe The title compound was prepared according to the method described for Preparation 37 using (5- ((diphenylmethylene)amino)pyridinyl)(7-(3-methyloxetanyl)-7H-pyrrolo[2,3-d]pyrimidin yl)methanone (Preparation 221) to afford the title compound as a white solid in 14% yield over two steps, 64 mg. 1H NMR (400 MHz, DMSO-da) 6: 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]+.

W0 2012/137089 207 Preparation 223: N-[5-({7-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)oxetanyl]—7H-pyrrolo[2,3- m idinyl}carbonyl)pyrid inyl]—2-(5-chloropyridinyl)acetamide \/0/ / N / OTBDMS (5-Amino-pyridinyl)-{7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-oxetanyl]-7H-pyrrolo[2,3-d]pyrimidin- methanone (Preparation 216, 30 mg, 0.068 mmol) was added to a stirred mixture of (5- chloropyridinyl)acetic acid (17.5 mg, 0.102 mmol) and HATU (38.8 mg, 0.102 mmol) in pyridine (2 ml).

The on mixture was warmed to 50°C and stirred at this ature 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 temperature for 8 hours and then allowed to cool to room temperature and stirred for a further 60 hours. The on mixture was then diluted with DCM (20ml) and the ant 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 preparation of Example 238.

Preparation 224: N-[5-({7-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)oxetanyl]—7H-pyrrolo[2,3- d]pyrimidinyl}carbonyl)pyridinyl]—2-[3-(trifluoromethyl)-1H-pyrazolyl]acetamide \ / O CF3 N / \ ”kiwi; OTBDMS (5-Amino-pyridinyl)-{7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-oxetanyl]-7H-pyrrolo[2,3-d]pyrimidin- -yl}-methanone (Preparation 216, 30 mg, 0.068 mmol) was added to a stirred mixture of [3- (trifluoromethyl)—1H-pyrazolyl]acetic acid (19.8 mg, 0.102 mmol) and HATU (38.8 mg, 0.102 mmol) in pyridine (2 ml). The on mixture was warmed to 50°C and stirred at this temperature for 14 hours.

The reaction mixture was then cooled to room temperature and diluted with DCM (20ml) and the resultant 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 preparation of Example 239.

Preparation 225: 4-Chloroiodo-7H-pyrrolo[2,3-d]pyrimidine W0 2012/137089 208 “I”\ 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 N- iodosuccinimide (120 g, 0.54 mol) in portions. After on, the mixture was stirred at room temperature ght. The solid was filtered and washed with water (250 mL), MeOH (280 mL) and CHZCIZ (280 mL) sequentially. The solid was dried under vacuum to afford roiodo-7H-pyrrolo[2,3-d]pyrimidine as a brown solid in 79% yield, 107g.

Preparation 226: 4-Chloroiodomethyl-7H-pyrrolo[2,3-d]pyrimidine ”C”\ To a mixture of 4-chloroiodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 225, 30 g, 0.1 mol), Cs2C03 (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 temperature 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 EtZO (100 mL) to afford 4-chloroiodomethyl-7H-pyrrolo[2,3-d]pyrimidine as a brown solid in 61% yield, 20g.

Preparation 227: 5-Bromo-N-methoxy-N-methyl-nicotinamide Br OMe \ N/ | | / Me To a solution of 5-bromo-nicotinic acid (100 g, 0.5 mol) in THF (2 L) at 0°C, (COC|)2 (95 g, 0.74 mol) was added. After stirring for 0.5 h, Et3N (152 g, 1.5 mol) and O, N-dimethyl hydroxylamine.HCl (140 g, 1.5 mol) were added. The reaction mixture was stirred at room temperature for 2.5 hours and then water (200 mL) and EtOAc (500 mL) were added. The organic layer was separated, dried (MgSO4) and trated in vacuo to afford 5-the title compound as a brown oil in 82% yield, 100%.

Preparation 228: (4-Chloromethyl-7H-pyrrolo[2,3-d]pyrimidinyl)(5- ((diphenylmethylene)amino)pyridinyl)methanol W0 2012/137089 209 To stirred solution of 4-chloroiodomethyl-7H-pyrrolo[2,3-d]pyrimidine ration 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 d for 50 min. A solution of 5- ((diphenylmethylene)amino)nicotinaldehyde (Preparation 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. NH4C| solution and extracted with EtOAc (300 mL). The organic layer was dried 4) and concentrated in vacuo to give the title compound as a brown solid in 48% yield, 5.2g.

Preparation 229: (4-chloromethyl-7H-pyrrolo[2,3-d]pyrimidinyl)(5- ((diphenylmethylene)amino)pyridinyl)methanone CI \/ To a solution of (4-chloromethyl-7H-pyrrolo[2,3-d]pyrimidinyl)(5-((diphenylmethylene)amino)pyridin- 3-yl)methanol (Preparation 228, 11.4 g, 25 mmol) in CHZCIZ (150 mL), artin periodinane (15.9 g, 37 mmol) was added in portions. The reaction mixture was stirred at room temperature 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 CHZCIZ (100 mL x 2). The combined organic layers were trated and washed with ether to provide the title compound as a brown solid in 99% yield, 11g. 1H NMR (400 MHz, CDCI3) 6 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=2.4,1H), 8.49 (d, J=1.2,1H), 8.68 (s, 1H).

Preparation 230: (5-Amino-pyridinyl)-(4-chloromethyl-7H-pyrrolo[2,3-d]pyrimidinyl)-methanone CI \ / [\L/ 2 I \ N N\ W0 2012/137089 210 A solution of [5-(benzhydrylidene-amino)pyridinyl]-(4-chloromethyl-7H-pyrrolo[2,3-d]pyrimidiny|)- methanone (Preparation 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 temperature. Ether was added and the layers were separated. The aqueous layer was ed to pH7 by aqueous Na2C03. 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 nd as a brown solid in 95% yield, 18g.

Preparation 231: (5-Amino-pyridinyl)-(7-methylmethylsulfanyl-7H-pyrrolo[2,3-d]pyrimidinyl)— methanone To a solution of (5-amino-pyridinyl)-(4-chloromethyl-7H-pyrrolo[2,3-d]pyrimidinyl)-methanone (Preparation 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 temperature. 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 no-pyridinyl)-(7-methyl-4—methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidinyl)-methanone as a brown solid in 69% yield, 15g.

Preparation 232: (5-Amino-pyridinyl)-(7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-methanone [\L/l NH2 N '1 A mixture of (5-amino-pyridinyl)-(7-methylmethylsulfanyl-7H-pyrrolo[2,3-d]pyrimidinyl)-methanone (Preparation 231, 1.5 g, 5 mmol), Raney Ni (10 g) and NH3H20 (150 mL) in e (150 mL) was refluxed for 6 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified via preparative HPLC to give (5-amino-pyridinyl)-(7-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-methanone as a brown solid in 15% yield, 0.19g. 1H NMR (400 MHz DMSO-da) 3.88 (s, 3H), 5.63 (s, 2H), .28 (m, 1H), 8.15-8.18 (m, 2H), 8.40 (s, 1H), 8.97 (s, 1H), 9.42 (s, 1H).

Preparation 233: 5,6,7,8-Tetrahydro-[1,7]naphthyridine hloride HN / HCI A methanolic solution (25 mL) of 7-Benzyl-5,6,7,8-tetrahydro-[1,7]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 HCI in dioxane (2 mL) and Pd/C (300 mg, 20 wt%) and stirred under 50 psi hydrogen pressure at room W0 2012/137089 211 temperature 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 s in vacuo and crystallized from methanol to afford the title compound as yellowish solid in 65% yield (calculated as 2HC| salt), 900 mg. 1H NMR (400 MHz, DMSO-D6) 6: 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 = 1.56 min; m/z135.2 [M+H]+.

Preparation 234: (5,8-Dihydro-6H-[1,7]naphthyridinyl)-acetic acid tert-butyl ester Me O MeMe>l\oJJ\/ N(IiN/ A DMF solution (8 mL) of 5,6,7,8-Tetrahydro-[1,7]naphthyridinehydrochloride (Preparation 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 Na2804 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) 6: 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/z 249.4 [M+H]+.

Preparation 235: (5,8-Dihydro-6H-[1,7]naphthyridinyl)-acetic acid hydrochloride 0 \ HoJJ\/N I (5,8—Dihydro-6H-[1,7]naphthyridinyl)—acetic acid utyl ester (Preparation 234, 1.25 g, 5.03 mmol) was treated with 4N HCI in e (25 ml) at room temperature 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 HCI salt), 900 mg. 1H NMR (400 MHz, MeOD) 6: 3.38 (t, 2H), 3.79 (t, 2H), 4.38 (s, 2H), 4.84 (s, 2H), 7.79 (dd, 1H), 8.25 (d, 1H), 8.70 (d, 1H).

Preparation 236: Phenyl-[(tetrahydro-pyranyloxy)]—acetic acid O O 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 hydro-2H-pyran (1.55 g, 18.4 mmol). The mixture was stirred at 0°C for another 15 min and then lly warmed up to room temperature and stirred for a r 1.5 hours. The reaction mixture was d with DCM (100 mL). The c phase was washed with saturated aq. Na2CO3 (2 x 20 mL), water (20 mL), brine (20 mL), dried (NaZSO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel W0 2012/137089 212 (EtOAc:petro|eum ether 2:5) to afford the title compound as a yellow sticky solid in 48% yield, 1.5 g.

LCMS (system 10): R = 1.82 min; m/z 237 [M+H]+.

Preparation 237: N-[5-(7-lsopropyl-7H-pyrrolo[2,3-d]pyrimidinecarbonyl)—pyridinyl]phenyl hydro-pyranyloxy)—acetamide \ / O t.\ N \ WC» N N O )‘Me Me C70 The title nd was prepared according to the method described for Example 1 using phenyl- [(tetrahydro-pyranyloxy)]-acetic acid (Preparation 236) and no-pyridinyl)-(7-isopropyl-7H- pyrrolo[2,3-d]pyrimidinyl)—methanone (Preparation 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]+.

Preparation 238: 5-Bromohydroxy—nicotinic acid HO \ N/ OH Bromine (3.6 mL, 70.5 mmol) was added dropwise to a suspension of oxy—nicotinic acid (7 g, 50.32 mmol) in water (70 mL) at 0°C and the mixture was stirred at room temperature 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. 1H NMR (400 MHz, DMSO-D6) 6: 8.03 (d, 1H), 8.14 (d, 1H), 12.57 (brs, 1H).

Preparation 239: 5-Bromohydroxy—N-methoxy—N-methyl-nicotinamide Me\ Br N \ . | ,o / Me N OH 5-Bromohydroxy—nicotinic acid (Preparation 238, 4 g, 18.4 mmol), HATU (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 ous DMF (30 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (150 mL), washed with saturated aq. Na2C03 (2 x 50 mL), water (4 x 30 mL), brine (30 mL), dried (Na2804) and ated 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) 6: 3.22 (s, 3H), 3.61 (s, 3H), 7.95 (d, 1H), 8.14 (d, 1H), 12.45 (brs, 1H); LCMS (system 10): R = 1.67 min; m/z 261, 263 [M+H]+.

Preparation 240: 5-Bromoethoxy—N-methoxy—N-methyl-nicotinamide W0 2012/137089 213 Me\N Br I I Me’O N/ OK A mixture of 5-bromohydroxy-N-methoxy—N-methyl-nicotinamide (Preparation 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 d at room ature for 40 hours. The reaction mixture was diluted with DCM (50 mL), washed with water (2 x 30 mL), brine (20 mL), dried (Na2804) 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) 6: 1.44 (t, 3H), 3.35 (s, 3H), 3.57 (s, 3H), 4.47 (q, 2H), 8.23 (d, 1H), 8.54 (d, 1H).

Preparation 241: (5-Bromoethoxy—pyridinyl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)— methanone / O\/Me NI \ \ kN/ N >‘Me A solution of 5-lodoisopropyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 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-Bromoethoxy-N-methoxy—N-methyl-nicotinamide (Preparation 240) in anhydrous diethyl ether (7 mL) was added slowly to the mixture and it was d at the same temperature for r 1 hour. The reaction mixture was warmed to room ature and allowed to stir for another hour before being quenched with sat. aq. NH4C| (15 mL). The mixture was extracted with EtOAc (3 x 15 mL), washed with water (20 mL), brine (15 mL), dried (Na2804) and evaporated in vacuo.

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. 1H NMR (400 MHz, CDCI3) 6: 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, 1H), 8.57 (d, 1H), 9.00 (s, 1H), 9.53 (s, 1H).

Preparation 242: (5-Aminoethoxy—pyridinyl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidinyl)-methanone W0 2012/137089 214 \ [<1 O\/Me N \ \ lN/ N Me)‘Me Copper(|) oxide (38.6 mg, 0.27 mmol) was added to (5-Bromoethoxy—pyridin3-yl)-(7-isopropyl-7H- pyrrolo[2,3-d]pyrimidinyl)-methanone (Preparation 241, 350 mg, 0.89 mmol) in concentrated a solution (6 mL) and NMP (1 mL). The mixture was heated in a sealed vessel at 130°C for 17 hours. The reaction mixture was cooled to room temperature and diluted with water (10 ml). It was extracted with % i-PrOH in DCM (6 x 50 mL), dried (NaZSO4) and evaporated in vacuo. The crude material was ed 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 = 2.99 min; m/z 326 .

Preparation 243: 2-(4-Chloro-phenyl)hydroxy-propionic acid methyl ester l\|/le O OH 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. Paraformaldehyde (342 mg, 11.4 mmol) was then added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (100 mL), washed with water (3 x 20 mL), brine (20 mL), dried (Na2804) 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) 8: 2.23 (t, 1H), 3.70 (s, 3H), 3.79-3.83 (m, 2H), .12 (m, 1H), 7.20 (d, 2H), 7.30 (d, 2H); LCMS (system 10): R = 3.03 min; m/z 215 [M+H]+.

Preparation 244: hloro-phenyl)hydroxy-propionic acid HO OH To a stirred solution of 2-(4-Chloro-phenyl)hydroxy-propionic acid methyl ester (Preparation 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 temperature for 1 hour.

The reaction mixture was acidified (pH~3) with 2N hydrochloric acid and extracted with DCM (3 x 20 mL).

The combined c layers were washed with brine (10 mL), dried 4) and evaporated in vacuo to afford the title compound as a white solid in 90% yield, 420 mg.

W0 37089 215 1H NMR (400 MHz, 6) 6: 3.58 (dd, 1H), 3.66 (t, 1H), 3.87 (t, 1H), 7.32 (d, 2H), 7.38 (d, 2H), 12.36 (br, 1H).

Preparation 245: 1-(4-Chloro-pyrrolo[2,3-d]pyrimidinyl)-cyclopropanecarboxylic acid methyl ester To a stirred solution of (4,6-dichloro-pyrimidinyl)acetaldehyde (Preparation 208, 2 g, 10.5 mmol) and 1-Amino-cyclopropane-carboxylicacidmethylester hydrochloride (1.33 g, 11.6 mmol) in ethanol (30 mL) was added triethylamine (4.4 mL, 31.6 mmol) and the mixture heated in a sealed 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 temperature and diluted with DCM (200 mL). The organic layer was washed with water (2 x 50 mL), brine (50 mL), dried (Na2804) and evaporated in vacuo.

The crude material was ed by column chromatography on silica gel ent of hexane:EtOAc 100:0 to 90:10) to afford the title nd as a solid in 35% yield, 900 mg. 1H NMR (400 MHz, CDCI3) 6: .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 = 2.89 min; m/z 252.1 [M+H]+.

Preparation 246: 1-Pyrrolo[2,3-d]pyrimidinyl-cyclopropanecarboxylic acid methyl ester A solution of 1-(4-chloro-pyrrolo [2,3-d]pyrimidinyl)-cyclopropanecarboxylic acid methyl ester (Preparation 245, 920 mg, 3.65 mmol) in ethanol (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 temperature under hydrogen (balloon pressure) for 5 hours. The reaction mixture was filtered on a celite bed, washed with ethanol (2 x 10 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) 6: 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 m 10): R, = 2.22 min; m/z218.2 [M+H]+.

Preparation 247: (1-Pyrrolo[2,3-d]pyrimidinyl-cyclopropyl)-methanol W0 2012/137089 216 To a stirred solution of 1-Pyrrolo[2,3-d]pyrimidinyl-cyclopropanecarboxylic acid methyl ester (Preparation 246, 610 mg, 2.80 mmol) in ethanol (15 mL) was added sodium borohydride (318.7 mg, 8.42 mmol) and the e heated to reflux for 16 hours. The reaction mixture was quenched with water (5 mL) and ted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (5 mL), brine (5 mL), dried (Na2804) 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) 6: 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 = 1.67 min; m/z189.9[M+H]+.

Preparation 248: Tetrahydro-pyranyloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidine “3kN/ To a d solution of (1-Pyrrolo[2,3-d]pyrimidinyl-cyclopropyl)-methanol (Preparation 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 on mixture was cooled to room temperature, ed 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 nd as a light brown gum in 90% yield, 320 mg. 1H NMR (400 MHz, CDCI3) 6: 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]+.

Preparation 249: 5-lodo[1-(tetrahydro-pyranyloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidine To a stirred solution of 7-[1-(Tetrahydro-pyranyloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidine (Preparation 248, 390 mg, 1.43 mmol) in DMF (8 mL) was added N-iodosuccinimide (481.5 mg, 2.14 mmol) and stirred at room temperature for 4 hours. The reaction mixture was quenched with water (8 mL) and extracted with ethyl acetate (3 x 20 mL). The combined c layer was washed with water (5 x 15 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.

W0 2012/137089 217 1H NMR (400 MHz, coc13) 5: 1.13-1.70 (m, 10H), 3.23-3.32 (m, 1H), 3.42 (t, 1H), 3.65 (d, 1H), 3.37 (d, 1H), 4.47 (s, 1H), 7.44 (s, 1H), 3.70 (s, 1H), 3.90 (s, 1H); LCMS m 10): Rt = 3.23 min; m/z 400.2 [M+H]+.

Preparation 250: (5-Bromo-pyridinyl)-{7-[1-(tetrahydro-pyranyloxymethyl)-cyclopropyl]-7H- pyrrolo[2,3-d]pyrim idinyl}-methanone \ K] “C \ N N 0 av 0o To a stirred solution of 5-lodo[1-(tetrahydro-pyranyloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3- midine (Preparation 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-methyl- namide (304 mg, 1.24 mmol) in l ether (2.5 mL) was added drop wise at -70°C and stirred at same temperature for another 30 minutes. The reaction was allowed to warm to room temperature 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 nd as a light brown sticky solid in 35% yield, 250 mg. 1H NMR (400 MHz, DMSO-D6) 6: .57 (m, 10H), 3.17-3.28 (m, 2H), 3.64 (d, 1H), 3.95 (d, 1H), 4.57 (s, 1H), 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 = 3.17 min; m/z 456.8, 459 [M+H]+. ation 251: (5-Amino-pyridinyl)-{7-[1-(tetrahydro-pyranyloxymethyl)-cyclopropyl]-7H- pyrrolo[2,3-d]pyrimidinyl}-methanone \ K1 “1 \ \ kN/ N To a stirred solution of (5-Bromo-pyridinyl)-{7-[1-(tetrahydro-pyranyloxymethyl)-cyclopropyl]-7H- pyrrolo[2,3-d]pyrimidinyl}-methanone (Preparation 250, 200 mg, 0.45 mmol) in 1-Methyl-pyrrolidin one (1.5 mL) was added ammonium hydroxide (15 mL). Then copper (l) 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 temperature, extracted with 10% methanol in dichloromethane (5 x 25 mL). The combined organic layer was dried over sodium sulphate and evaporated in vacuo. The crude material was W0 2012/137089 218 purified by column chromatography on silica gel (gradient of dichloromethane:methano| 100:0 to 96:4) to afford the title compound as a white sticky solid in 45% yield, 80 mg. 1H NMR (400 MHz, 6) 8: 1.17-1.53 (m, 10H), .28 (m, 2H), 3.63 (d, 1H), 3.94 (d, 1H), 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 .

Preparation 252: (S)—2-Pyrrolo[2,3-d]pyrimidinyl-propano| Me\\\\ The title compound was prepared according to the method described for Preparation 8 using (2S)—2-(4- Chloro-7H-pyrrolo[2,3-d]pyrimidinyl)propano| (Preparation 4) to afford the title compound as a white solid in 100% yield, 2.8 g. 1H NMR (400 MHz, DMSO-d6) 8: 1.43 (d, 3H), .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).

Preparation 253: (2-Hydroxy-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester Me36 0 Me OANH Mei/OH To a mixture of 2-Aminomethyl-propano| (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 temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium te and evaporated in vacuo to afford the title compound as colourless oil in 92% yield, 3.9 1H NMR (400 MHz, CDCI3) 8: 1.23 (s, 6H), 1.42 (s, 9H), 3.56-3.58 (d, 2H), 4.00 (brs, 1H), 4.62 (brs, 1H).

Preparation 254: (2-Methoxy—1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester Me36 0 Me OANH MekOMe KOH (3.47 g, 61.82 mmol) was added to a solution of (2-Hydroxy-1,1-dimethyl-ethyl)-carbamic acid tert- butyl ester (Preparation 253, 3.9 g, 20.6 mmol) in 1,4-dioxane (30 mL) followed by the slow addition of dimethyl sulphate at room temperature. The mixture was further allowed to stir at room temperature for 48 hours. Reaction mass was filtered through a short pad of celite, washed with DCM (3 x 50 mL). The W0 2012/137089 219 combined filtrate was washed with water (2 x 50 mL), brine (30 mL), dried over sodium sulphate and evaporated in vacuo to afford the title compound as yellow oil in 88% yield, 3.7 g. 1H NMR (400 MHz, CDCI3) 6: 1.27 (s, 6H), 1.41 (s, 9H), 3.29 (s, 2H), 3.35 (s, 3H), 4.73 (brs, 1H).

Preparation 255: oxy-1,1-dimethyl-ethylamine Me#\/0Me 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 (Preparation 254, 3.2 g, 15.74 mmol) at 0°C. The mixture was allowed to stir at room temperature for another 3 hours and then all the volatiles were removed in vacuo. The residue was treated with aqueous saturated NaHCO3 solution (50 mL) and extracted with a mixture of lPA/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) 6: 1.32 (s, 6H), 3.30 (s, 2H), 3.35 (s, 3H), 7.80 (brs, 2H). ation 256: (5-Bromo—2-chloro-pyrimidinyl)-(2-methoxy-1,1-dimethyl-ethyl)—amine ClAN N/jBrI MeJVOMe Triethyl 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 (Preparation 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 temperature. TLC showed the presence of unreacted starting pyrimidine, but the reaction was not ued further. All the volatiles were removed in vacuo and the e was taken in ethyl acetate, washed with water, brine, dried over sodium sulphate and evaporated to s in vacuo. The crude material was ed by column chromatography on silica gel (100-200 mesh, gradient of ethyl acetate:hexane 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. 1H NMR (400 MHz, DMSO-D6) 6: 1.40 (s, 6H), 3.32 (s, 3H), 3.48 (s, 2H), 6.19 (s, 1H), 8.29 (s, 1H); LCMS (system 10): R = 3.56 min; m/z 294, 296 [M+H]+.

Preparation 257: [2-Chloro((E)ethoxy-viny|)-pyrimidinyl]-(2-methoxy-1,1-dimethyl-ethyl)—amine if\OMe N \ Cl N NH MeJVOMe The title compound was prepared according to the method bed for ation 61 using (5-Bromo— 2-chloro-pyrimidinyl)-(2-methoxy-1,1-dimethyl-ethyl)—amine (Preparation 256), catechol borane and ethoxyacetylene (40% in hexane) to afford the title compound as light brown gum in 44% yield, 2.6 g.

W0 2012/137089 220 2012/051363 1H NMR (400 MHz, DMSO-D6) 6: 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 = 3.65 min; m/z 286.3 [M+H]+.

Preparation 258: 2-Chloro—7-(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine CIAN/m3N MefiflOMe The title compound was prepared according to the method described for Preparation 62 using [2-Chloro- ethoxy-vinyl)-pyrimidinyl]-(2-methoxy-1,1-dimethyl-ethyl)—amine (Preparation 257) to afford the title compound as off white solid in 91% yield, 2g. 1H NMR (400 MHz, DMSO-D6) 6 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+H]+.

Preparation 259: 2-Chloroiodo—7-(2-methoxy—1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine The title compound was ed according to the method described for Preparation 63 using ro- 7-(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine (Preparation 258) to afford the title compound as yellowish solid in 75% yield, 2.3 g. 1H NMR (400 MHz, DMSO-D6) 6: 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]+.

Preparation 260: (5-Bromo—pyridinyl)-[2-chloro(2-methoxy—1,1-dimethyl-ethyl)-7H-pyrrolo[2,3- d]pyrimidinyl]-methanone CIA/N N The title compound was prepared according to the method described for Preparation 64 using 2-Chloro- -iodo—7-(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine (Preparation 259) and 5-Bromo-N- methoxy—N-methyl-nicotinamide to afford the title compound as yellow gum in 34% yield, 900 mg. 1H NMR (400 MHz, DMSO-D6) 6: 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).

Preparation 261: no(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]—(5-aminopyridinyl )-methanone W0 2012/137089 221 N \ \ JL / H2N N N Me+/OMe The title compound was prepared according to the method described for Preparation 65 using mo— pyridinyl)-[2-chloro(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]-methanone (Preparation 260) to afford the title compound as yellow solid in 41% yield, 300 mg. 1H NMR (400 MHz, 6) 6: 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+H]+.

Preparation 262: (2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine An anhydrous THF (100 mL) solution of 2-(5-lodo-pyrrolo[2,3-d]pyrimidinyl)methyl-propano| (Preparation 22) (32 g, 100.91 mmol) was added slowly to a sion of NaH (60% in in oil, 2.98 g, 121.13 mmol) in anhydrous THF (200 mL) at 0°C under nitrogen. The mixture was warmed to room temperature 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 temperature 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. 1H NMR (400 MHz, DMSO-D6) 6: 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+H]+.

Preparation 263: (5-Bromo—pyridinyl)-[7-(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin yl]-methanone \ :1 m / N Me%\/OM9 The title compound was prepared according to the method described for ation 64 using 5-lodo hoxy—1,1-dimethyl-ethyl)—7H-pyrrolo[2,3-d]pyrimidine (Preparation 262) and 5-Bromo—N-methoxy— N-methyl-nicotinamide to afford the title compound as light brown gum in 51% yield, 3g.

W0 2012/137089 222 1H NMR (400 MHz, DMSO-d6) 6: 1.76 (s, 6H), 3.19 (s, 3H), 3.96 (s, 2H), 8.17 (s, 1H), 8.42 (t, 1H), 8.98 (brs, 2H), 900 (s 1H), 947 (s 1H); LCMS (system 10): R: 3.13 mm m/z 388.6 390.6 [M+H].

Preparation 264: 2-(3,5-Difluoro-pyridinyl)-malonic acid diethyl ester 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 cesium ate (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 temperature 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 oil in 85% yield, 3.5 g. 1H NMR (400 MHz, CDCI3) 6: .30 (m, 6 H), 4.20-4.29 (m, 4 H), 4.88 (s, 1 H), .81 (m, 1 H), 8.01 (s, 1 H).

Preparation 265: (3,5-Difluoro-pyridinyl)-acetic acid F F 0 / HO N To a stirred solution of 2-(3,5-difluoro-pyridinyl)-malonic acid diethyl ester (1 g, 3.56 mmol) (Preparation 264) in THF (15 mL) was added a solution of lithium hydroxide monohydrate (462 mg, 10.4 mmol) in water (4 mL) se at 0°C and the mixture heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, acidified (pH ~3) with 2N hloric acid and extracted with 20% panol-dichloromethane (5 x 20 mL). The combined organic layers were dried (NaZSO4) and ated 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) 6 3.32 (s, 2H), 7.74-7.79 (m, 1H), 7.99 (t, 1H); LCMS (system 10): R = 0.65 min; m/z174[M+H]+.

Preparation 266: (4--Nitro-phenyl))-acetic acid ethyl ester Me“Wm To a stirred solution of (4--nitro--phenyl))-acetic acid (3 g, 16.4 mmol) in ethanol (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 (Na2804) 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) 6: 1.25 (t, 3H), 3.71 (s, 2H), 4.16 (q, 2H), 7.45 (d, 2H), 8.18 (d, 2H).

Preparation 267: (4-Amino-phenyl)—acetic acid ethyl ester W0 2012/137089 223 MeAO/K/Q/NHZ A solution of (4-n-itro--phenyl))-acetic acid ethyl ester (Preparation 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 temperature under hydrogen (balloon pressure) for 16 hours. The reaction mixture was 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) 8: 1.23 (t, 3H), 3.47 (s, 2H), 3.60 (br s, 2H), 4.11 (q, 2 H), 6.63 (d, 2H), 7.05 (d, 2H). ation 268: (4-Formylamino-phenyl)—acetic acid ethyl ester Me/\ O fH 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-amino-phenyl)—acetic acid ethyl ester (Preparation 267, 500 mg, 2.79 mmol) in THF (10 mL) was added slowly to the on mixture and the reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was lized with sat. aq. Na2CO3 solution and extracted with diethyl ether (2 x 25 mL). The ed organic layers were dried (Na2804) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel ent of OH 100:0 to 98:2) to afford the title compound as an oil in 93% yield, 500 mg. 1H NMR (400 MHz, DMSO-d6) 8: 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).

Preparation 269: (4-Methylamino-phenyl)—acetic acid ethyl ester Me“O/K/Q/Ezvle To a stirred solution of (4-formylamino-phenyl))-acetic acid ethyl ester ration 268, 500 mg, 2.41 mmol) in THF (10 mL) was added borane-dimethyl sulphide complex (0.3 mL, 3.13 mmol) at 0°C and the mixture stirred at room temperature for 1 hour. The reaction mixture was quenched with MeOH (5 mL) and evaporated in vacuo. The crude al 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) 8: 1.23 (t, 3H), 2.81 (s, 3H), 3.48 (s, 2H), 3.66 (br s, 1 H), 4.11 (q, 2H), 6.56 (d, 2H), 7.09 (d, 2 H).

Preparation 270: [4-(Methanesulfonyl-methyl-amino)-phenyl]-acetic acid ethyl ester W0 2012/137089 224 Me/\O/K/Q/(lfvl‘e To a stirred solution of (4-methylamino-phenyl))-acetic acid ethyl ester (Preparation 269, 418 mg, 2.16 mmol)'In ne (4 mL) was added methanesulfonyl chloride (0.25 mL, 3.24 mmol) and the mixture stirred at room temperature for 3 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried (Na2804) and evaporated in vacuo to afford the title compound as a gum in 78% yield, 460 1H NMR (400 MHz, CDCI3) 6: 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).

Preparation 271: [4-(Methanesulfonyl-methyl-amino)-phenyl]-acetic acid 0 Me HOWONIS’Me”\\ The title compound was ed according to the method described for ation 265 using [4- (methanesulfonyl-methyl-amino)-phenyl]-acetic acid ethyl ester (Preparation 270) to afford the title nd as a solid in 85% yield, 350 mg. 1H NMR (400 MHz, DMSO-D6) 6: 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]+.

Preparation 272: —5-methyl-pyridine N\Me To a stirred solution of 2-bromomethyl-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 se under reflux conditions and the reaction mixture was heated to reflux for 16 hours.

The reaction mixture was cooled to room temperature, quenched with sat. aq. Na2C03 solution (15 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (10 mL), dried (NaZSO4) 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]+.

Preparation 273: 2-(5-Methyl-pyridinyl)-malonic acid diethyl ester MeAO / MeAO 0 To a stirred solution of 2-lodo—5-methyl-pyridine (Preparation 272, 1 g, 4.57 mmol) and diethyl malonate (2.08 mL, 13.70 mmol) in anhydrous dioxane (12 mL) was added cesium carbonate (4.46 gm, 13.7 mmol) W0 2012/137089 225 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 resultant mixture was heated in a sealed tube at 100°C for 16 hours.

The reaction mixture was cooled to room temperature, quenched with water (25 mL) and extracted with EtOAc (3 x 25 ml). The combined organic layers were washed with water (2 x 10 mL) and brine (10 mL), dried (Na2804) 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) 6: 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).

Preparation 274: (5-Methyl-pyridinyl)-acetic acid O / HO N The title compound was prepared according to the method described for Preparation 265 using 2-(5- -pyridinyl)-malonic acid diethyl ester ration 273) to afford the title compound as a solid in 83% yield, 100 mg. 1H NMR (400 MHz, DMSO-D6) 6: 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]+.

Preparation 275: [1 ,2,4]triazolo[1 ,5-a]pyridinecarboxylic acid HO / xN \ N \ N/> To a on 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 °C for 12 hours. The mixture was then concentrated to give a residue. To the residue was added MeOH (381 mL), ed by NHZOHSO4 (31.9 g, 248 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to give methyl [1 ,2,4]triazolo[1 ,5-a]pyridinecarboxylate in 18% yield, 6g. To a solution of methyl [1 ,2,4]triazolo[1 ,5-a]pyridinecarboxylate (3 g, 16 mmol) in methanol was added 1M aq. LiOH (70 mL) and the ing e stirred for 10 hours at room temperature. The pH was adjusted to 5-6 using aq. HCI and the whole mixture extracted with EtOAc (30 mL><3).The combined organic layers were dried (Na2804) and concentrated in vacuo to give the title nd as a white solid in 38% yield, 1.05 g 1H NMR (400 MHz, DMSO-d6) 6: 7.56-7.58 (m, 1H), 8.32 (m, 1H), 8.66 (m, 1H), .06 (m, 1H), 13.5- 14.0 (s, 1H).

Preparation 276: 1-methyl-1H-pyrrolo[2,3-c]pyridinecarboxylic acid W0 2012/137089 226 1-methyl-1H-pyrrolo[2,3-c]pyridinecarbaldehyde (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-Methylbutene (120 mL of a 2M solution in THF, 46 mmol) was added followed by a solution of NaClOz (11.0 g, 122 mmol) and NaH2PO4 (21.9 g, 183 mmol) in water (30 mL). The on mixture was stirred at room temperature overnight under nitrogen. The reaction mixture was concentrated in vacuo to remove organic solvents, and the residue was filtered. The itate contained the title compound as a white solid in 57% yield, 4.1 g. 1H NMR (400MHz, DMSO-d6) 6: 3.96 (8, 3H), .89 (d, 1H), 8.23 (s, 1H), 8.28 (d, 1H), 8.91 (s, 1H), 12.3 (s, 1H). ation 277: 2-(4-Cyano-phenyl)-N-{5-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3- midinecarbonyl]-pyridinyl}-acetamide \ / 0 le \ N \ HW N/ N [SJ-Me Me Me The title compound was prepared according to the method described for Example 1 using (5-Aminopyridinyl )-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]-methanone (Preparation 103) and 4-cyanophenylacetic acid to afford the title compound as an off-white solid in 71% yield, 235 mg. 1H NMR (400 MHz, DMSO-D6) 6: -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, 1H), 10.75 (s, 1H); LCMS (System 10): R = 3.25 min; m/z 513 [M+H]+.

Preparation 278: 2-Methylpyrrolo[2,3-d]pyrimidinyl-propane-1,3-diol N \ \ kN/1%N MefiOH The title compound was prepared according to the method described for Preparation 246 using 2-(4- Chloro-pyrrolo[2,3-d]pyrimidinyl)methyl-propane-1,3-diol (Preparation 217) to afford the title compound as an ite solid in 93% yield, 800 mg. 1H NMR (400 MHz, DMSO-D6) 6: 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).

Preparation 279: N-(5-{7-[2-(tert-Butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7H-pyrrolo[2,3- d]pyrimidinecarbonyl}-pyridinyl)(4-cyclopropyl-pyrazoly|)-acetamide W0 2012/137089 227 \ / o le\ \ H/ZgN N N Me N. f | N TBDMSO Me The title compound was prepared according to the method described for Example 1 using (5-Aminopyridinyl )-{7-[2-(tert-butyl-dimethyl-silanyloxy)—1,1-dimethyl-ethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}- methanone (Preparation 38) and (4-Cyclopropyl-1H-pyrazolyl)acetic acid (Preparation 88) to afford the title compound as an an off-white solid in 41% yield, 55 mg. 1H NMR (400 MHz, 6) 6:-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, 1H), 8.91 (d, 1H), 8.99 (s, 1H), 9.47 (s, 1H), 10.75 (s, 1H); LCMS (System 10): R = 3.78 min; m/z 574 [M+H]+.

Preparation 280: Bicyclo[1.1.1]penty|-(5-bromochloro-pyrimidinyl)-amine jjBr CI N NH To a solution of 5-Bromo-2,4-dichloro-pyrimidine (6 g, 26.3 mmol) and bicyclo[1.1.1]pent—1-ylamine (4.7 g, 39.5 mmol) in acetonitrile (60 mL), was added TEA (16.5 mL, 118 mmol), and the mixture was stirred at °C for 18 hours. The volatiles were removed in vacuo and the residue partitioned between water and EtOAc. The c phase was dried (Na2804) and evaporated in vacuo. Purification by column tography on silica gel (EtOAc:Hexane 1:99) afforded the title compound as a white solid in 82% yield, 4.8 g. 1H NMR (400 MHz, 6) 6: 2.10 (d, 6H), 2.48-2.50 (m, 1H), 8.26 (d, 2H); LCMS m 10): R = 3.64 min; m/z 276 [M+H]+.

Preparation 281: Bicyclo[1 .1 .1]pentyl-[2-chloro((Z)ethoxy-vinyl)-pyrimidinyl]-amine A?\OEt N \ CI N NH To a stirred solution of Bicyclo[1.1.1]pentyl-(5-bromochloro-pyrimidinyl)-amine (Preparation 280, 2 g, 7.29 mmol) in dry toluene (70 mL) was added (Z)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 1100 C under N2 overnight. The on was cooled to room temperature, quenched with a 2M solution of KF and filtered through a pad of Celite.

The filtrate was partitioned n water (50 mL) and EtOAc (200 mL). The organic phase was washed with brine (2 x 25 mL), dried (NaZSO4) and evaporated in vacuo.The crude residue was purified by column W0 2012/137089 228 chromatography on silica gel : 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) 6: 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 .

Preparation 282: 7-Bicyclo[1.1.1]pentylchloro-7H-pyrrolo[2,3-d]pyrimidine 842% The title compound was prepared according to the method described for Preparation 62 using bicyclo[1.1.1]penty|-[2-chloro((Z)ethoxy-vinyl)-pyrimidinyl]-amine (Preparation 281) to afford the title compound as an off-white solid in 89% yield, 1.4 g. 1H NMR (400 MHz, DMSO-D6) 6:2.41 (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+H]+. ation 283: 7-Bicyclo[1.1.1]pent—1-ylchloroiodo-7H-pyrrolo[2,3-d]pyrimidine CI—(/N \ ' N— | The title compound was prepared according to the method described for Preparation 63 using 7- bicyclo[1.1.1]pentylchloro-7H-pyrrolo[2,3-d]pyrimidine (Preparation 282) to afford the title compound as a brown solid in 72% yield, 1.3g . 1H NMR (400 MHz, DMSO-D6) 6: 2.40 (d, 6H), 2.68 (m, 1H), 7.90 (s, 1H), 8.67 (s, 1H); LCMS (System ): R = 3.89 min; m/z 346 [M+H]+.

Preparation 284: (7-Bicyclo[1.1.1]pentylchloro-7H-pyrrolo[2,3-d]pyrimidinyl)—(5-bromo-pyridin yl)-methanone The title compound was prepared according to the method described for Preparation 64 using 7- bicyclo[1.1.1]pentylchloroiodo-7H-pyrrolo[2,3-d]pyrimidine ration 283) to afford the title compound as an off-white solid in 58% yield, 1.1 g. 1H NMR (400 MHz, DMSO-D6) 6: 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+H]+.

Preparation 285: [7-Bicyclo[1.1.1]pentyl(4-methoxy—benzylamino)-7H-pyrrolo[2,3-d]pyrimidinyl]— (5-bromo-pyridinyl)-methanone W0 2012/137089 229 To a solution of (7-Bicyclo[1.1.1]penty|chloro-7H-pyrrolo[2,3-d]pyrimidinyl)-(5-bromo-pyridiny|)- methanone ration 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) 6: 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)-pyridinyl]-[7-bicyclo[1.1.1]pentyl(4-methoxy- benzylamino)-7H-pyrrolo[2,3-d]pyrimidinyl]-methanone To a stirred solution of [7-Bicyclo[1.1.1]pentyl(4-methoxy—benzylamino)-7H-pyrrolo[2,3-d]pyrimidin -bromo-pyridinyl)—methanone (Preparation 285, 1.18 g, 2 mmol) and benzophenoneimine (0.50 mL, 3 mmol) in dry e (50 mL), cesium carbonate (3.2 g, 10 mmol) was added and the reaction 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 ing overnight. The reaction mass was cooled to room temperature and filtered through a pad of Celite. The filtrate was partitioned between water (25 mL) and EtOAc (100 mL). The c phase was washed with brine (10 mL), dried (NaZSO4) and evaporated in vacuo. Purification by column tography 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) 6: 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]+. ation 287: (5-Amino-pyridinyl)—[7-bicyclo[1.1.1]pentyl(4-methoxy—benzylamino)-7H- pyrrolo[2,3-d]pyrimidinyl]-methanone W0 2012/137089 230 To a solution of [5-(Benzhydrylidene-amino)-pyridinyl]-[7-bicyclo[1.1.1]pent—1-yl(4-methoxy— benzylamino)-7H-pyrrolo[2,3-d]pyrimidinyl]-methanone (Preparation 286, 475 mg, 0.78 mmol) in THF (15 mL), citric acid (15 mL of a 1N aq. solution) was added at room temperature and the reaction mixture stirred for 2 hours. The reaction was then quenched with sat. aq. NaZCO3 solution and extracted with EtOAc (2 x 25 mL). The ed organic phases were dried (NaZSO4) and ated in vacuo.

Purification by column chromatography on neutral alumina (Methanol:DCM 3: 97) to afford the title compound as a pale yellow solid in 92 % yield, 320 mg. 1H NMR (400 MHz, DMSO-D6) 6: 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 (br s, 1H), 8.10-8.12 (m, 2H), 8.92 (s, 1H); LCMS (System 10): R = 3.10 min; m/z 441 [M+H]+.

Preparation 288: 1-Cyclobutyl-1H-imidazolecarboxylic acid hydrochloride COZH <5 HCI Ethyl 3-(dimethylamino)isocyanoacrylate (WO 2007042545) (45 g, 0.27 mol) was added to utylamine (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 Heptane).

The oily residue was ated with TBME:heptane (1:1) and the resulting solid was collected and dried, giving 1-cyclobutyl-1H-imidazolecarboxylic acid ethyl ester (35 g, 67%, second crop not harvested). 1- Cyclobutyl-1H-imidazolecarboxylic acid ethyl ester (35 g, 0.21 mol) was dissolved in 6 N HCI (300 mL) and refluxed for 1 day. The solution was trated to dryness in vacuo. The solid was azeotroped with toluene, triturated with toluene and then dried under vacuum, giving the title compound 88% yield, 37.2 g, m/z 167 [M+H]+.

Preparation 289: (2-Methylimidazo[2,1-b][1,3]thiazolyl)acetic Acid Hydrochloride )1 >¢N OH 8 HCI W0 2012/137089 231 Ethyl 4-bromooxobutanoate (92 g, 0.35 mol) was added to a solution of 5-methylthiazolamine (40 g, 0.35 mol) in e (400 mL). The e was left to stand overnight and then evaporated to give 2- amino(4-ethoxy-2,4-dioxobutyl)methylthiazolium bromide in 82% yield, 101 g. 2-amino(4- ethoxy-2,4-dioxobutyl)methylthiazolium bromide (101g, 0.28 mol) was then refluxed in ethanol (250 mL) for 2 hours. The solvent was then evaporated to give ethyl 2-(2-methylimidazo[2,1-b]thiazol yl)acetate hydrobromide as yellow crystals in 97% yield, 85 g. Solid K2003 was added to a solution of ethyl 2-(2-methylimidazo[2,1-b]thiazolyl)acetate hydrobromide (85 g, 0.28 mol) in water (300 mL) to pH ~8. The product was extracted with form (3 X 100 mL), and the combined extracts were dried over NaZSO4 and evaporated to give ethyl 2-(2-methylimidazo[2,1-b]thiazolyl)acetate in 84% yield 52 g.

Ethyl 2-(2-methylimidazo[2,1-b]thiazolyl)acetate (52 g, 0.23 mol) was refluxed in 10% aqueous HCI (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+H]+.

Preparation 290: 3-Methyl(trifluoromethyl)-1H-pyrazolecarboxylic acid HO Me F / \ F H To a solution of benzyl cetate (57.6 g, 300 mmol) in MeOH (50 mL) in a 350 mL pressure vessel was added HZNMe (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 oC and the reaction mixture was stirred for 16 hours. After the mixture had cooled to room temperature, the solvent was evaporated in vacuo leaving a yellow on, 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 hylamino)butenoate as a viscous yellow oil in quantitative yield 60 g which was used without further purification.

To a solution of benzyl 3-(methylamino)butenoate (60 g, 300 mmol) and pyridine (27 mL, 330 mmol) in THF (500 mL), cooled to —20 0C, was added triflic anhydride (45 mL, 315 mmol) over a 30 min period.

During the addition, the temperature was kept below -10 oC. The reaction mixture was allowed to warm to room temperature overnight ing in a yellow clear on mixture. The solvent was evaporated in vacuo and the orange residue was taken up in water (1L) and EtZO (1L). Upon g the mixture well in a 3-L separatory funnel, all 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 evaporation of the solvent in vacuo provided benzyl 3-(Methylamino)(trifluoroacetyl)butenoate as an ite solid in 97% yield, 90 g that was used without additional purification.

To a solution of benzyl 3-(methylamino)(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 on mixture was heated to reflux for 3 hours, allowed to cool to room temperature 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, allowed to cool to room temperature and the aqueous layer was neutralized to pH 7-8 with NaHCO3. This mixture was transferred to a 3-L separating funnel, the W0 2012/137089 232 layers were mixed vigorously, separated and the organic layer was washed with water (3 x 500 mL) dried (MgSO4), filtered and ated in vacuo to give benzyl 3-methyl(trifluoromethyl)-1H-pyrazole carboxylate as an off-white solid in 89% yield 74 g that was used without r purification.

A mixture of benzyl 3-methyl(trifluoromethyl)-1H-pyrazolecarboxylate (74 g, 285 mmol), Pd/C (45 g, % on C) and EtOAc (1L) was treated in a Parr apparatus at room temperature with H2 (15 psi) for 5 hours. The st was filtered off over Celite and the solvent was removed in vacuo. EtZO (1 L) and water (200 mL) were added and the aqueous layer was made slightly basic (pH 8—9) with NaZCO3. The layers were ted and the aqueous layer was extracted with EtZO (5 x 200 mL). To the aqueous layer was added dropwise conc. HCI until pH 4-5 and followed by extraction with EtZO (3 x 500 mL). The combined organic layers were dried (MgSO4), filtered, evaporated in vacuo to give the title compound in 74% yield 7.4 g; mp. 308-310 °C(dec.)m/z195[M+H]+ Preparation 291: Ethyl [4-(3-Hydroxyphenyl)-1H-1,2,3-triazolyl]acetate Me\/0\(\N\ _\N—N Ethyl azidoacetate (14.9 g, 115 mmol) was dissolved in tert—butanol (200 mL), and 95% 3- hydroxybenzonitrile (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 temperature for 12 hours. The solution was evaporated to dryness in vacuo, the residue was dissolved in EtOAc (100 mL), dried (MgSO4), ed, evaporated in vacuo to give the title compound as brown crystals in ~100% (27.7 g) yield.

MS m/z 246 [M-H]' Preparation 292 : [4-(3-Hydroxyphenyl)-1H-1,2,3-triazolyl]acetic Acid Hydrate W0 2012/137089 233 Ethyl [4-(3-Hydroxyphenyl)-1H-1,2,3-triazolyl]acetate (Preparation 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 ature for 24 hours. Methanol was evaporated in vacuo, water (120 mL) was added, and the solution was ed with activated charcoal. The mixture was filtered, and 11 M HCI was added to the filtrate. The e 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 ated to dryness to afford the title compound as brown crystals (mp 186.3-188.7 °C) in 99.0% yield 23.9 9. MS m/z 218 [M-H]' Preparation 293: Ethyl [4-(1-hydroxycyclopentyl)-1H-1,2,3-triazolyl]acetate Me\\ Of’l \ OH Ethyl azidoacetate (2.58 g, 20 mmol) was ved in tert—butanol (15 mL), and 1- hydroxycyclopentanecarbonitrile (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 temperature for a further 48 hours. The solution was evaporated to dryness in vacuo and the e was dissolved in EtOAc (50 mL), dried (M9804), filtered and evaporated in vacuo to afford the title compound as green-yellow crystals in 98% yield, 4.69 9.

MS m/z 238 [M-H]' Preparation 294: [4-(1-hydroxycyclopentyl)-1H-1,2,3-triazolyl]acetic acid HO\(\N\ \ OH To a solution of ethyl [4-(1-hydroxycyclopentyl)-1H-1,2,3-triazolyl]acetate (Preparation 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 refluxed 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 itate was filtered, washed with ethyl e (2 x 50 mL), and concentrated under reduced pressure to afford the title compound as a ess crystalline substance in 87% yield, 27.8 9. mp 1240-1260 0C; MS m/z 212 [M+H]+ Preparation 295: Di-tert-butyl 1-(1-methyl-1H-pyrazolyl)hydrazine-1,2-dicarboxylate W0 2012/137089 234 To a solution of 4-iodomethyl-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 t-butyl (Z)-diazene-1,2-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 resultant mixture stirred at - 78°C for 1 hour. The reaction was warmed to 0 °C and quenched with ice-water and ted with ether (3 x 100mL). The organic layer was separated, dried (NaZSO4) 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) + Preparation 296: 3-tert-butyl-1'-methyl-1'H-1,4'-bipyrazolamine / \ N NH N-N‘ A mixture of di-tert-butyl 1-(1-methyl-1H-pyrazolyl)hydrazine-1,2-dicarboxylate (Preparation 295 ,12.3 g, 0.039 mol) and 4,4-dimethyloxopentanenitrile (5.4 g, 0.043 mol) was dissolved in MeOH (36 mL) and HCI (12 mL) was added slowly. The reaction mixture was stirred at 65 °C for 16 hours. The reaction was led to remove MeOH and basified with sat. aq. NaHCO3 solution to pH~8 followed by extraction with DCM. The organic layer was ted, dried (NaZSO4) followed by concentration in vacuo. The crude mixture was ed by column tography 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]+.

Preparation 297: 3-cyclopropyl-1'-methyl-1'H-1,4'-bipyrazolamine W0 2012/137089 235 The title compound was prepared according to the method described for Preparation 296: using di-tert- butyl 1-(1-methyl-1H-pyrazolyl)hydrazine-1,2-dicarboxylate (Preparation 295) and opropyl oxopropanenitrile to afford the title compound in 48% yield, 1.7g. 1HNMR (400 MHZ, DMSO-d6): 0.55-0.57 (m, 2H), .80 (m, 2H), .72 (m, 1H), 3.83(s, 3H), 5.08- 5.09 (m, 3H), 7.57(s, 1H), 7.90(s, 1H).

LCMS: [M+H]+ 204 Preparation 298: N-[5-({7-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)oxetanyl]-7H-pyrrolo[2,3-d]pyrimidin- -yl}carbonyl)pyridinyl]—2-(4-chlorophenyl)acetamide \/ 0 / NWCI KN N OTBDMS The title compound was prepared according to the method described for Preparation 223 using (5- aminopyridinyl)(7-(3-methyloxetanyl)—7H-pyrrolo[2,3-d]pyrimidinyl)methanone (Preparation 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]+.

Preparation 299: 5-(methoxymethyl)methyl-1H-pyrazolecarboxylic acid Me To a on of ethyl 5-(methoxymethyl)methyl-1H-pyrazolecarboxylate (W09743277) (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 temperature ght. The on was evaporated to dryness and the residue was adjusted to pH5 with a 2 N HCI solution. The aqueous solution was extracted with EtOAc and the organic layer was dried over NaZSO4 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]+ Preparation 300: lmidazo[1,2-a]pyrimidinecarboxylic acid N N HO \ NJ A mixture of 6-bromoimidazo[1,2-a]pyrimidine (1.17 g, 6 mmol), BINAP (18 mg, 0.06 mmol), PdCl2 (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 W0 2012/137089 236 (97.5 mL). A (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]pyrimidinecarboxylate (365 mg, %) as a yellow solid which was used in the next step without further purification. To a solution of methyl imidazo[1,2-a]pyrimidinecarboxylate (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 temperature. The pH was adjusted to 5-6 using aq. HCI and the whole mixture ted with EtOAc (3x30mL).The ed organic layers were dried over NaZSO4 and evaporated in vacuo to give the title compound as white solid in 39% yield, 133 mg 1H NMR (400 MHz, DMSO-d6): 69.15 (m, 1H), 8.8 (m, 1H), 7.9 (m, 1H), 7.65 (m, 1H), Preparation 301: [1 ,2,4]triazolo[1 ,5-a]pyridinecarboxylic acid HO / /N \ N \ 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 °C for 12 hours. The mixture was then concentrated to give a residue. To the residue was added methanol (381 mL), ed by NH2OHSO4 (31.9 g, 248 mmol) and the resulting e was stirred at room temperature overnight. The reaction mixture was concentrated to give methyl [1,2,4]triazolo[1,5-a]pyridinecarboxylate in 18% yield, 6g. To a solution of methyl [1 riazolo[1 ,5-a]pyridinecarboxylate (3 g, 16 mmol) in methanol was added 1M aq. LiOH (70 mL) and the resulting mixture stirred for 10 hours at room temperature. The pH was adjusted to 5-6 using aq. HCI and the whole mixture extracted with EtOAc (30 mL><3).The combined organic layers were dried over NaZSO4 and 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, 1H), 9.04-9.06 (m, 1H), 8.66 (m, 1H), 8.32 (m, 1H), 67.56- 7.58 (m, 1H).

Preparation 302: 1-methyl-1H-pyrrolo[2,3-c]pyridinecarboxylic acid | \ 1-methyl-1H-pyrrolo[2,3-c]pyridinecarbaldehyde (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-methylbutene solution in THF (120 mL, 46 mmol) was added followed by a solution of NaClOz (11.02 g, 122 mmol) and 4 (21.9 g, 183 mmol) in water (30 mL). The reaction mixture was d at room temperature overnight under nitrogen. The reaction mixture was concentrated in vacuo to remove organic solvents, and the e was filtered. The precipitate ned the title compound as white solid in 57% yield, 4.1 g. 1H NMR: DMSO-d6 400MHz: 6 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).

Preparation 303: 2-((tert-butoxycarbonyl)amino)(4-chlorophenyl)acetic acid W0 2012/137089 237 To 4-chlorophenylglycine (1.50 g, 8.08 mmol) and sodium hydroxide (0.65 g, 16.2 mmol) in water (20 mL) was added di-tert—butyl onate (1.76 g, 8.08 mmol) in acetonitrile (15 mL) and the mixture was stirred at room temperature for 18 hours. The mixture was then washed with DCM (20 mL) and acidified using 2N HCI. 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.

Preparation 304: tert-Butyl (1-(4-chlorophenyl)((5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine carbonyl)pyridinyl)am ino)oxoethyl)carbamate 0 HN \,( 3‘0 N \ \ Me kN/| N MeaM/e )‘Me Me To pyridine (4 mL) in a sealed vessel was added 2-((tert-butoxycarbonyl)amino)(4-chlorophenyl)acetic acid (67 mg, 0.24 mmol) (see Preparation 303), (5-aminopyridinyl)(7-isopropyl-7H-pyrrolo[2,3- d]pyrimidinyl)methanone (52 mg, 0.18 mmol) (see Preparation 95) and N,N,N',N'-tetramethyl-O-(7- azabenzotriazolyl)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 100:0 to 88:12 DCM:MeOH) to give the title compound in 49% yield, 64 mg. LCMS (basic): R = 0.81 min; m/z 549 .

Biological Activity lsolated TRK Enzyme assays use the HTRF KinEASE-TK kit (Cisbio Cat# 62TKOPEJ) with recombinant His-tagged cytoplasmic s of each TRK receptor sourced from lnvitrogen (see table . This activity-assay measures the phosphorylation of ne es 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: W0 37089 238 -Target Invitrogen Cat# FAC enzyme FAC ATP—Assay Reaction Time TRKA PV3144 aa 441-796 4nM 40uM 35min (NTRK1) I-- --PV3616 aa 526-838 1nM 1.4uM I-----TRKC PV3617 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 PF00 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 d using the Bravo nanolitre dispenser. 1X enzyme buffer is ed from 5X Enzymatic Buffer from the Cisbio KinEASE TK kit using MilliQ water. The buffer is then mented with 10mM MgCl and 2mM DTT (both from Sigma). In the case of TRKB, the buffer is also supplemented with 125nM Supplement Enzymatic Buffer (SEB) from the Cisbio kit. 2X FAC of enzyme and 2X FAC ATP diluted in 1X complete enzyme buffer is incubated at room temperature for 20minutes to preactivate the enzyme. Following this preactivation step, 5ul/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 temperature before adding 5ul of 2uM TK—substrate-Biotin (from the Cisbio kit) diluted in 1X enzyme buffer (1uM FAC) using the Multidrop Micro. The on is incubated at room temperature for the optimized assay reaction time (see table). The reaction is stopped by adding 10u|/well HTRF Detection Buffer containing 0.25uM Streptavidin-XL665 (0.125uM FAC) and 1:200 TK Antibody-Cryptate using a Multidrop.

After the Detection Reagent addition, plates are covered and incubated at room temperature for 60 minutes. HTRF signal is read using an Envision reader, measured as a ratio of emissions at two different wavelengths, 620nm and 665nm. Any compound that inhibits the action of the TRK kinase will have a lower fluorescence ratio value 665/620nM than compounds which do not inhibit theTRK kinase. Test compound data are sed as percentage inhibition defined by HPE and ZPE values for each plate.

Percentage inhibition in the ce of test compound is plotted against compound concentration on a log scale to ine an |C50 from the resultant sigmoid curve.

Cell Based Assays were carried out using Cell lines from DiscoveRx utilising their PathHunter technology and reagents in an antagonist assay: DiscoveRx cell line Cat# e rophin TRKA co sed with p75 93-0529C3 — W0 2012/137089 239 2012/051363 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 eRx’s etary Enzyme Fragment Complementation (EFC) logy. In the case of the TRK cell lines, the enzyme acceptor (EA) n is fused to a 8H2 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 8H2 protein binds. This results in functional complementation and ed B-Galactosidase activity which is can be measured using the luminescent Galacton Star substrate within the PathHunter reagent kits.

Generally, small molecule inhibitors bind to the kinase domain so are not competing with the neurotrophin (agonist) which binds to an ellular site. This means that the |C50 is a good e of affinity and should be unaffected by concentration neurotrophin stimulant.

Cryopreserved PathHunter cells are used from either in-house produced batches or bulk s bought directly from DiscoveRx. Cryopreserved cells are resuscitated, spun 1000rpm for 4min to remove ng media, and resuspended in MEM + 0.5% horse serum (both lnvitrogen) to 5e5cells/ml. The cells are then plated using a Multidrop into Greiner white tissue culture treated plates at 20u|/well and incubated for 24h at 37°C, 5% C02, high ty. On the day of the assay, the cell plates are allowed to cool to room temperature 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, WO2005/116035 at a top concentration of 150uM is also prepared on each test plate. High percentage effect (HPE) is d by 150uM of the compound of Example 135, WO2005/116035 and 0% effect (ZPE) is defined by 100% DMSO. Plates containing 1u| 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 Wellmate. 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 temperature before addition of agonist stimulus: 10u|/well of 2nM (0.571nM FAC) of the cognate neurotrophin (Peprotech) diluted in agonist buffer (HBSS with 0.25% BSA). Final assay concentration of the test compounds is , (the compound of Example 135, WO2005/116035 FAC is 0.325uM). The plates are left at room temperature for a further 2hours before addition of 10u| of the DiscoveRx PathHunter detection reagent (made up by adding 1 part Galacton Star, 5 parts Emerald II and 19 parts Cell Assay Buffer as per the manufacturer’s instructions).

After reagent addition, plates are covered and incubated at room temperature for 60 minutes.

Luminescence signal is read using an Envision. Test compound data are expressed as percentage inhibition d by HPE and ZPE values for each plate. Percentage inhibition in the presence of test W0 37089 240 compound is plotted against compound tration on a log scale to determine an |C50 from the resultant sigmoid curve.

Brain Penetration Assays In Vitro MDCK-BCRP: MDCK-BCRP data were collected according to the method described in “A 96-Well Efflux Assay To Identify ABCG2 Substrates Using a Stably Transfected MDCK ll Cell Line” http://pubs.acs.org/doi/full/10.1021/mpO50088t Yongling Xiao, Ralph Davidson, Arthur Smith, Dennis Pereira, Sabrina Zhao, John Soglia, David Gebhard, Sonia de , and David B. Duignan, Mol. Pharm. 3 (1), pp 45—54. , 2006, MDCK-MDR1: MDCK-MDR1 data were collected according to the method described in “Are MDCK Cells Transfected with the Human MDR1 Gene a Good Model of the Human lntestinal Mucosa? “ http://wwwspringerlink.com/content/gfhglgbr4fnp3khf/fulltext.pdf Fuxing Tang, Kazutoshi Horie, and Ronald T. rdt, Pharmaceutical Research, Vol. 19, No. 6, June 2002.

In Vivo Brain penetration was measured according to the method described in ”Assessing brain free fraction in early drug ery”. Read, K; Braggio, 8., Expert Opinion Drug Metab Toxicol. (2010) 6 (3) 337- 344.

Example TrkA enzyme TrkB enzyme TrkA cell TrkB cell TrkC cell MDCK MDRl MDCK MDRl RRCK BCRP RRCK BCRP number potency (nM) potency (nM) y (nM) potency (nM) potency (nM) Papp AB (x10— Papp BA (x10— Papp AB (x10—6 Papp BA (x10— 6 cm/sec) 6 cm/sec) cm/sec) 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 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 5.7 78 30 18 18 <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 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 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 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 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 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 45 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 5.0 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 1.8 0.4 5.6 20 54 1.5 19 2.0 1.4 <1 4.2 W0 37089 242 Trka enzyme Trka enzyme Trka enzyme 71-5 94-1 67 49-1 300 174 976 230 1080 283 6270 567 233 1840 133 203 22 5840 166 110 23 44s 3470 392 24 244 702 44s 3400 908 26 3100 355 27 1280 28 206 3840 29 9810 284 240 831 2590 681 3100 330 3100 312 3080 334 3100 496 3100 1850 40 579 4 67-4 42 719 43 2630 we 44 277 101 204 45 836 102 46 573 820 103 147 873 104 148 173 105 149 3570 406 404 107 232 835 108 791 W0 37069 243 Trka enzyme Trka enzyme Trka enzyme 197 430 242 267 4350 198 243 288 43-1 199 244 289 1370 200 245 290 167 201 462 246 291 3230 202 412 247 292 37.7 203 248 293 20-2 204 249 294 61-4 205 250 295 31-9 206 123 25 296 47.7 207 252 297 299 206 129 253 296 1460 209 272 254 299 539 210 255 300 52-2 211 256 301 428 212 257 302 156 256 303 1220 259 304 3900 260 305 2640 26 126 306 N/D 262 307 N/D 263 306 592 264 309 53.9 265 -=__ 98-4 223 268 579 224 269 557 225 343 233 323 234 439 324 235 496 325 236 326 237 327 236 297 326 239 329 240 330 241 331 W0 37089 244 Trka enzyme Trka enzyme Trka enzyme 332 381 426 228 333 382 427 93-4 334 383 428 336 384 429 2740 337 385 430 297 338 386 431 235 339 251 387 432 2790 340 451 388 433 248 343 389 434 344 328 390 435 5490 345 382 39 246 438 205 348 253 392 437 107 347 393 438 312 348 394 439 22-5 350 395 440 676 333 333 443 3333 352 397 442 36-6 353 N/D 398 443 47.7 354 N/D 399 444 498 355 302 400 593 445 5.51 356 40 446 812 357 302 402 447 919 358 403 448 272 359 404 449 155 360 958 405 450 3150 361 406 451 7170 362 407 452 542 383 408 854 453 834 364 409 454 633 365 455 1070 366 354 456 6960 367 412 457 674 368 753 458 213 369 414 459 4-06 370 460 9800 371 461 9800 372 432 3323 373 463 186 374 224 434 3333 375 420 465 2130 376 421 466 400 377 422 451 487 538 378 423 468 5100 379 424 469 523 380 422 425 798 470 W0 37069 245 Trka enzyme Trka enzyme Trka enzyme 471 562 3-75 472 563 3-11 473 564 1-57 474 520 565 17-9 475 643 52 567 20.6 476 522 566 12.1 477 523 569 34.4 476 524 570 6970 479 525 571 2.92 460 526 572 9.5 461 527 573 17.9 482 526 574 14.2 463 529 575 3.09 464 530 576 296 53 577 1-9 466 532 576 6.07 487 533 579 8-11 488 534 580 0-825 489 535 581 3-21 490 536 582 9-79 491 537 583 0-681 492 538 584 581 493 646 539 565 36.7 494 540 586 1000 495 54 N/D 567 20.5 496 542 N/D 566 334 497 543 589 31-3 498 544 590 71-2 499 545 591 142 500 546 —_ 501 201 547 —_ 502 548 —_ 503 963 549 —_ 504 550 —_ 505 55 —_ 506 552 —_ 507 553 —_ 508 554 270 _ 509 555 —_ 510 249 556 —_ 511 144 557 —_ 512 558 —_ 559 374 _ 514 560 —_ 561—— W0 2012/137089 246 All publications cited in this application are each herein incorporated by reference in their entirety.

Although the invention has been bed above with reference to the disclosed embodiments, those skilled in the art will readily iate that the specific experiments detailed are only illustrative of the invention. It should be understood that various cations can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

Claims (30)

1. A compound of a I: N R101 N X R102 R3 N N 5 (I) or a pharmaceutically able salt thereof, wherein R1 is H, or C1-5 alkyl optionally substituted by up to 3 substituents independently selected from OH, 10 CON(R5R6), SO2R7, SR7, OR7, CH2OH, CO2R5, SONR7R7, NR7SO2R5, CN, NO2 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 , OH, CON(R5R6), SO2R7, OR7, CH2OH, CO2R5, SONR7R7, NR7SO2R5, CN, NO2 and R8; R2 is H or methyl; R3 is H, NH2 or NH(C1-3 alkyl optionally substituted with up to 3 substituents ndently selected from OH and O(C1-3 alkyl)); R101 is H, OH, methyl, cyclopropyl, methoxy, ethyl, ethoxy or CN, X is a bond, O, (CH-R4)n, NR104, OCH2 or CH2O; 25 R4 is independently H, CH3, CH2OH, CH2OCH3, OH, NH2, NHCH3, N(CH3)2, CH2NH2, CH2NHCH3,or CH2N(CH3)2; R104 is H, C1-3 alkyl or a C4-6 saturated carbocycle, each of which is ally substituted by up to 3 substituents independently selected from C1-3 alkyl, CH2OH and NH2; n is 1 or 2; R102 is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic system, or an 8membered bicyclic system, which ring system may be saturated or partially or fully unsaturated, wherein the heterocyclic ring system may have up to 5 ring hetero-atoms selected from N, S, and O, wherein the bicyclic ring system can be 2 rings (carbocyclic-carbocyclic, carbocyclic-heterocyclic, 5 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, SO 7, SR7, C 2R 1-4 alkyl ally substituted by up to 3 OH and/or C 1-3 alkoxy groups, 10 C3-6 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(C1-3 alkyl), O(C3-6 cycloalkyl optionally substituted by up to 3 OH and/or C1-3 alkoxy groups, O(C1-3 alkyl substituted by up to 3 halogen), O(C1-3 alkyl substituted by up to 3 OH and/or C1-3 alkoxy groups), NR5SO 7, =O, R8, C(O)R8, NO 5CO 7, NR5COR 7,OR 8, S(O)R7, 2R 2, NR 2R and CH2R8; R5 and R6 are each independently H, or C1-5 alkyl optionally substituted by up to 3 substituents independently selected from OH, CONR 7R7, SO 7, 7, CN, NO 9 , 2R OR7, CH2OH, CO2R7, SONR7R7, NR7SO 2R 2 and R 20 or a ring system selected from C3-5 cycloalkyl, propellanyl, or a 4-6 ed ted heterocyclyl ring, which ring system is optionally substituted by up to 3 substituents independently selected from OH, CON(R7R7), SO2R7, CO2R7, SONR7R7, NR7SO 7, CN, NO 7R7,SR 7,C 2R 2, halo, NR 1-4 alkyl ally tuted by up to 3 OH and/or C1-3 alkoxy groups, C3-6 cycloalkyl optionally tuted 25 by up to 3 OH and/or C1-3 alkoxy groups, C1-3 alkyl substituted by 1 to 3 halogen, O(C3-6 cycloalkyl optionally substituted by up to 3 OH and/or C1-3 alkoxy groups, O(C1-3 alkyl substituted by up to 3 halogen, O(C1-3 alkyl substituted by up to 3 OH and/or C1-3 alkoxy, NR7SO 7,=O,NO 7CO 7, 2R 2,NR 2R and S(O)R7, or R5 and R6 together with the N to which they are ed can be a 4-7 ed ring optionally 30 including up to 2 further ring hetero-atoms independently selected from N, O, S, which ring is optionally substituted by C1-3 alkoxy and / or C1-3 alkyl; R7 is H, C1-5 alkyl or C1-5 alkoxy, which C1-5 alkyl or C1-5 alkoxy is optionally substituted by up to 3 tuents independently selected 35 from halogen; R8 is a is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic system, or an 8membered bicyclic , which ring system may be saturated or partially or fully unsaturated, wherein the heterocyclic ring system may have up to 5 ring hetero-atoms selected from 40 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, C1-4 alkyl optionally tuted by up to 3 OH and/or C1-3 alkoxy groups, 5 C3-6 cycloalkyl optionally tuted by up to 3 OH and/or C1-3 alkoxy groups, C1-3 alkyl substituted by 1 to 3 halogen, OH, O(C1-3 alkyl), O(C3-6 cycloalkyl optionally substituted by up to 3 OH and/or C1-3 alkoxy groups, O(C1-3 alkyl substituted by up to 3 halogen, O(C1-3 alkyl substituted by up to 3 OH and/or C1-3 alkoxy, NR5SO 7, =O, NO 7COR 7,NR 5CO 7, and ; 2R 2, NR 2R 10 R9 is a is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic system, or an 8membered bicyclic system, which ring system may be saturated or partially or fully unsaturated, wherein the heterocyclic ring system may have up to 5 ring hetero-atoms selected from N, S, and O, n the bicyclic ring system can be 2 rings (carbocyclic-carbocyclic, yclic-heterocyclic, 15 heterocyclic-carbocyclic or cyclic-heterocyclic) fused or linked by a single bond, which ring system is optionally substituted by up to 3 substituents ndently selected from, where possible - halo, CN, NR7R7, SO2R7, SR7, C1-4 alkyl optionally substituted by up to 3 OH and/or C1-3 alkoxy groups, 20 C3-6 cycloalkyl optionally substituted by up to 3 OH and/or C1-3 alkoxy , C1-3 alkyl substituted by 1 to 3 halogen, OH, O(C1-3 alkyl), O(C3-6 cycloalkyl ally substituted by up to 3 OH and/or C1-3 alkoxy groups, O(C1-3 alkyl substituted by up to 3 halogen, O(C1-3 alkyl substituted by up to 3 OH and/or C1-3 alkoxy, NR7SO 7, =O, NO 7CO 7, NR7COR 7,and S(O)R7; 2R 2, NR 2R 25 wherein each CH moiety can be replaced by a CF moiety.

2. A compound or salt according to claim 1 wherein R 1 is H, C 1-5 alkyl optionally substituted by up to 2 OH, or R1 is C1-5 alkyl substituted by CONH2, CONHCH3, CON(CH3)2, CO2H, CO2CH 3, OCH3, SCH3, 30 SO 2CH 3, 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.

3. A compound or salt according to any one of claims 1 or 2 wherein R1 is t-butyl, hydroxy-t- 35 butyl, dihdyroxy-t-butyl, 1-hydroxypropyl or 1,3-dihydroxypropyl.

4. A nd or salt according to any one of claims 1 to 3 wherein R2 is H.

5. A compound or salt according to any one of claims 1 to 4 wherein R3 is H or NH2.

6. A compound or salt according to any one of claims 1 to 5 wherein R3 is NH2.

7. A compound or salt according to any one of claims 1 to 5 wherein R3 is H.

8. A compound or salt according to any one of claims 1 to 7 n R101 is H. 5

9. A compound or salt according to any one of claims 1 to 7 wherein R101 is OH.

10. A compound or salt according to any one of claims 1 to 9 wherein X is a bond, O, CH 2, C2H4, CH(CH 3)CH 2, CH(CH3), CH(CH2OH), CH2O, CH(NH2), CH(OH) or NH. 10

11. A compound or salt according to any one of claims 1 to 10 wherein X is CH2.

12. A compound or salt according to any one of claims 1 to 11 wherein R102 is an optionally substituted nitrogen-containing ring system which is linked to the X moiety via a en ring atom.

13. A compound or salt according to any one of claims 1 to 11 wherein R102 is an optionally substituted ring system where the ring system is selected from - benzimidazolyl, benzisoxazolyl, benzofuranyl, benzoxazolyl, benzotriazolyl, biphenyl, bipyrazolyl, cinnolinyl, cyclobutylimidazolyl, cyclobutylpyrazolyl, cyclobutylthiazolyl, entyltriazolyl, 20 cyclopropylisoxazolyl, cyclopropyloxazolyl, cyclopropylpyrazolyl, cyclopropyltriazolyl, diazirenylphenyl, dihydronaphthyridinyl, dihydropyrrolopyrazolyl, dioxinopyridinyl, furazanyl, ridinyl, furopyrrolyl, imidazolyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, othiadiazolyl, 25 imidazothiazolyl, indanyl, indazolyl, indolyl, isoindolyl, isoxazolopyridinyl, isoxazolyl, isoquinolinyl, naphthyridinyl, oxazolyl, phenyl, phenylcyclopropyl, imidazolyl, phenylpyrazolyl, phenylpyrrolyl, phenyltetrazolyl, phthalazinyl, purinyl, nyl, pyrazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyridinyl, pyridazinyl, pyridinyltriazolyl, pyrimidinyl, pyrroloimidazolyl, pyrrolopyrazinyl, 30 opyrimidinyl, pyrrolopyridinyl, pyrrolyl, quinolinyl, quinazolyl, quinoxalinyl, tetrahydrobenzisoxazolyl, tetrahydrocyclopentapyrazolyl, ydrotriazolopyridinyl, tetrazolopyridazinyl, olopyridinyl, thiazolyl, thiazolopyridinyl, thiazolopyrimidinyl, thienylpyrazolyl, thienopyridinyl, triazolopyridinyl and triazolyl.

14. A compound or salt according to claim 13 where the optional substituents are independently selected from, where possible - halo, methyl, ethyl, propyl, pyl, cyclopropyl, CF3, CHF2, CH2F, CH2OCH 3, CN, CH2OH, OCH3, =O, NH2, SCH3, SO2CH 3, phenoxy, fluorophenoxy, , SCF3, OCF3, SO2CF 3, NHSO2CH 3, 40 NHSO 2CF 3, C(O)CF3, C(O)CH3, benzoyl, azetidinylmethyl, fluoroazetidinylmethyl and morpholinomethyl.

15. A compound or salt according to any one of claims 1 to 11, 13 or 14, wherein R102 is selected from phenyl, pyrazolyl, 1,2,3-triazolyl, benzotriazolyl, pyridinyl, nyl and pyridinyl, each of which is optionally substituted by halo, methyl, ethyl, propyl, isopropyl, cyclopropyl, CF3, 5 CHF2, CH2F, CH2OCH3, CN, CH2OH, OCH3, =O, NH2, SCH3, SO2CH3, phenoxy, fluorophenoxy, benzyl, SCF3, OCF3, SO2CF3, NHSO2CH3, NHSO2CF3, C(O)CF3, C(O)CH3, l, azetidinylmethyl, fluoroazetidinylmethyl and/or morpholinomethyl.

16. A nd or salt according to any one of claims 1 to 15 with R5 and R6 groups present, 10 wherein R5 and R6 are each independently H, C1-3 alkyl ally substituted by C1-3 alkoxy, C3-5 lkyl, 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 C1-3 alkoxy and / or C1-3 alkyl.

17. A compound ing to claim 1 of the Formula IA: N R101 O R102 R3 N N (IA) or a pharmaceutically acceptable salt thereof, wherein R3 is H or NH2; 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, n each heterocycle has from 1 to 3 ring heteroatoms selected from N, O and 30 and which ring system is ally substituted by up to 3 substituents independently selected from halo, CF3, C1-4 alkyl and C3-5 cycloalkyl.

18. A compound or salt according to claim 17 wherein R101 is H.

19. A compound or salt according to claim 18 wherein R1 is t-butyl, hydroxy-t-butyl or 1-hydroxypropyl; and R102 is 4-trifluromethylphenyl, 4-chlorophenyl, 2,4-difluorophenyl, 5-chloropyridinyl, 5- 5 fluoropyridinyl, 3-trifluromethylpyrazolylyl, 4-trifluromethylpyrazolyl, 3-trifluromethyl methylpyrazolyl, 3-cyclopropylpyrazolyl, opropylpyrazolyl, 4-trifluromethyl (1,2,3-triazolyl), 4-cyclopropyl- (1,2,3-triazolyl), or benzotriazolyl. 10 20. A compound ing to claim 1, selected from: N-(5-{[2-amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridin yl)[4-(trifluoromethyl)phenyl]acetamide; N-(5-{[2-amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin yl]carbonyl}pyridinyl)(4-chlorophenyl)acetamide; 15 N-(5-{[2-amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin yl]carbonyl}pyridinyl)(5-fluoropyridinyl)acetamide; N-(5-{[2-amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin bonyl}pyridinyl)[3-(trifluoromethyl)-1H-pyrazolyl]acetamide; N-(5-{[2-amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin 20 yl]carbonyl}pyridinyl)(3-cyclopropyl-1H-pyrazolyl)acetamide; N-{5-[(2-aminotert-butyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}(4- cyclopropyl-1H-1,2,3-triazolyl)acetamide; N-{5-[(2-aminotert-butyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}[4- (trifluoromethyl)-1H-pyrazolyl]acetamide; 25 N-{5-[(2-aminotert-butyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}[4- (trifluoromethyl)-1H-1,2,3-triazolyl]acetamide; N-{5-[(2-aminotert-butyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}(5- chloropyridinyl)acetamide; N-(5-{[2-Amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin 30 yl]carbonyl}pyridinyl)(5-chloropyridinyl)acetamide; N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}[4-(trifluoromethyl)- 1H-1,2,3-triazolyl]acetamide; 2-(4-chlorophenyl)-N-[5-({7-[(1S)hydroxymethylethyl]-7H-pyrrolo[2,3-d]pyrimidin yl}carbonyl)pyridinyl]acetamide 35 N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}[4-(trifluoromethyl)- azolyl]acetamide; N-[5-({7-[(1S)Hydroxymethylethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}carbonyl)pyridinyl]- trifluoromethyl)phenyl]acetamide; N-[5-({7-[(1R)hydroxymethylethyl]-7H-pyrrolo[2,3-d]pyrimidinyl}carbonyl)pyridinyl]- 40 2-[4-(trifluoromethyl)phenyl]acetamide; 2-(4-chlorophenyl)-N-[5-({7-[(1R)hydroxymethylethyl]-7H-pyrrolo[2,3-d]pyrimidin yl}carbonyl)pyridinyl]acetamide; N-(5-{[7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridinyl) [5-methyl(trifluoromethyl)-1H-pyrazolyl]acetamide; 2-(5-chloropyridinyl)-N-(5-{[7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin yl]carbonyl}pyridinyl)acetamide; 5 N-(5-{[2-Amino(2-hydroxymethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridin yl)(4-chlorophenyl)acetamide; [2-amino(2-hydroxymethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridin yl)[4-(trifluoromethyl)phenyl]acetamide; N-(5-{[2-amino(2-hydroxymethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridin 10 yl)(4-chlorophenyl)acetamide; N-(5-{[2-amino(2-hydroxymethylethyl)-7H-pyrrolo[2,3-d]pyrimidinyl]carbonyl}pyridin yl)[4-(trifluoromethyl)phenyl]acetamide; N-(5-{[2-Amino(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin bonyl}pyridinyl)[5-methyl(trifluoromethyl)-1H-pyrazolyl]acetamide; 15 and N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidinyl)carbonyl]pyridinyl}(4-cyclopropyl-1H- 1,2,3-triazolyl)acetamide; or a pharmaceutically acceptable salt thereof.

20

21. A pharmaceutical ition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of the preceding claims 1 to 20, and a pharmaceutically acceptable carrier.

22. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in 25 any one of claims 1 to 20, for use as a medicament.

23. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as d in any one of claims 1 to 20 for use in the treatment of a disease for which an Trk receptor antagonist is ted.

24. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 20 for use in the treatment of pain.

25. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or 35 composition thereof, as d in any one of claims 1 to 20, for the manufacture of a medicament to treat a disease for which an Trk receptor nist is indicated.

26. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or composition thereof, as defined in any one of claims 1 to 20, for the manufacture of a 40 medicament to treat pain.

27. A compound or salt according to any one of claims 1 to 20 for use in a medical treatment in ation with a further drug susbtance.

28. A compound according to claim 1, substantially as herein described with reference to any 5 one of the examples.

29. A pharmaceutical composition according to claim 21, substantially as herein described with nce to any one of the examples. 10

30. The use according to claim 25 or claim 26, substantially as herein described with reference to any one of the examples.