HK1191641A

HK1191641A - Pyrrolo [2,3-d] pyrimidine derivatives as inhibitors of tropomyosin-related kinases

Info

Publication number: HK1191641A
Application number: HK14104722.1A
Authority: HK
Inventors: M．D．安德鲁斯; S.K.巴盖尔; K.R.吉布森; 大本清之; T．李克曼斯; S．E．斯卡拉特; P.A.斯图普尔
Original assignee: 辉瑞有限公司
Priority date: 2011-04-05
Filing date: 2012-03-22
Publication date: 2014-08-01

Description

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

The invention described herein relates to certain pyrrolo [2,3-d ] pyrimidines and pharmaceutically acceptable salts of these compounds. The invention is also directed to processes for the preparation of such compounds, compositions comprising such compounds and the use of such compounds and salts in the treatment of diseases or disorders associated with tropomyosin-related kinase (Trk) activity. More particularly, the present invention relates to compounds and their salts useful as Trk inhibitors.

Background

Tropomyosin-related kinases (Trks) are a family of receptor tyrosine kinases activated by neurotrophic factors. Trks play an important role in pain sensation as well as tumor cell growth and survival signaling. Thus, Trk receptor kinase inhibitors may provide targeted treatment of conditions such as pain and cancer. Recent developments in this area have been made by Wang et al in Expert opin. 305-319, the excerpts of which are now reproduced below.

"1.1 Trk receptor

Protein kinases, one of the largest family of proteins encoded by the human genome, are central regulators of signal transduction and control of various complex cellular processes. Receptor Tyrosine Kinases (RTKs) are a subfamily (up to 100 members) of protein kinases that bind to cell membranes that act specifically on protein tyrosine residues. A subset within this subfamily are Trk kinases, which have three highly homologous isoforms: TrkA, TrkB and TrkC. All three isoforms are activated by high affinity growth factors called neurotrophic factors (NTs): i) nerve Growth Factor (NGF), which activates TrkA; ii) Brain Derived Neurotrophic Factor (BDNF) and NT-4/5, which activate TrkB; and iii) NT-3, which activates TrkC. Binding of neurotrophins to the extracellular domain of Trks causes the Trk kinases to autophosphorylate at several intracellular tyrosine sites and trigger downstream signaling pathways. Trks and neurotrophic factors are well known for their effect on neuronal growth and survival.

1.2Trks and cancer

Trks were originally isolated from neuronal tissue and are thought to primarily affect neuronal cell maintenance and survival. However, over the past 20 years, increasing evidence has suggested that Trks play a critical role in malignant transformation, chemotaxis, metastasis and survival signaling in human tumors. The association between Trks and cancer has been focused on prostate cancer in the early years, and the subject has been reviewed. For example, malignant prostate epithelial cells are reported to secrete a range of neurotrophic factors and at least one Trks. In pancreatic cancer, it is proposed that paracrine and/or autocrine neurotrophic factor-Trk interactions may influence the aggressive behavior of cancer. TrkB has also been reported to be overexpressed in metastatic human pancreatic cancer cells. Recently, there have been a number of new discoveries in other cancer settings. For example, translocation results in expression of a fusion protein derived from the N-terminus of the ETV6 transcription factor and the C-terminal kinase domain of TrkC. The resulting ETV6-TrkC fusions are carcinogenic in vitro and have been shown to be responsible for secretory breast cancer and some Acute Myeloid Leukemia (AML). Constitutively active TrkA fusions occur in a subset of papillary thyroid carcinomas and colon carcinomas. In neuroblastoma, TrkB expression is reported to be a strong predictor of progressive tumor growth and poor prognosis, and TrkB overexpression is also associated with increased resistance to chemotherapy in neuroblastoma cells in vitro. One report shows that a novel splice variant of TrkA, referred to as TrkAIII, signals through the phosphoinositide-AKT pathway in the absence of neurotrophic factors in a subset of neuroblastoma tumors. In addition, mutational analysis of the tyrosine kinase panel revealed Trk mutations in colorectal and lung cancers. In summary, Trks are associated with a wide variety of human cancers, and finding a Trk inhibitor and testing it clinically may provide additional insight into the biological and medical implications of treating cancer with targeted therapies.

1.3Trks and pain

In addition to the newly developed association with cancer, Trks is also considered an important mediator of pain sensation. Congenital insensitivity to pain with anhidrosis (CIPA) is a disorder of the peripheral nerves (and usually the innervated sweat glands) that prevents patients from adequately feeling painful stimuli or sweating. Defects in TrkA have been shown to lead to CIPA in different human populations.

Currently, non-steroidal anti-inflammatory drugs (NSAIDs) and opioids have low potency and/or side effects on neuropathic pain (e.g., gastrointestinal/renal and psychotropic side effects, respectively), and thus the development of new pain treatments is highly desirable. Increased NGF levels in response to chronic pain, injury and inflammation and administration of exogenous NGF have been recognized to increase pain hypersensitivity. Furthermore, inhibition of NGF function using anti-NGF antibodies or non-selective small molecule Trk inhibitors has been shown to have an effect on pain in animal models. It has been shown that selective Trk inhibitors (inhibiting at least NGF targets, TrkA receptors) may provide clinical benefit for the treatment of pain. An excellent early review has covered the targeting of NGF/BDNF for the treatment of pain and therefore this review focuses only on the claimed small molecule Trk kinase inhibitors against cancer and pain. However, it is noteworthy that the NGF antibody, tanizumab (tanezumab), was recently reported to show good efficacy against osteoarthritis knee pain in phase II trials. "

International patent application publication No. WO2009/012283 relates to a variety of fluorophenyl compounds as Trk inhibitors; international patent applications publication nos. WO2009/152087, WO2008/080015, and WO2008/08001 and WO2009/152083 relate to a variety of fused pyrroles as kinase modulators; international patent applications publication nos. WO2009/143024 and WO2009/143018 relate to a variety of substituted pyrrolo [2,3-d ] pyrimidines as Trk inhibitors; international patent applications, publication Nos. WO2004/056830 and WO2005/116035, describe a variety of 4-amino-pyrrolo [2,3-d ] pyrimidines as Trk inhibitors. International patent application publication No. WO2011/133637 describes different pyrrolo [2,3-d ] pyrimidines and pyrrolo [2,3-b ] pyridines as different kinase inhibitors.

U.S. provisional application US61/471758, filed on 5/4/2012, is hereby incorporated by reference in its entirety.

Trk inhibitors, therefore, have a wide variety of potential medical applications. There is a need to provide new Trk inhibitors as good drug candidates. In particular, the compounds should bind preferentially and efficiently to the Trk receptor in a selective manner compared to other receptors, while showing little affinity for other receptors, including other kinase and/or GPC receptors, and exhibiting functional activity as Trk receptor antagonists. They should be non-toxic and show few side effects. In addition, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic, and easily formulated. They should preferably be, for example, sufficiently gastro-intestinal to be absorbed, and/or can be injected directly into the bloodstream, intramuscularly or subcutaneously, and/or metabolically stable and have favourable pharmacokinetic properties.

Within the object of the present invention, potent compounds and salts with oral activity are provided, which can be used as active pharmaceutical substances, in particular as Trk antagonists, i.e. they block the intracellular kinase activity of Trk, such as trka (ngf), receptors. Other desirable characteristics include good HLM/hepatocyte stability, oral bioavailability, metabolic stability, absorbability, selectivity over other types of kinases, dofetilide selectivity. Preferred compounds and salts will exhibit no CYP inhibitory/inducing effect and little effect on the CNS.

SUMMARY

The present invention provides compounds of formula I:

and pharmaceutically acceptable salts thereof, wherein the substituents are as defined below.

The invention also includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I as defined herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The invention also relates to methods of treating a disease or disorder adapted for treatment with a Trk antagonist in a subject by administering to a subject in need thereof a therapeutically effective amount of one or more compounds herein or a pharmaceutically acceptable salt thereof.

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

Preferably, the compounds of the present invention are potent Trk receptor antagonists and have suitable PK properties to enable once-daily administration.

The compounds of the invention are potentially useful in the treatment of a range of disorders, particularly pain indications, for which Trk antagonists are indicated. The term "treating" as used herein may include one or more of curative, palliative and prophylactic treatment, depending on the disease or condition of the patient.

According to the invention, the compounds of the invention can be used for the treatment of any physiological pain, such as inflammatory pain, nociceptive pain, neuropathic pain, acute pain, chronic pain, musculo-skeletal pain, progressive pain, central pain, cardiac and vascular pain, headache, orofacial pain. Other pain conditions that may be treated include strong acute pain and chronic pain conditions, which may involve the same pain pathways driven by pathophysiological processes and thus terminate the provision of protective mechanisms, but rather contribute to debilitating symptoms associated with a wide range of disease states.

Pain is a characteristic of many trauma and disease states. When substantial damage occurs to body tissue due to disease or trauma, the characteristics of nociceptor activation are altered, which results in hypersensitivity reactions at the site of the injury and in adjacent normal tissue. In acute pain, once the injury heals, sensitivity returns to normal. However, in many chronic pain states. Hypersensitivity reactions persist far in the healing process and are often attributed to nervous system injury caused by maladaption of afferent fibers (Woolf & Salter2000Science 288: 1765-. Clinical pain exists when discomfort and abnormal sensitivity is present in the patient's symptoms. There are a number of typical pain subtypes: 1) spontaneous pain which may be dull, burning or needle-prick; 2) the pain response to noxious stimuli is amplified (hyperalgesia); 3) pain (allodynia) results from normal innocuous stimulation (Meyer et al, 1994Textbook of Pain 13-44). Pain can be divided into many different areas due to different pathophysiology, including nociceptive pain, inflammatory pain, neuropathic pain, etc. It should be noted that some types of pain have multiple etiologies and thus can be divided into more than one area, e.g., back pain, cancer pain, have both nociceptive and neuropathic components.

Nociceptive pain

Nociceptive pain is induced by tissue damage or intense stimuli with the potential to cause injury. The pain afferents are activated by the stimulation of conduction by nociceptors at the site of injury and sensitize the spinal cord at the level of their extremities. It is then transmitted up the spinal cord tract to the brain where Pain is felt (Meyer et al, 1994, Textbook of Pain, 13-44). Activation of nociceptors activates two types of afferent nerve fibers. The myelinated a-delta fibers are rapidly transported and responsible for the sensation of severe pain and sting, while unmyelinated C fibers are transported at a slower rate and deliver dull or aching pain. Moderate to severe acute nociceptive pain is a major feature of pain caused by, but not limited to, strain/sprain, post-operative pain (pain after any surgical procedure), post-traumatic pain, burns, myocardial infarction, acute pancreatitis, and renal colic. In addition, cancer-related acute pain syndromes are often attributed to therapeutic interactions such as chemotherapy toxicity, immunotherapy, hormonal therapy, and radiation therapy. Moderate to severe acute nociceptive pain is, but is not limited to, a major feature of cancer pain, which can be tumor-related pain (e.g., bone pain, headache and facial pain, visceral pain) or pain associated with cancer therapy (e.g., post-chemotherapy syndrome, chronic post-operative pain syndrome, post-radiation syndrome), back pain that can be caused by herniated or ruptured intervertebral discs or abnormalities of the lumbar facet joints, sacroiliac joints, paraspinal muscles, or posterior longitudinal ligaments.

Neuropathic pain

According to the present invention, the compounds of the present invention can potentially be used for the treatment of neuropathic pain and symptoms of neuropathic pain, including hyperalgesia, allodynia and progressive pain. Neuropathic pain is defined as pain that is caused or caused by a primary lesion or dysfunction of the nervous system (IASP definition). Nerve damage can result from trauma and disease, and thus the term "neuropathic pain" encompasses many conditions with multiple etiologies. These include, but are not limited to, diabetic neuropathy, post herpetic neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia, uremia, or vitamin deficiency. Neuropathic pain is pathological as it has no protective effect. It also frequently appears after the disappearance of the original cause, usually lasting several years, thereby significantly reducing the quality of life of the patient (Woolf and Mannion, 1999, Lancet, 353: 1959-. Symptoms of neuropathic Pain are difficult to treat because they are often heterogeneous even among patients with the same disease (Woolf and Decostd 1999Pain Sup.6: S141-S147; Woolf and Mannion1999Lancet 353: 1959-1964). They include spontaneous pain (which can persist) and paroxysmal and abnormally induced pain, such as hyperalgesia (increased sensitivity to noxious stimuli) and allodynia (sensitivity to normally innocuous stimuli).

Acute pain and chronic pain

Strong acute and chronic pain may involve the same pathways driven by pathophysiological processes and thus cease to provide protective mechanisms, but instead contribute to debilitating symptoms associated with a wide range of disease states. Pain is a characteristic of many trauma and disease states. When substantial damage is caused to body tissue by disease or trauma, the characteristics of nociceptor activation are altered. Sensitization occurs locally and centrally around the termination of nociceptors, around lesions. This results in hypersensitivity at the site of the lesion and adjacent normal tissue. In acute pain, these mechanisms may be useful and allow a repair process to occur, and once the injury heals, the hypersensitivity returns to normal. However, in many chronic pain states, hypersensitivity far exceeds the healing process and is often attributed to nervous system injury. Such damage often results in maladaptation of afferent fibers (Woolf & Salter2000Science 288: 1765-. Clinical pain exists when discomfort and abnormal sensitivity is present in the patient's symptoms. Patients tend to be very heterogeneous and may present with various pain symptoms. There are a number of pain subtypes: 1) spontaneous pain which may be dull, burning or needle-prick; 2) an amplified pain response to noxious stimuli (hyperalgesia); 3) pain (allodynia) results from normal innocuous stimulation (Meyer et al, 1994Textbook of Pain 13-44). Although patients with back pain, arthritic pain, CNS trauma, or neuropathic pain may have similar symptoms, the underlying mechanisms are different and thus may require different treatment strategies.

Chronic pain

Chronic pain comprises one or more of the following: chronic nociceptive pain, chronic neuropathic pain, chronic inflammatory pain, penetrating pain, persistent pain hyperalgesia, allodynia, central sensitization, peripheral sensitization, disinhibition, and enhanced facilitation. Chronic pain includes cancer pain, for example, cancer pain caused by: malignant tumor, adenocarcinoma in glandular tissue, blastoma in embryonic tissue of an organ, cancer in epithelial tissue, leukemia in a tissue forming blood cells, lymphoma in lymphoid tissue, myeloma in bone marrow, sarcoma in connective tissue or supportive tissue, adrenal cancer, AIDS-related lymphoma, anemia, bladder cancer, bone cancer, brain cancer, breast cancer, carcinoid tumor, cervical cancer, chemotherapy, colon cancer, cytopenia, endometrial cancer, esophageal cancer, stomach cancer, head cancer, neck cancer, hepatobiliary cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, Hodgkin's disease, lymphoma, non-Hodgkin's lymphoma, central system tumor, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, urinary tract cancer, bone cancer, sarcoma cancer of connective tissue, cancer of bone tissue, lymphoma, carcinoma of prostate cancer, colon cancer, Hematopoietic cancer, bone marrow cancer, multiple myeloma, leukemia, primary or secondary bone cancer, tumors that metastasize to bone, tumors that infiltrate nerves and hollow organs, tumors that are close to neural structures. Cancer pain also includes visceral pain (e.g., visceral pain caused by pancreatic cancer and/or metastatic cancer in the abdomen), somatic pain (e.g., somatic pain caused by one or more bone cancers), metastatic cancer in the bone, post-operative pain, sarcoma cancer of connective tissue, cancer of bone tissue, cancer of hematopoietic cells of the bone marrow, multiple myeloma, leukemia, primary or secondary bone cancer.

Inflammatory pain

Inflammatory disorders 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, where chronic inflammatory pain may be pain involving both peripheral and central sensitization and/or pain involving a mixed etiology of both inflammatory and neuropathic or nociceptive pain components. Inflammatory pain also includes hyperalgesia, such as primary and/or secondary hyperalgesia. Additionally or alternatively, the inflammatory pain may comprise allodynia. Inflammatory pain also includes pain that persists with difficulty in resolving underlying disorders or inflammatory conditions or injury healing.

Inflammatory pain is pain resulting from an inflammatory condition, such as for example, in a wound; diseases, such as inflammatory diseases; an immune response; acute tissue injury in response to the presence of foreign matter, chemicals, or infectious particles (e.g., microorganisms). The inflammatory disorder may be acute or chronic inflammation or both.

Inflammatory pain may result from an inflammatory condition due to an inflammatory disease, such as inflammatory joint disease, inflammatory connective tissue disease, inflammatory autoimmune disease, inflammatory myopathy, inflammatory digestive system disease, inflammatory airway disease, cellular immune inflammatory disease, hypersensitivity and anaphylaxis, vascular inflammatory disease, non-immune inflammatory disease, synovitis, villous nodular synovitis, joint pain, ankylosing spondylitis, spondyloarthritis, spondyloarthropathies, gout, Pagets's disease, periarticular disorders such as bursitis, rheumatoid disease, rheumatoid arthritis and osteoarthritis, rheumatoid arthritis or osteoarthritis. In particular, rheumatoid arthritis represents a progressive inflammation associated with severe pain. Arthritic pain is a form of inflammatory pain and is due to inflammation in the joints, which leads to peripheral and central sensitization. In inflammatory conditions, the nociceptive system is usually activated by harmless and painless mechanical stimuli. In addition, when the joint is at rest, pain is present and manifests itself as spontaneous pain and hyperalgesia (increased pain response to noxious stimuli and increased pain response to normally non-painful stimuli). Inflammatory processes in the surrounding tissues lead to central sensitization in the spinal cord, which contributes to hyperalgesia and allodynia typically associated with inflammatory pain. Other types of inflammation include Inflammatory Bowel Disease (IBD).

Other types of pain

Other types of pain include, but are not limited to:

-musculo-skeletal disorders including, but not limited to, myalgia, fibromyalgia, spondylitis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, pyomyositis;

central pain or ' thalalgia ', which is defined as pain caused by damage 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;

-cardiac and vascular pain including, but not limited to, angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleroderma, skeletal muscle ischemia;

-visceral pain and gastrointestinal disorders. The viscera includes organs of the abdominal cavity. These organs include the sexual organs, spleen and part of the digestive system. Visceral associated pain can be divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered Gastrointestinal (GI) tract disorders include Functional Bowel Disorder (FBD) and Inflammatory Bowel Disease (IBD). These GI disorders include a wide range of disease states, which are currently only moderately controlled, including gastroesophageal reflux, dyspepsia, Irritable Bowel Syndrome (IBS) and Functional Abdominal Pain Syndrome (FAPS) in the case of FBD, crohn's disease, ileitis and ulcerative colitis in the case of IBD, all of which produce visceral pain on a regular basis. Other types of visceral pain include pain associated with dysmenorrhea, pelvic pain, cystitis, and pancreatitis;

Headache, including but not limited to migraine, migraine with aura, migraine without aura, cluster headache, tension type headache. Orofacial pain, including but not limited to dental pain, temporomandibular muscularis disc pain, tinnitus, hot flashes, restless legs syndrome and the development of blockade of abuse potential. Additional pain conditions may include back pain (e.g., chronic low back pain), cancer pain, complex regional syndrome, HIV-associated neuropathic pain, post-operative induced neuropathic pain, post-stroke pain, spinal cord injury pain, traumatic nerve injury pain, diabetic peripheral neuropathy, moderate/severe interstitial cystitis pain, irritable bowel syndrome pain, moderate/severe endometriosis pain, moderate/severe pelvic pain, moderate/severe prostatitis pain, moderate/severe osteoarthritis pain, post-herpetic neuralgia, rheumatoid arthritis pain, painful menstrual pain, pre-emergent postoperative pain, trigeminal neuralgia, bursitis, dental pain, fibromyalgia or facial muscle pain, menstrual pain, migraine, neuropathic pain (including painful diabetic neuropathy), pain associated with post-herpetic neuralgia, pain associated with post-inflammatory pain, pain associated with post-surgical pain, pain associated with post-operative, Postoperative pain, referred pain, trigeminal neuralgia, visceral pain (including interstitial cystitis and IBS) and pain associated with AIDS, allodynia, burns, cancer, hyperalgesia, hypersensitivity, spinal cord trauma and/or degeneration and stroke.

Detailed Description

Embodiment 1 of the invention is a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein

R¹Is that

H, or

C optionally substituted with up to 3 substituents_1-5Alkyl, the substituents are independently selected from OH, CON (R)⁵R⁶)、SO₂R⁷、SR⁷、OR⁷、CH₂OH、CO₂R⁵、SONR⁷R⁷、NR⁷SO₂R⁵、CN、NO₂And R⁸Or is or

A ring system selected from C_3-5Cycloalkyl, spiroalkyl, or a 4-to 6-membered saturated heterocyclic ring, the ring system having up to 3 ring heteroatoms selected from N, O and S, and the ring system being optionally substituted with up to 3 substituents independently selected from methyl, OH, CON (R)⁵R⁶)、SO₂R⁷、OR⁷、CH₂OH、CO₂R⁵、SONR⁷R⁷、NR⁷SO₂R⁵、CN、NO₂And R⁸；

R²Is H or methyl;

R³is H, NH₂Or NH (optionally substituted by up to 3 independently selected from OH and O (C)_1-3Alkyl) substituted C_1-3Alkyl groups);

R¹⁰¹h, OH, methyl, cyclopropyl, methoxy, ethyl, ethoxy or CN;

x is a bond, O, (CH-R)⁴)_n、NR¹⁰⁴、OCH₂Or CH₂O；

R⁴Independently is H, CH₃、CH₂OH、CH₂OCH₃、OH、NH₂、NHCH₃、N(CH₃)₂、CH₂NH₂、CH₂NHCH₃Or CH₂N(CH₃)₂；

R¹⁰⁴Is H, C_1-3Alkyl or C_4-6Saturated carbocycles, each of which is optionally substituted with up to 3 independently selected from C_1-3Alkyl radical, CH₂OH and NH₂Substituted with the substituent(s);

n is 1 or 2;

R¹⁰²is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic ring system or an 8-14 membered bicyclic ring system which may be saturated or partially or fully unsaturated, wherein the heterocyclic ring system may have up to 5 ring heteroatoms selected from N, S and O, wherein the bicyclic ring system may be 2 rings (carbocyclic-carbocyclic, carbocyclic-heterocyclic, heterocyclic-carbocyclic or heterocyclic-heterocyclic) fused or connected by single bonds, which ring system is optionally substituted, if possible, with up to 3 substituents independently selected from halogen, CN, NR ⁵R⁶、SO₂R⁷、SR⁷Optionally substituted by up to 3 OH and/or C_1-3Alkoxy radicalRadical substituted C_1-4Alkyl, optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_3-6Cycloalkyl, C substituted by up to 3 halogens_1-3Alkyl, OH, O (C)_1-3Alkyl), O (optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_3-6Cycloalkyl), O (C optionally substituted with up to 3 halogens_1-3Alkyl), O (optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_1-3Alkyl), NR)⁵SO₂R⁷、=O、R⁸、C(O)R⁸、NO₂、NR⁵CO₂R⁷、NR⁵COR⁷、OR⁸、S(O)R⁷And CH₂R⁸；

R⁵And R⁶Each independently is

H, or

C optionally substituted with up to 3 substituents_1-5Alkyl, the substituents are independently selected from OH, CONR⁷R⁷、SO₂R⁷、OR⁷、CH₂OH、CO₂R⁷、SONR⁷R⁷、NR⁷SO₂R⁷、CN、NO₂And R⁹Or is or

A ring system selected from C_3-5Cycloalkyl, spiroalkyl or a 4-to 6-membered saturated heterocyclic ring, which ring system is optionally substituted with up to 3 substituents independently selected from OH, CON (R)⁷R⁷)、SO₂R⁷、CO₂R⁷、SONR⁷R⁷、NR⁷SO₂R⁷、CN、NO₂Halogen, NR⁷R⁷、SR⁷Optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_1-4Alkyl, optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_3-6Cycloalkyl, C substituted by 1-3 halogens_1-3Alkyl, O (optionally substituted by up to 3 OH and/or C)_1-3Alkoxy-substituted C_3-6Cycloalkyl), O (C substituted by up to 3 halogens)_1-3Alkyl), O (optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_1-3Alkyl), NR) ⁷SO₂R⁷、=O、NO₂、NR⁷CO₂R⁷And S (O) R⁷；

Or R⁵And R⁶Together with the N to which they are attached may be a 4-7 membered ring optionally including up to 2 additional ring heteroatoms independently selected from N, O, S, the ring optionally being C_1-3Alkoxy and/or C_1-3Alkyl substitution;

R⁷is H, C_1-5Alkyl or C_1-5An alkoxy group;

the C is_1-5Alkyl or C_1-5Alkoxy is optionally substituted with up to 3 substituents independently selected from halogen;

R⁸is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic ring system or an 8-14 membered bicyclic ring system which may be saturated or partially or fully unsaturated, wherein the heterocyclic ring system may have up to 5 ring heteroatoms selected from N, S and O, wherein the bicyclic ring system may be 2 rings (carbocyclic-carbocyclic, carbocyclic-heterocyclic, heterocyclic-carbocyclic or heterocyclic-heterocyclic) fused or connected by single bonds, which ring system is optionally substituted, if possible, with up to 3 substituents independently selected from halogen, CN, NR⁵R⁶、SO₂R⁷、SR⁷Optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_1-4Alkyl, optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_3-6Cycloalkyl, C substituted by 1-3 halogens_1-3Alkyl, OH, O (C)_1-3Alkyl), O (optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_3-6Cycloalkyl), O (C optionally substituted with up to 3 halogens _1-3Alkyl), O (optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_1-3Alkyl), NR)⁵SO₂R⁷、=O、NO₂、NR⁷COR⁷、NR⁵CO₂R⁷And S (O) R⁷；

R⁹Is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic ring system or an 8-14 membered bicyclic ring system which may be saturated or partially or fully unsaturated, wherein the heterocyclic ring system may have up to 5 ring heteroatoms selected from N, S and O, wherein the bicyclic ring system may be 2 rings (carbocyclic-carbocyclic, carbocyclic-heterocyclic, heterocyclic-carbocyclic or heterocyclic-heterocyclic) fused or connected by single bonds, which ring system is optionally substituted, if possible, with up to 3 substituents independently selected from halogen, CN, NR⁷R⁷、SO₂R⁷、SR⁷Optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_1-4Alkyl, optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_3-6Cycloalkyl, C substituted by 1-3 halogens_1-3Alkyl, OH, O (C)_1-3Alkyl), O (optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_3-6Cycloalkyl), O (C optionally substituted with up to 3 halogens_1-3Alkyl), O (optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_1-3Alkyl), NR)⁷SO₂R⁷、=O、NO₂、NR⁷CO₂R⁷、NR⁷COR⁷And S (O) R⁷；

Wherein each CH moiety may be replaced by a CF moiety.

Embodiment 2 of the present invention is a compound or salt of embodiment 1 of the present invention, wherein R ¹Is H, C optionally substituted by 2 OH_1-5An alkyl group; or R¹Is C_1-5Alkyl radical, which is CONH₂、CONHCH₃、CON(CH₃)₂、CO₂H、CO₂CH₃、OCH₃、SCH₃、SO₂CH₃Substitution; or R¹Is a ring system selected from C_3-5Cycloalkyl, spiroalkyl or oxetanyl, the ring system being optionally substituted by methyl, OH or CH₂OH substitution。

Embodiment 3 of the present invention is the compound or salt of any one of embodiments 1 or 2 of the present invention, wherein R¹Is tert-butyl, hydroxy-tert-butyl, dihydroxy-tert-butyl, 1-hydroxypropan-2-yl or 1, 3-dihydroxypropan-2-yl.

Embodiment 4 of the present invention is a compound or salt of any one of embodiments 1-3 of the present invention, wherein R²Is H.

Embodiment 5 of the present invention is a compound or salt of any one of embodiments 1-4 of the present invention, wherein R³Is H or NH₂。

Embodiment 6 of the present invention is a compound or salt of any one of embodiments 1 through 5 of the present invention, wherein R³Is NH₂。

Embodiment 7 of the present invention is a compound or salt of any one of embodiments 1 through 5 of the present invention, wherein R³Is H.

Embodiment 8 of the present invention is a compound or salt of any one of embodiments 1-7 of the present invention, wherein R¹⁰¹Is H.

Embodiment 9 of the present invention is a compound or salt of any one of embodiments 1-7 of the present invention, wherein R¹⁰¹Is OH.

Embodiment 10 of the present invention is a compound or salt of any one of embodiments 1-9 of the present invention, wherein X is a bond, O, CH ₂、C₂H₄、CH(CH₃)CH₂、CH(CH₃)、CH(CH₂OH)、CH₂O，CH(NH₂) CH (OH) or NH.

Embodiment 11 of the present invention is a compound or salt of any one of embodiments 1-10 of the present invention, wherein X is CH₂。

Embodiment 12 of the present invention is a compound or salt of any one of embodiments 1 through 11 of the present invention, wherein R¹⁰²Is an optionally substituted nitrogen containing ring system attached to the moiety X through a nitrogen ring atom.

Embodiment 13 of the present invention is a compound or salt of any one of embodiments 1-11 of the present invention, wherein R¹⁰²Is an optionally substituted ring system, wherein the ring system is selected from benzimidazolyl, benzisoxazoleAzolyl, benzofuranyl, benzoAzolyl, benzotriazolyl, biphenyl, bipyrazolyl, cinnolinyl, cyclobutylimidazolyl, cyclobutylpyrazolyl, cyclobutylthiazolyl, cyclopentyltriazolyl, cyclopropylisopropylAzolyl, cyclopropylAzolyl, cyclopropylpyrazolyl, cyclopropyltriazolyl, diazacyclopropen (diazirenyl) phenyl, dihydronaphthyridinyl, dihydropyrrolopyrazolyl, dioxanaphthyridinyl, furazanyl, furopyridinyl, furopyrrolyl, imidazolyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazothiadiazolyl, imidazothiazolyl, indanyl, indazolyl, indolyl, isoindolyl Azolopyridinyl, isoAzolyl, isoquinolyl, naphthyridinyl,Azolyl, phenyl, phenylcyclopropyl, phenylimidazolyl, phenylpyrazolyl, phenylpyrrolyl, phenyltetrazolyl, phthalazinyl, purinyl, pyrazinyl, pyrazolyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazolotriazinePyridyl, pyridazinyl, pyridyltriazolyl, pyrimidinyl, pyrroloimidazolyl, pyrrolopyrazinyl, pyrrolopyrimidinyl, pyrrolopyridyl, pyrrolyl, quinolinyl, quinazolinyl, quinoxalinyl, tetrahydrobenzisoxazinylOxazolyl, tetrahydrocyclopentapyrazolyl, tetrahydrotriazolopyridyl, tetrazolopyridazinyl, tetrazolopyridyl, thiazolyl, thiazolopyridyl, thiazolopyrimidinyl, thienylpyrazolyl, thienopyridinyl, triazolopyridyl and triazolyl.

Embodiment 14 of the present invention is a compound or salt of embodiment 13 of the present invention wherein the optional substituents are independently selected from halogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, CF, if possible₃、CHF₂、CH₂F、CH₂OCH₃、CN、CH₂OH、OCH₃、=O、NH₂、SCH₃、SO₂CH₃Phenoxy, fluorophenoxy, benzyl, SCF₃、OCF₃、SO₂CF₃、NHSO₂CH₃、NHSO₂CF₃、C(O)CF₃、C(O)CH₃Benzoyl, azetidinylmethyl, fluoroazetidiylmethyl and morpholinomethyl.

Embodiment 15 of the invention is a compound or salt of any one of embodiments 1-11, 13 or 14 of the invention, wherein R¹⁰²Selected from phenyl, pyrazol-1-yl, 1,2, 3-triazol-1-yl, benzotriazol-2-yl, pyridin-3-yl and pyridin-4-yl, each optionally substituted with halogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, CF₃、CHF₂、CH₂F、CH₂OCH₃、CN、CH₂OH、OCH₃、=O、NH₂、SCH₃、SO₂CH₃Phenoxy, fluorophenoxy, benzyl, SCF₃、OCF₃、SO₂CF₃、NHSO₂CH₃、NHSO₂CF₃、C(O)CF₃、C(O)CH₃Benzoyl, azetidinylmethyl, fluoroazetidiylmethyl and/or morpholinomethyl.

Embodiment 16 of the present invention is a compound or salt of any one of embodiments 1-15 of the present invention, wherein the group R is present⁵And R⁶Wherein R is⁵And R⁶Each independently is H, optionally substituted by C_1-3Alkoxy-substituted C_1-3Alkyl radical, C_3-5Cycloalkyl, spiroalkyl, oxetanyl, tetrahydrofuranyl or pyranyl; or R⁵And R⁶Together with the N to which they are attached may be an azetidine, pyrrolidine, piperidine, piperazine or morpholine ring, optionally substituted with C_1-3Alkoxy and/or C_1-3Alkyl substitution.

Embodiment 17 of the present invention is a compound of embodiment 1 of the present invention having formula IA:

or a pharmaceutically acceptable salt thereof, wherein

R³Is H or NH₂；

R¹Is C optionally substituted by 1 or 2 OH groups _2-4An alkyl group;

R¹⁰¹is H or OH;

and R is¹⁰²Is phenyl or an aromatic or partially unsaturated 5-or 6-membered heterocyclic ring optionally fused with another phenyl or 5-to 7-membered aromatic or partially unsaturated heterocyclic ring, wherein each heterocyclic ring has 1 to 3 ring heteroatoms selected from N, O and S, and the ring system is optionally interrupted by up to 3 ring heteroatoms independently selected from halogen, CF₃、C_1-4Alkyl and C_3-5Cycloalkyl substituents.

Embodiment 18 of the present invention is an embodiment of the present inventionThe compound or salt of scheme 17, wherein R¹⁰¹Is H.

Embodiment 19 of the present invention is a compound or salt of embodiment 18 of the present invention, wherein R¹Is tert-butyl, hydroxy-tert-butyl or 1-hydroxypropan-2-yl, and R¹⁰²Is 4-trifluoromethylphenyl, 4-chlorophenyl, 2, 4-difluorophenyl, 5-chloropyridin-2-yl, 5-fluoropyridin-2-yl, 3-trifluoromethylpyrazolyl-1-yl, 4-trifluoromethylpyrazol-1-yl, 3-trifluoromethyl-5-methylpyrazol-1-yl, 3-cyclopropylpyrazol-1-yl, 4-trifluoromethyl (1,2, 3-triazol-1-yl), 4-cyclopropyl (1,2, 3-triazol-1-yl) or benzotriazol-2-yl.

Embodiment 20 of the present invention is a compound of embodiment 1 selected from:

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

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

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

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

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

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

n- {5- [ (2-amino-7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } -2- [4- (trifluoromethyl) -1H-pyrazol-1-yl ] acetamide;

n- {5- [ (2-amino-7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } -2- [4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl ] acetamide;

n- {5- [ (2-amino-7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } -2- (5-chloropyridin-2-yl) acetamide;

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

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

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

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

n- [5- ({7- [ (1S) -2-hydroxy-1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } carbonyl) pyridin-3-yl ] -2- [4- (trifluoromethyl) phenyl ] acetamide;

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

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

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

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

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

n- (5- { [ 2-amino-7- (2-hydroxy-1-methylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] carbonyl } pyridin-3-yl) -2- [4- (trifluoromethyl) phenyl ] acetamide;

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

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

or a pharmaceutically acceptable salt thereof.

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

Embodiment 22 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 of the invention, above, for use as a medicament.

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

Embodiment 24 of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1 to 20 of the invention for use in the treatment of pain.

Embodiment 25 of the present invention is the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, as defined in any one of embodiments 1 to 20 of the invention above, in the manufacture of a medicament for the treatment of a disease for which a Trk receptor antagonist is indicated.

Embodiment 26 of the invention is the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, as defined in any one of embodiments 1 to 20 of the invention above, in the manufacture of a medicament for the treatment of pain.

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

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

Embodiment 29 of the invention is a compound or salt of any one of embodiments 1-20 of the invention for use in combination with another drug substance in medical therapy.

Additional embodiments of the invention include:

a compound or salt of formula (I), wherein R¹Having the values as exemplified in the following examples;

a compound or salt of formula (I) wherein X has the values as exemplified in the examples below;

a compound or salt of formula (I), wherein R¹⁰²Having the values as exemplified in the following examples;

a compound or salt of formula (I), wherein R¹、R²、R³、R¹⁰¹X and R¹⁰²Having the values as exemplified in the following examples;

a compound selected from any one of the following examples or a pharmaceutically acceptable salt thereof; and

any novel intermediate compounds disclosed herein.

Other embodiments of the present invention can be conceived based on the following description.

"halo" means a fluoro, chloro, bromo, or iodo group.

An "alkyl" group, which contains the requisite number of carbon atoms, may be unbranched or branched. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

"pharmaceutically acceptable salts" of the compounds of formula I include acid addition salts and base addition salts (including disalts, hemisalts, and the like) thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, salicylate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogenphosphate, glucarate, stearate, succinate, citrate, dihydrogenphosphate, glucarate, stearate, gluconate, salicylate, and salicylate, Tartrate, tosylate and trifluoroacetate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum salts, arginine salts, dibenzylethylenediamine salts, calcium salts, choline salts, diethylamine salts, dialcohol salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts. For reviews on suitable salts, see Stahl and Wermuth, the handbook for pharmaceutical salts: properties, Selection and uses (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) "(Wiley-VCH, Weinheim, Germany, 2002).

The compounds of the invention include compounds of formula I as defined above and salts thereof, polymorphs and isomers thereof (including optical, geometric and tautomeric isomers) as defined below, and isotopically labeled compounds of formula I.

Unless otherwise specified, compounds of formula (I) containing one or more asymmetric carbon atoms may exist in the form of two or more stereoisomers. When the compounds of formula (I) contain, for example, a keto or guanidino group or an aromatic moiety, tautomerism ('tautomerism') may occur. It follows that a single compound may exhibit more than one type of isomerism.

The scope of the claimed compounds of the present invention includes within its scope all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism and mixtures of one or more thereof. Also included are acid addition salts or base addition salts in which the counterion is optically active, for example D-lactate or L-lysine; or racemic, such as DL-tartrate or DL-arginine.

Examples of the types of potential tautomerism exhibited by the compounds of the present invention include hydroxypyridine A pyridone; amides of carboxylic acidsHydroxy-imines and keto groupsEnol tautomerism:

the cis/trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

Conventional techniques for the preparation/separation of the individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or the racemate of a salt or other derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example an alcohol, or an acid or base (in the case where the compound of formula (I) contains an acidic or basic moiety), for example tartaric acid or 1-phenylethylamine. The diastereomers obtained may be separated by chromatography and/or fractional crystallization and one or both diastereomers normalized to the corresponding pure enantiomers in a manner well known to those skilled in the art.

The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography (typically HPLC) on a resin with an asymmetric stationary phase and a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0-50% isopropanol, typically 2-20%; and 0-5% of an alkylamine, typically 0.1% diethylamine. Concentrating the eluate to obtain said enriched mixture.

The mixture of stereoisomers may be separated by conventional techniques well known to those skilled in the art. [ see, for example, "stereoschemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994). ]

The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by a protomer having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in practice.

Examples of isotopes suitable for inclusion in compounds of the invention include isotopes of hydrogen, for example²H and³h; isotopes of carbon, e.g.¹¹C、¹³C and¹⁴c; isotopes of chlorine, e.g.³⁶Cl; isotopes of fluorine, e.g.¹⁸F; isotopes of iodine, e.g.¹²³I and¹²⁵i; isotopes of nitrogen, e.g.¹³N and¹⁵n; isotopes of oxygen, e.g.¹⁵O、¹⁷O and¹⁸o; isotopes of phosphorus, e.g.³²P; and isotopes of sulfur, e.g.³⁵S。

Certain isotopically-labeled compounds of formula (I), for example those into which a radioisotope is incorporated, are useful in drug and/or substrate tissue distribution studies. The radioactive isotope tritium, that is,³h, and carbon-14, that is,¹⁴c, are particularly suitable for this purpose in view of their ready availability for easy binding and detection.

By heavier isotopes such as deuterium, i.e.²H substitution may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life or reduced dosage requirements in vivo and, therefore, may be preferred in certain circumstances.

Using positron-emitting isotopes, e.g.¹¹C、¹⁸F、¹⁵O and¹³n substitution, can be suitable for examining Positron Emission Tomography (PET) research with a high substrate receptor occupancy.

Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations, using a suitable isotopically-labelled reagent in place of the non-isotopically-labelled reagent employed above.

The following routes, including those exemplified in the examples and preparations, illustrate the synthesis of compounds of formula (I). It will be appreciated by those skilled in the art that the compounds of the invention and intermediates thereof may be prepared by methods other than those specifically described herein, for example by modifying the methods described herein, for example by methods well known in the art. Suitable guidance regarding synthesis, functional group interconversion, protecting group application, etc., are for example: "Comprehensive Organic Transformations" by RC Larock, VCH Publishers Inc. (1989); advanced Organic Chemistry, March, WileyInterscience (1985); "design Organic Synthesis" by S Warren, WileyInterscience (1978); s Warren, WileyInterscience (1982) "Organic Synthesis-The DisconnectionApproach"; RK Mackie and DM Smith, Longman (1982) "Guideeook to organic Synthesis; TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", John Wiley and Sons, Inc. (1999); and PJ, "Protecting Groups" by Kocienski, Georg Thieme Verlag (1994); and newer versions of any of the standard works.

In the following general synthetic methods, unless otherwise specified, substituents have the meanings defined for the compounds of the formula (I) above. R¹⁰¹¹And R¹⁰¹The same or in a form suitably protected thereof.

Scheme 1 illustrates the preparation of intermediates of the general formula (intermediate (Int)1), where they can be prepared from an amine (Int3), where at R¹In those cases where the alcohol is included, R is used¹Wherein a suitable hydroxy Protecting Group (PG) is used. Any suitable oxygen Protecting group may be used (as described in "Protecting Groups in Organic Synthesis" 3 rd edition T.W.Greene and P.G.Wuts, Wiley-Interscience, 1999). Common oxygen protecting groups suitable for use herein include t-butyldimethylsilyl (TBDMS), Tetrahydropyranyl (THP), and t-butylsilyl (TBS).

As illustrated in scheme 1, compounds of general formula (intermediate 1) were prepared from compounds of general formula (intermediate 2).

Scheme 1

Wherein R is³⁰¹May be H or halogen, typically chlorine. The compounds of general formula (intermediate 1) can be prepared from the amines (intermediate 3) and (intermediate 4) in a cyclisation step, followed by a dechlorination step. Typical use conditions include co-stirring of the amine of formula (intermediate 3) and the aldehyde (intermediate 4), preferably in ethanol at a temperature of from room temperature to 80 ℃. Such as exemplified in preparations 1-5. The intermediate chloride (intermediate 2) is reduced using standard literature conditions, such as hydrogenation, using a suitable catalyst, such as palladium on carbon, and an additive, such as ammonia in a suitable solvent, such as ethanol. Alternatively, the chloride may be removed by replacing the chlorine with methyl mercaptan and then removing the SMe intermediate with raney nickel. Such as exemplified in preparations 8-13. At R ¹In those cases where one or more of the alcohols are involved, R with a suitable hydroxy Protecting Group (PG) may be used¹A protected form. Any suitable oxygen Protecting group protection/deprotection system may be used (as described in "Protecting Groups in organic Synthesis" 3 rd edition t.w.greene and p.g.wuts, Wiley-Interscience, 1999). Common oxygen protecting groups suitable for use herein include t-butyldimethylsilyl (TBDMS) and Tetrahydropyranyl (THP). Intermediates of the general formulae (intermediate 3) and (intermediate 4) are commercially available or are well known to the person skilled in the art with reference to the literature citation and/or the preparation herein.

As illustrated in scheme 2, compounds of general formula (intermediate 1) may be prepared from compounds of general formula (intermediate 7).

Scheme 2

Compounds of the general formula (intermediate 1)Wherein R is³Which may be H or halogen, typically chlorine, can also be prepared from compounds of general formula (intermediate 7) by replacement of halogen, typically chlorine, with amines of general formula (intermediate 3) in a palladium catalysed Suzuki reaction followed by acid cyclisation. Typical conditions include co-stirring the amine of formula (intermediate 3) and the intermediate of formula (intermediate 7) with a suitable base such as triethylamine in a solvent such as acetonitrile or dichloromethane to give the compound of formula (intermediate 6). The vinyl ether may be introduced by reacting the intermediate (intermediate 6) with a suitable boronic ester and a suitable base such as sodium hydroxide and a suitable catalyst such as tetrakis (triphenylphosphine) palladium (0) in a solvent such as THF at a temperature of from room temperature to 70 ℃. Intermediates of general formula (intermediate 1) can be prepared by treating intermediate (intermediate 5) with an acid such as hydrogen chloride in an organic solvent such as isopropanol at a temperature of from room temperature to 70 ℃. Such as exemplified in preparations 60-62. Intermediates of the general formulae (intermediate 3) and (intermediate 7) are commercially available or are well known to the person skilled in the art in the literature references and/or the preparations herein.

As illustrated in scheme 3, compounds of general formula (intermediate 8) may be prepared from compounds of general formula (intermediate 1).

Scheme 3

Wherein R is³⁰¹Is H or halogen, typically chlorine; the compounds of general formula (intermediate 8) are typically prepared by iodination of the pyrrolopyrimidine intermediate (intermediate 1). Typical conditions of use include stirring the intermediate of formula (XI) with an iodinating agent, such as N-iodosuccinimide, in a suitable solvent, such as DMF or acetonitrile. For example as exemplified in preparations 14-19, 40, 63.

As exemplified in scheme 4, compounds of general formula (intermediate 8) may also be prepared from compounds of general formula (intermediate 9).

Scheme 4

Wherein R is³⁰¹Is H or halogen, typically chlorine; LG is halogen or tosylate, triflate or mesylate; alternatively, intermediates of general formula (intermediate 8) may be prepared by alkylating the pyrrolopyrimidine intermediate (intermediate 9) with a compound of general formula (intermediate 10) using a suitable base such as cesium carbonate or potassium carbonate in an organic solvent. A suitable alternative is to use an additive (e.g. potassium iodide) and a base. Preferred conditions include a DMF solution of cesium carbonate at room temperature. At R¹In those cases where one or more alcohols are included, R can be used as described in scheme 1 ¹In a protected form. Such as exemplified in preparation example 20.

As exemplified in scheme 5, compounds of general formula (intermediate 12) may be prepared from compounds of general formula (intermediate 11).

Scheme 5

Wherein R is³⁰¹Is H or halogen, typically chlorine; the intermediate of formula (intermediate 9) is reacted in an alkylation reaction to give an ester intermediate (intermediate 11) or (intermediate 13) from which the ester group is reduced and protected to give a compound of formula (intermediate 14) wherein R is²⁰⁰Is H or methyl. As mentioned in scheme 1 above, the hydroxyl group may be protected with a suitable oxygen Protecting Group (PG), wherein the preferred protecting groups are TBDMS, TBS and THP. Typical conditions for alkylation include stirring the compound of formula (intermediate 9) with a suitable halide and a suitable base as described in scheme 4. Can be obtained by advancingStep alkylation typically involves the reaction of a compound of formula (intermediate 11), wherein R is methyl iodide, with a suitable alkylating agent such as methyl iodide and a suitable base such as potassium tert-butoxide in an organic solvent such as THF²⁰⁰Is H, is converted to an intermediate (intermediate 13), wherein R²⁰⁰Is methyl. For example as exemplified in preparations 20, 21, 41, 53. The ester intermediates (intermediate 11) and (intermediate 13) may be reduced by using a suitable reducing agent such as lithium borohydride, lithium aluminium hydride or diisobutylaluminium hydride in a suitable solvent such as ethanol or THF. Alternatively, intermediates of general formula (intermediate 12) can be prepared in a 2-step reaction, by: the ester of formula (intermediate 11) or (intermediate 13) is hydrolysed to the appropriate acid using a suitable base such as aqueous lithium hydroxide in a suitable organic solvent such as THF, then the acid is activated using a suitable reagent such as isobutyl chloroformate and using a suitable reducing agent such as sodium borohydride. For example as exemplified in preparations 22, 42, 43, 54. Compounds of general formula (intermediate 14) may be prepared as described in scheme 1 by protecting the hydroxy group of intermediate (intermediate 12) with a suitable oxygen Protecting Group (PG), with the preferred protecting groups being TBDMS and THP. For example as exemplified in preparations 44, 45, 55.

As exemplified in scheme 6, compounds of general formula (intermediate 16) may be prepared from compounds of general formula (intermediate 8).

Scheme 6

Wherein R is³⁰¹Is H or halogen, typically chlorine; x₁Are suitable halogens, typically bromine or iodine; compounds of general formula (intermediate 16) may be prepared from compounds of general formulae (intermediate 8) and (intermediate 15) by: the intermediate (intermediate 8) is metallated (using a suitable organometallic reagent such as butyllithium chloride or isopropylmagnesium) and reacted with the Weinreb amide intermediate (intermediate 15) at-78 ℃ to room temperatureThe reaction is carried out at a warm temperature. For example as exemplified in preparations 26, 27, 46, 47, 56, 58, 64. Alternatively, compounds of general formula (intermediate 15) may be converted to aldehydes of general formula (intermediate 17) by reduction of the Weinreb amide intermediate using a suitable reducing agent. Preferred conditions include diisopropylaluminum hydride in THF at-78 deg.C as exemplified in preparation 106. The compound of formula (intermediate 17) may then be reacted with the compound of formula (intermediate 8) according to the same metallation procedure described above. The intermediate alcohol (intermediate 18) may then be oxidized to the ketone (intermediate 16). Typical oxidation conditions include the use of an oxidising agent, such as Dess-Martin (Dess-Martin) reagent in DCM or 2-iodoxybenzoic acid, in a suitable solvent, such as ethyl acetate, at a temperature between room temperature and reflux temperature. Such as exemplified in preparations 29, 30. Intermediates of general formula (intermediate 15) and (intermediate 17) are commercially available or are well known to those skilled in the art in the literature references and/or preparations herein.

Wherein R is¹⁰¹The corresponding intermediates which are OH and the compounds of formula (I) are considered to be tautomers of pyridones and can be prepared using analogous methods using the benzyl protecting group for the Weinreb amide step, where R is¹⁰¹¹Is benzyloxy (OBn), exemplified as follows:

as illustrated in scheme 7, compounds of general formula (intermediate 20) may be prepared from compounds of general formula (intermediate 8).

Scheme 7

Wherein R is³⁰¹Is H or halogen, typically chlorine; general formula (A)Intermediate 20) can be prepared from compounds of general formulae (intermediate 8) and (intermediate 19) according to the metallation procedure described in scheme 6 above. Typical use conditions include metallation of the intermediate halide (intermediate 8) (using a suitable organometallic reagent such as butyl lithium chloride or isopropyl magnesium) and reaction with the Weinreb amide intermediate (intermediate 19) at temperatures from-78 ℃ to room temperature in a suitable solvent such as THF. Such as exemplified in preparations 24, 25, 28, 50. Intermediates (intermediate 19) are well known to those skilled in the art in the literature references and/or preparations herein. Such as exemplified in preparation 23.

As exemplified in scheme 8, compounds of general formula (intermediate 21) may be prepared from compounds of general formula (intermediate 16).

Scheme 8

Wherein X₁Is bromine or iodine; the compound of formula (intermediate 21) may be prepared from the compound of formula (intermediate 16) by direct amination of the halide using standard literature conditions. For example, the amine (intermediate 21) is typically prepared in a sealed vessel at a temperature between room temperature and 140 ℃ using ammonia and a suitable copper catalyst such as copper (II) sulfate or copper (I) oxide in a suitable solvent such as NMP. When R is³⁰¹When Cl, it is replaced by ammonia under the same conditions to give amines of the general formula (intermediate 21), in which R is³Is NH₂. For example as exemplified in preparations 31, 32, 36, 48, 49, 57, 59, 65. R¹Deprotection of the hydroxyl protecting group (if present) may also be carried out under these conditions. In these cases, the protecting group can be reused as described in scheme 5 above or the amine of general formula (intermediate 21) can be used directly. Alternatively, R may be transformed by reaction with a compound (intermediate 22) wherein R³⁰¹Intermediate of formula (intermediate 16) which is H, preparation of compound of formula (intermediate 21), which isWherein R3 is H. Typical conditions of use include agitation wherein R³⁰¹The halide of the general formula (intermediate 16) which is H is reacted with benzophenone imine, a suitable base such as potassium phosphate, a suitable ligand such as 2-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl and a suitable catalyst such as tris (dibenzylideneacetone) dipalladium in an organic solvent such as 1, 2-dimethoxyethane at room temperature-the solvent melting point temperature. The intermediate (intermediate 22) may be deprotected to give amines of general formula (intermediate 21). Typical conditions use treatment with a suitable acid such as hydrogen chloride or citric acid in an organic solvent such as THF. For example, as exemplified in preparation examples 33, 37 to 39.

As illustrated in scheme 9, compounds of general formula (intermediate 20) may be prepared from general formula (intermediate 22, wherein R is³⁰¹Is Cl).

Scheme 9

The compound of formula (intermediate 20) may be prepared from wherein R³⁰¹The compound of formula (intermediate 22) which is chloro is prepared by an amination reaction as described above in which chloro is reacted with 2, 4-dimethoxybenzylamine and the amine may be deprotected as described above. Typical conditions of use include agitation wherein R³⁰¹Chloro-pyrimidines of formula (intermediate 22) which are Cl, with 2, 4-dimethoxybenzylamine and suitable additives such as 4-dimethylaminopyridine in suitable solvents such as 1, 4-bisThe reaction is carried out in an alkane at a temperature ranging from room temperature to reflux temperature. Such as exemplified in preparation 51.

As illustrated in scheme 10, compounds of general formula (I) can be prepared from compounds of general formula (intermediate 21) and (intermediate 23).

Scheme 10

The compounds of formula (I) may be prepared from the compounds of formulae (intermediate 21) and (intermediate 23) by amide formation, with the addition of a suitable base (e.g. DIPEA) and/or an additive (e.g. DMAP) and a suitable solvent (e.g. pyridine), if necessary. Typical use conditions include co-stirring of the amine of formula (intermediate 21) and the acid of formula (intermediate 23) with a suitable coupling reagent, for example HATU or 1-propylphosphonic cyclic anhydride, and if necessary, addition of a suitable base, for example NMM, DIPEA or TEA, in a suitable solvent, for example pyridine, THF, DMF or DMA, at a temperature of from room temperature to 50 ℃. A suitable alternative is to use an additive (e.g. 4-dimethylaminopyridine) and a base. Any suitable solvent may be used in place of those listed above. At least 1 equivalent of the acid (intermediate 23) and at least 1 equivalent of the coupling reagent should be used, and an excess of either or both of them may be used if desired. For example, as exemplified in examples 1 to 8, 34 to 45, 48 to 53, 57 to 64, preparation examples 34, 35, 52, 66 to 78. In intermediate (intermediate 21) R ¹Containing the appropriate hydroxy protecting group, the Protecting Group (PG) can then be removed in situ or as an additional step, and the appropriate acid and organic solvent added to the crude residue after amide formation has occurred. Commonly used protecting groups used include TBDMS, which is easily removed by: treatment with an acid such as aqueous hydrogen chloride or citric acid in an organic solvent such as THF; or with a fluoride source such as tetrabutylammonium fluoride in organic solvents such as THF and THP, which are also readily removed by treatment with an acid such as aqueous hydrogen chloride in an organic solvent such as THF. Such as exemplified in examples 9-33, 54-56. Intermediates of general formula (intermediate 23) are commercially available or are well known to those skilled in the art in the literature references and/or preparations herein.

As illustrated in scheme 11, wherein R³Is NH₂A compound of formula (II)Compound (I) may be prepared from compounds of general formula (intermediate 20).

Scheme 11

Compound (I) of formula (la) may be prepared from a compound of formula (intermediate 24) by the following steps: amide bond formation as described in scheme 10 above, followed by removal of the dimethoxybenzylamino group in situ, and addition of a suitable acid and organic solvent to the crude residue after amide formation has occurred. Suitable acids for such deprotection include hydrogen chloride or trifluoroacetic acid in an organic solvent such as THF. Such as exemplified in examples 46-47.

As illustrated in scheme 12, wherein R²The compounds of formula (I) which are methyl may be prepared from those in which R is²Preparation of a compound of formula (I) which is H.

Scheme 12

Wherein R is²Compounds of the formula (I) which are methyl may be prepared from those in which R is²The compound of general formula (I) which is H is prepared according to the alkylation reaction with methyl iodide as described in scheme 4. When XR is used¹⁰²In the case of boc, deprotection can be carried out using standard protecting group conditions to give the intermediate (intermediate 21).

As illustrated in scheme 13, wherein X is NR¹⁰⁴The compound of formula (I) may be prepared from a compound of formula (intermediate 21).

Scheme 13

Wherein X is NR¹⁰⁴The compound of the general formula (I) can be prepared from the compound of the general formula (intermediate 21), (intermediate 25) and phenyl chloroformate. As exemplified in example 526, typical conditions include phenyl chloroformate and the compound of formula (intermediate 24) with pyridine in THF, 0-100 ℃.

As illustrated in scheme 14, wherein R¹⁰²The substituent on the ring being aminomethyl CH₂NR₂The compound of formula (I) may be prepared from a compound of formula (1).

Scheme 14

Compounds of formula (I) in which a primary alcohol is present can be oxidized to an aldehyde using desmartin periodinane (periodinane) in DCM at room temperature followed by sodium triacetoxyborohydride and acetic acid in DCM with the appropriate amine HNR ₂Reductive amination is performed.

As exemplified in scheme 15, compounds of general formula (intermediate 26) may be prepared from compounds of general formula (intermediate 27).

Scheme 15

Wherein R is¹⁰³Is Me or CH₂OH; the compound of formula (intermediate 26) may be prepared from the compound of formula (intermediate 27) by converting the alcohol to a suitable leaving group and then cyclising under basic conditions. Preferred conditions include tosyl chloride with n-butyllithium in THF。

According to another embodiment of the present invention, the present invention provides novel intermediate compounds.

Pharmaceutically acceptable salts of the compounds of formula (I) are readily prepared by mixing the compounds of formula (I) and the desired acid or base with each other, if appropriate. The salt may be precipitated from the solution and collected by filtration, or may be recovered by evaporation of the solvent. The degree of ionization of a salt can vary from fully ionized to nearly non-ionized.

The compounds of the invention intended for pharmaceutical use may be administered alone or together with one or more other compounds of the invention or with one or more additional pharmaceutically active agents (or as any combination thereof). In general, they may be administered as a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" as used herein is intended to describe any biologically inactive ingredient other than the compounds and salts of the present invention. The choice of excipient will depend in large part on such factors as the particular mode of administration, the effect of the excipient on solubility and stability, and the characteristics of the dosage form. For example, a compound of formula I as defined above, or a pharmaceutically acceptable salt or solvate thereof, may be administered simultaneously (e.g. as a fixed dose combination), sequentially or separately with one or more additional pharmaceutically active agents.

Typical additional active agents may be combined with one or more selected from the group consisting of:

nav1.7 channel modulators, such as compounds disclosed in WO2009/012242 or WO 2010/079443;

an alternative sodium channel modulator, e.g., a nav1.3 modulator (e.g., as disclosed in WO 2008/118758); or a nav1.8 modulator (e.g. as disclosed in WO2008/135826, more specifically N- [ 6-amino-5- (2-chloro-5-methoxyphenyl) pyridin-2-yl ] -1-methyl-1H-pyrazole-5-carboxamide);

nerve growth factor signalling inhibitors, for example: an agent that binds NGF and inhibits NGF signaling-mediated biological activity and/or downstream pathways of NGF (e.g., talnizumab), a TrkA antagonist, or a p75 antagonist;

compounds that increase the level of endocannabinoids, such as compounds having fatty amidohydrolase inhibitory (FAAH) activity, in particular those disclosed in WO2008/047229 (e.g. N-pyridazin-3-yl-4- (3- { [5- (trifluoromethyl) pyridin-2-yl ] oxy } benzylidene) piperidine (piperylene) -1-carboxamide);

opioid analgesics such as morphine (morphine), heroin (heroin), hydromorphone (hydromorphone), oxymorphone (oxymorphone), levorphanol (levorphanol), levorphanol (levalophan), methadone (methadone), meperidine (meperidine), fentanyl (fentanyl), cocaine (cocaine), codeine (codeine), dihydrocodeine (dihydrocodeine), oxycodone (oxycodone), dihydrocodeinone (hydrocodone), proparaffine (propofol), nalmefene (nalmefene), propylenemene (nalorphine), naloxonone (naloxonone), naltrexone (naltrexone), buprenorphine (buprenorphine), butorphanol (butorphanol), naloxone (naloxonine) or ketoprofen (ketoprofen);

Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac (diclofenac), diflunisal (diflusinal), etodolac (etodolac), fenbufen (fenbufen), fenoprofen (fenoprofen), flufenisal (flufenisal), flurbiprofen (flurbiprofen), ibuprofen (ibuprofen), indomethacin (indomethacin), ketoprofen (ketoprofen), ketorolac (ketorolac), meclofenamic acid (meclofenamic acid), mefenamic acid (mefenamic acid), meloxicam (meloxicam), naproxen (nabumetone), naproxen (naproxen), nimesulide (nimesulide), nitroflurbiprofen (nitroflurbiprofen), olsalan (salazine), oxazine (oxazin), oxyphenbutazone (oxyphenbutazone), fludarabine (sulfasalazine), sulfasalazine (sulfasalazine);

barbiturate sedatives, such as amobarbital (amobarbital), alprental (aprobarbital), butarbital (butarbital), butabarbital (butarbital), meprobital (mephobarbital), methamphetal (methabarbital), methohexital (methohexital), pentobarbital (pentobarbital), phenobarbital (phenobarbital), secobarbital (secobarbital), tabarbital (talbarbital), semaphobarbital (theobarbital), or thiobarbital (thiobarbital);

Benzodiazepines with sedative actionClasses such as chlordiazepane (chlordiazepade), chlordiazepoxide (clorazepate), diazepam (diazepam), fluvalin (flurazepam), lorazepam (lorazepam), oxazepam (oxazepam), temazepam (temazepam) or triazolam (triazolam);

h having sedative action₁Antagonists, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorocyazone;

sedatives, such as glutethimide (glutethimide), meprobamate (meprobamate), methaqualone (methaqualone) or dichloralphenazone (dichloralphenazone);

skeletal muscle relaxants, such as baclofen (baclofen), carisoprodol (carisoprodol), chlorzoxazone (chlorzoxazone), cyclobenzaprine (cyclobenzapine), methocarbamol (methocarbamol) or orthophenylhydramine (orphenylenedine);

NMDA receptor antagonists, for example dextromethorphan (dextromethorphan) (+) -3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan (dextrorphan) (+) -3-hydroxy-N-methylmorphinan), ketamine (ketamine), mectins (memantine), pyrroloquinoline quinine (pyrroloquinolinone quinine), cis-4- (phosphonomethyl) -2-pipecolic acid, budipine (budipine), EN-3231 (N-3231: (N-methyl-N-methylmorphinan) Morphine in combination with dextromethorphan (dextromethorphan), topiramate (topiramate), neramexane (neramexane) or perzinfotel), including NR2B antagonists, such as ifenprodil (ifenprodil), trexopride (traxoprodil) or (-) - (R) -6- {2- [4- (3-fluorophenyl) -4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3, 4-dihydro-2 (1H) -quinolinone;

α -adrenergic agents, such as doxazosin (doxazosin), tamsulosin (tamsulosin), clonidine (clonidine), guanfacine (guanfacine), dexmetomidine (dexmetylamidine), modafinil (modafinil) or 4-amino-6, 7-dimethoxy-2- (5-methyl-sulfonamido-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -5- (2-pyridyl) quinazoline;

tricyclic antidepressants, such as desipramine (desipramine), imipramine (imipramine), amitriptyline (amitriptyline) or nortriptyline (nortriptyline);

anticonvulsants such as carbamazepine (carbamazepine), lamotrigine (lamotrigine), topiramate (topiramate) or valproate (valproate);

tachykinin (NK) antagonists, in particular NK-3, NK-2 or NK-1 antagonists, such as (α R, 9R) -7- [3, 5-bis (trifluoromethyl) benzyl ] -8, 9, 10, 11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1, 4] diazocino [2, 1-g ] [1, 7] -naphthyridine-6-13-dione (TAK-637), 5- [ [ (2R, 3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy-3- (4-fluorophenyl) -4-morpholinyl ] -methyl ] -1, 2-dihydro-3H-1, 2, 4-triazol-3-one (MK-869), aprepitant (aprepitant), lanepitant (lanepitant), dapitant (dapitant), or 3- [ [ 2-methoxy-5- (trifluoromethoxy) phenyl ] -methylamino ] -2-phenylpiperidine (2S, 3S);

Muscarinic antagonists such as oxybutynin (oxybutynin), tolterodine (tolterodine), propiverine (propiverine), trospium chloride (tropsium chloride), darifenacin (darifenacin), solifenacin (solifenacin), tilmicorine (temiverine), and ipratropium (ipratropium);

COX-2 selective inhibitors, such as celecoxib (celecoxib), rofecoxib (rofecoxib), parecoxib (parecoxib), valdecoxib (valdecoxib), deracoxib (deracoxib), etoricoxib (etoricoxib) or lumiracoxib (lumiracoxib);

coal tar analgesics, especially acetaminophen (paracetamol);

neuroleptics, such as dapipritol (droperidol), chlorpromazine (chlorpromazine), haloperidol (haloperidol), fluphenazine (perphenazine), thioridazine (thioridazine), mesoridazine (mesoridazine), trifluoperazine (trifluorperazine), fluphenazine (fluphenazine), clozapine (clozapine), olanzapine (olanzapine), risperidone (risperidone), ziprasidone (ziprasidone), quetiapine (quetiapine), quintiazepine (quetiapine), selinuline (sertindole), aripiprazole (aripiprazole), sonapine (lonone), sulpride (sulpride), sulpride (sulpride), sulpride (, Or soriztan (sariztan);

vanilloid receptor agonists (e.g. a cholla toxin (resiniferatoxin) or antagonists (e.g. anti-capsaicin);

β -adrenergic agents, such as propranolol (propranolol);

local anesthetics, such as mexiletine (mexiletine);

corticosteroids, such as dexamethasone (dexamethasone);

5-HT receptor agonists or antagonists, especially 5-HT_1B/1DAgonists, e.g. ElephantoneTriptan (eletriptan), sumatriptan (sumatriptan), naratriptan (naratriptan), zolmitriptan (zolmitriptan) or rizatriptan (rizatriptan);

·5-HT_2Areceptor antagonists, e.g. R (+) - α - (2, 3-dimethoxy-phenyl) -1- [2- (4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

·5-HT₃antagonists, such as ondansetron;

cholinergic (nicotine) analgesics such as, for example, epothilone (TC-1734), (E) -N-methyl-4- (3-pyridyl) -3-buten-1-amine (RJR-2403), (R) -5- (2-azetidinylmethoxy) -2-chloropyridine (ABT-594) or nicotine;

·；

PDEV inhibitors, for example 5- [ 2-ethoxy-5- (4-methyl-1-piperazinyl-sulfonyl) phenyl ] -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one (sildenafil)), (6R, 12aR) -2,3,6,7,12,12 a-hexahydro-2-methyl-6- (3, 4-methylenedioxyphenyl) -pyrido [2 ', 1'; 6,1] -pyrido [3,4-b ] indole-1, 4-dione (IC-351 or rhinoceros (tadalafil)), 2- [ 2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl-) -phenyl ] -5-methyl-7-propyl-3H-imidazo [5,1-f ] [1,2,4] -triazin-4-one (vardenafil), 5- (5-acetyl-2-butoxy-3-pyridyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one, 5- (5-acetyl-2-propoxy-3-pyridyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one, 5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl 2- [ 2-methoxyethyl ] -2, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one, 4- [ (3-chloro-4-methoxybenzyl) amino ] -2- [ (2S) -2- (hydroxymethyl) pyrrolidin-1-yl ] -N- (pyrimidin-2-ylmethyl) pyrimidine-5-carboxamide, 3- (1-methyl-7-oxo-3-propyl-6, 7-dihydro-1H-pyrazolo [4,3-d ] pyrimidin-5-yl) -N- [2- (1-methylpyrrolidin-2-yl) ethyl ] -4-propoxybenzenesulfonamide;

Alpha-2-delta ligands, e.g. gabapentin (gabapentin), pregabalin (pregabalin), 3-methyl gabapentin, (1 alpha, 3 alpha, 5 alpha) (3-amino-methyl-bicyclo [3.2.0 ]]Hept-3-yl) -acetic acid, (3S,5R) -3-aminomethyl-5-methyl-heptanoic acid, (3S,5R) -3-amino-5-methyl-octanoic acid, (2S,4S) -4- (3-chlorophenoxy) proline, (2S,4S) -4- (3-fluorobenzyl) -proline, [ (1R,5R,6S) -6- (aminomethyl) bicyclo [3.2.0]Hept-6-yl]Acetic acid, 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4]Oxadiazol-5-ones, C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl]-methylamine, (3S,4S) - (1-aminomethyl-3, 4-dimethyl-cyclo-phenyl) -acetic acid, (3S,5R) -3-aminomethyl-5-methyl-octanoic acid, (3S,5R) -3-amino-5-methyl-nonanoic acid, (3S,5R) -3-amino-5-methyl-octanoic acid, (3R,4R,5R) -3-amino-4, 5-dimethyl-heptanoic acid and (3R,4R,5R) -3-amino-4, 5-dimethyl-octanoic acid;

metabotropic glutamate subtype 1 receptor (mGluR1) antagonists;

5-hydroxytryptamine reuptake inhibitors, such as sertraline (sertraline), sertraline metabolite desmethylsertraline, fluoxetine (fluoxetine), norfluoxetine (norfluoxetine) (fluoxetine demethyl metabolite), fluvoxamine (fluvoxamine), paroxetine (parooxetine), citalopram (citalopram), citalopram metabolite desmethylcitalopram (desmethlcitalopram), escitalopram (escitalopram), d, l-fenfluramine (d, l-fenfluramine), non-moxetaine (femoxetine), efoxetine (ifoxidine), cyanoduloxetine (cyazothidine), ritoxetine (litoxepine), dapoxetine (dapoxetine), nefazodone (nefazodone), vinpocetine (tricine), and trazodone (zolozolone);

Norepinephrine reuptake inhibitors, such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamide, tolnaftateMoxidectin (tomoxetine), mianserin (mianserin), bupropion (buprion), the metabolite hydroxyamphipropion (hydroxybuprion) of bupropion, nomifensine (nomifensine), and viloxazine (viloxazine) (tomoxetine), mianserin (mianserin), and mefenoxan (viloxazine)) Especially selective noradrenaline reuptake inhibitors, such as reboxetine, especially (S, S) -reboxetine;

5-hydroxytryptamine-norepinephrine dual reuptake inhibitors, such as venlafaxine (venlafaxine), venlafaxine metabolite O-desmethylvenlafaxine (O-desmethylvenlafaxine), clomipramine (clomipramine), clomipramine metabolite desipramine (desmethylclomipramine), duloxetine (duloxetine), milnacipran (milnacipran), and imipramine (imipramine);

inducible Nitric Oxide Synthase (iNOS) inhibitors, for example S- [2- [ (1-iminoethyl) amino ] ethyl ] -L-homocysteine, S- [2- [ (1-iminoethyl) -amino ] ethyl ] -4, 4-dioxo-L-cysteine, S- [2- [ (1-iminoethyl) amino ] ethyl ] -2-methyl-L-cysteine, (2S,5Z) -2-amino-2-methyl-7- [ (1-iminoethyl) amino ] -5-heptanoic acid, 2- [ [ (1R,3S) -3-amino-4-hydroxy-1- (5-thiazolyl) -butyl ] thio ] -5-chloro-3- Picolyl nitrile, 2- [ [ (1R,3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl ] thio ] -4-fluorobenzyl nitrile, (2S,4R) -2-amino-4- [ [ 2-chloro-5- (trifluoromethyl) phenyl ] thio ] -5-thiazolylbutanol, 2- [ [1R,3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl ] thio ] -6- (trifluoromethyl) -3-picolyl nitrile, 2- [ [ (1R,3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl ] thio ] -5-chlorobenzonitrile, and mixtures thereof, N- [4- [2- (3-chlorobenzylamino) ethyl ] phenyl ] thiophene-2-carboxamidine or guanidinoethyl disulfide;

Acetylcholinesterase inhibitors, such as donepezil (donepzil);

prostaglandin E₂Subtype 4(EP4) antagonists, e.g. N- [ ({2- [4- (2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c) ]]Pyridinyl-1-yl) phenyl]Ethyl } amino) -carbonyl]-4-methylbenzenesulfonylAmine or 4- [ (1S) -1- ({ [ 5-chloro-2- (3-fluorophenoxy) pyridin-3-yl]Carbonyl } amino) ethyl]Benzoic acid;

microsomal prostaglandin E synthase type 1 (mPGES-1) inhibitors;

leukotriene B4 antagonist; such as 1- (3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl) -cyclopentanecarboxylic acid (CP-105696), 5- [2- (2-carboxyethyl) -3- [6- (4-methoxyphenyl) -5E-hexenyl ] oxyphenoxy ] -pentanoic acid (ONO-4057) or DPC-11870; 5-lipoxygenase inhibitors, for example zileuton (zileuton), 6- [ (3-fluoro-5- [ 4-methoxy-3, 4,5, 6-tetrahydro-2H-pyran-4-yl ]) phenoxy-methyl ] -1-methyl-2-quinolone (ZD-2138) or 2,3, 5-trimethyl-6- (3-pyridylmethyl), 1, 4-benzoquinone (CV-6504).

Pharmaceutical compositions suitable for delivery of the compounds and salts of the invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in ' Remington's Pharmaceutical Sciences ', 19 th edition (Mack publishing company, 1995).

The compounds and salts of the present invention may be administered with the preparation of a compound and salt for pharmaceutical use and as a crystalline or amorphous product. They may be obtained, for example, as solid fillers, powders or films by, for example, precipitation, crystallization, freeze drying, spray drying or evaporation 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 include swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, by which route the compound may pass directly from the mouth into the bloodstream.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particles, liquids, or powders, lozenges (including liquid-filled), chewable lozenges, poly-and nano-particles, gels, solid solutions, liposomes, films (including mucoadhesive), ovules (ovule), sprays and liquid formulations.

Liquid preparations include, for example, suspensions, solutions, syrups and elixirs. The formulations may be employed as fillers in soft or hard gelatin capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil and one or more emulsifying agents and/or suspending agents. Liquid formulations can also be prepared by reconstitution of a solid (e.g., from a small pack).

The compounds of the invention may also be in fast-dissolving, fast-disintegrating dosage forms such as those described by Liang and Chen in Expert Opinion in Therapeutic Patents,11(6) those of 981-.

For tablet dosage forms, depending on the dosage, the drug may comprise from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form. In addition to the drug, tablets typically contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant will comprise from 1 to 25 weight percent, preferably from 5 to about 20 weight percent of the dosage form.

Binders are commonly used to impart cohesive qualities to the tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (monohydrate, spray dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

The tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactant may comprise 0.2% to 5% by weight of the tablet and the glidant may comprise 0.2% to 1% by weight of the tablet.

Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant typically comprises from 0.25% to 10%, preferably from about 0.5% to 3% by weight of the tablet.

Other possible ingredients include antioxidants, coloring agents, flavoring agents, preservatives, and taste-masking agents.

A typical tablet contains up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegrant, and about 0.25% to about 10% lubricant by weight [ these specific ranges are believed to be relevant ].

The tablet blend may be compressed directly or by roller compression to form tablets. The tablet blend or portion of the blend can alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded prior to tableting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

In "Pharmaceutical Dosage Forms" by h.lieberman and l.lachman: tablet formulation is discussed in Tablets, volume 1 ", Marcel Dekker, New York, 1980(SIBN 0-8247-6918-X).

Formulations for the different types of administration described above may be formulated for immediate and/or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release.

A suitable modified release formulation for the purposes of the present invention is described in U.S. patent No. 6,106,864. Details of other suitable delivery techniques such as high energy dispersion and penetration and coating of particles are found in Pharmaceutical Technology On-line, 25(2), 1-14(2001) of Verma et al. The use of chewing gum to achieve controlled release is described in WO 00/35298.

Parenteral administration

The compounds of the invention may also be administered directly into the bloodstream, into muscle, or into internal organs. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffers (preferably a pH of about 3 to about 9), but, for some applications, they may be more suitably formulated as sterile non-aqueous solutions or in dry form for use in combination with a suitable vehicle, e.g. sterile pyrogen-free water.

Preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compounds of formula (I) for use in the formulation of parenteral solutions may be increased by the use of appropriate formulation techniques, for example the incorporation of solubility enhancing agents.

Formulations for parenteral administration may be formulated for immediate release and/or modified release. The compounds of the present invention may therefore be formulated as solids, semi-solids, or thixotropic liquids for administration in an implanted depot form that provides for modified release of the active compound. Examples of such formulations include drug-coated stents and stents.

Topical administration of drugs

The compounds of the present invention may also be administered topically to the skin or mucosa, i.e., through the skin or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water Mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can be incorporated [ see, e.g., JPharm Sci by Finnin and Morgan,88(10) 955 additionally 958 (10 months 1999)]. Other devices for topical administration include by electroporation, iontophoresis, sonophoresis, and microneedles or needles-free devices (e.g., Powderject)^TM、Bioject^TMEtc.) injection delivery.

Inhalation/intranasal administration

The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, in a mixture, e.g., as a dry blend with lactose, or as mixed component particles, e.g., mixed with a phospholipid, e.g., phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, nebulizer, atomizer (preferably an atomizer that produces a fine mist using electrohydrodynamic (electro-hydrodynamic)), or nebulizer, with or without the use of a suitable propellant, e.g., 1,1,1, 2-tetrafluoroethane or 1,1,1,2,3,3, 3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive, for example, chitosan or cyclodextrin.

A pressurized container, pump, nebulizer, atomizer, or nebulizer contains a solution or suspension of a compound of the invention comprising, for example, ethanol, aqueous ethanol, or a substitute suitable for dispersion, dissolution, or extended release of the active ingredient, a propellant as a solvent, and optionally a surfactant, such as sorbitan trioleate, oleic acid, or oligomeric lactic acid.

Prior to use in dry powder or suspension formulations, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, with gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention, a suitable powder base such as lactose or starch and a potency-modifying agent such as l-leucine, mannitol or magnesium stearate. Lactose can be in anhydrous or monohydrate form, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Solution formulations suitable for use in nebulizers that generate fine mist using electrohydrodynamic devices may contain from about 1 microgram to about 20 milligrams of a compound of the present invention per actuation and the actuation volume may vary from about 1 microliter to about 100 microliters. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable flavouring agents, for example menthol and levomenthol, or sweetening agents, for example saccharin or saccharin sodium, may be added to the formulations of the invention intended for inhalation/intranasal administration.

Formulations for inhalation/intranasal administration may be formulated for immediate and/or modified release using, for example, (DL-lactic-co-glycolic acid) (PGLA). Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release.

In the case of dry powder inhalers and aerosols, the unit of metering is determined by the valve delivering the metered amount. The unit of the invention is typically arranged to administer a metered dose or "puff" containing from 1 to 5000 μ g of the compound or salt. The total daily dose is typically between 1. mu.g and 20mg, which may be administered in a single dose or in multiple (often) divided doses throughout the day.

Rectal/intravaginal administration

The compounds of the invention may be administered rectally or vaginally, for example, in the form of suppositories, pessaries, or enemas. Cocoa butter is a traditional suppository base, but various well-known alternatives may be used.

Eye/ear administration

The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and particle or vesicle systems, such as vesicular agents (niosomes) or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, fibrous polymers, e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methyl cellulose, or heteropolysaccharide polymers, e.g., agarose gel, may be blended with preservatives, such as benzalkonium chloride. The formulation may also be delivered by iontophoresis.

Other techniques

The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol containing polymers in order to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability when used in any of the above modes of administration.

Drug-cyclodextrin complexes, for example, are found to be generally useful in most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, cyclodextrins may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. The most commonly used for these purposes are alpha-, beta-and gamma-cyclodextrins, examples of which may be found in international patent applications WO91/11172, WO94/02518 and WO 98/55148.

For administration to human patients, the total daily dose of the compounds and salts of the invention will typically range from 0.1mg to 200mg, although depending on the mode of administration, preferably 1mg to 100mg, more preferably 1mg to 50 mg. The total daily dose may be administered in a single dose or in divided doses.

These doses are based on human subjects having an average body weight of about 65 kg-70 kg. Clinicians can readily determine subject doses that are over this range, for example infants and elderly people.

For the above-mentioned therapeutic applications, the dosage administered will, of course, vary depending upon the compound or salt employed, the mode of administration, the desired treatment and the disorder being indicated. The total daily dose of the compound/salt/solvate of formula (I) (active ingredient) is generally in the range of from 1mg to 1 gram, preferably from 1mg to 250mg, more preferably from 10mg to 100 mg. The total daily dose may be administered in a single dose or in divided doses. The invention also includes sustained release compositions.

For example, the pharmaceutical compositions may 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 form suitable for single administration of precise dosages. Pharmaceutical compositions will include the usual pharmaceutical carriers or excipients and the compounds of the invention as active ingredients. In addition, it may include other medically or pharmaceutically active agents, carriers, adjuvants, and the like.

Typical parenteral administration forms include solutions or suspensions of the active ingredient in sterile aqueous solutions, for example, propylene glycol or dextrose solutions. Such dosage forms may 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 flavoring agents, binders, excipients and the like. Thus, for oral administration, tablets containing various excipients, such as citric acid, in combination with various disintegrants, such as starch, alginates and some complex silicates, and binders, such as sucrose, gelatin and acacia, may be used. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are commonly used for tableting purposes. Solid compositions of a similar type may also be used in soft and hard capsules. Thus, preferred materials include lactose and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring matter or dyes, and if desired, emulsifying or suspending agents in combination with diluents such as water, ethanol, propylene glycol, glycerin or combinations thereof.

The dosage regimen may be adjusted to provide an optimized desired response. For example, a single bolus injection may be given, several divided doses may be given over time, or the doses may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is particularly advantageous to formulate parenteral compositions in unit dosage form for administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages for the mammalian subjects being treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the unit dosage form of the present invention are specified and directly dependent on: (a) the unique characteristics of chemotherapeutic agents and the specific therapeutic or prophylactic effect achieved; and (b) limitations inherent in the art of compounding such active compounds for treating sensitivity in an individual.

Thus, based on the disclosure provided herein, one of skill in the art will appreciate that the dosage and dosing regimen will be adjusted according to methods well known in the therapeutic arts. I.e., the maximum tolerable dose is readily established and an effective amount that provides a detectable therapeutic benefit to the patient can also be determined, as may be momentarily required for each active agent to be administered in order to provide the patient with a detectable therapeutic benefit. Thus, while some dosages and dosing regimens are exemplary herein, these examples in no way limit the dosages and dosing regimens that can be provided for practicing the invention.

It is noted that dosage values may vary depending on the type and severity of the condition alleviated and may include single or multiple doses. It is further understood that the specific dosage regimen for any particular subject will be adjusted over time according to the individual requirements and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions. For example, the dosage may be adjusted based on a pharmacokinetic-independence or pharmacodynamic parameter, which may include clinical effects, such as toxicity effects and/or laboratory values. Thus, the present invention encompasses a proportional increase in the dosage in a patient as determined by one of skill in the art. Determining suitable dosages and dosing regimens for chemotherapeutic agents is well known in the relevant art, and it will be understood that they may be covered by one of skill in the art once the teachings disclosed herein are provided.

The pharmaceutical compositions of the present invention may be prepared, packaged or sold as a single unit dose or as multiple single unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition that contains a predetermined amount of active ingredient. The amount of active ingredient is generally equivalent to the dose of active ingredient that can be administered to a subject or a convenient fraction, e.g., half or such a dose, of such a dose.

For parenteral dosage, it may be conveniently formulated as a solution or as a dry powder for dissolution by a smoker, health care provider or patient. It may be provided in a bottle or sterile syringe. For example, it can be formulated as a powder in a multi-compartment syringe, which can be mixed with a solvent prior to administration (to aid long-term stability and storage). A syringe may be used which is capable of administering multiple doses from a single device.

The relative amounts of the active ingredient, pharmaceutically acceptable carrier, and any other ingredients in the pharmaceutical compositions of the invention will vary depending on the identity, size, and condition of the subject being treated, and further depending on the route of administration of the composition. As an example, the composition may comprise 0.1% to 100% (w/w) of the active ingredient.

In addition to the active ingredient, the pharmaceutical compositions of the present invention may also comprise one or more additional pharmaceutically active agents. Controlled or sustained release formulations of the pharmaceutical compositions of the present invention can be prepared using conventional techniques.

"parenteral administration" of a pharmaceutical composition as used herein includes any route of administration characterized by penetration of a subject's body tissue to administer the pharmaceutical composition through a breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of the pharmaceutical composition by injection of the composition, by administration of the composition through a surgical incision, by administration of the composition through a non-surgical wound penetrating tissue, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal injection, and renal dialysis infusion techniques.

Pharmaceutical composition formulations suitable for parenteral administration comprise the active ingredient in combination 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 or continuous administration. Injections may be prepared, packaged or sold in unit dosage form, e.g., ampoules or multi-dose containers, containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions, pastes and implantable sustained release or biodegradable formulations in oil or aqueous vehicles as described below. Such formulations may also contain one or more additional ingredients, including but not limited to suspending, stabilizing or dispersing agents. In one embodiment of the invention for the preparation of parenteral administration, the active ingredient is provided in dry (i.e., powder or granules) form and is reconstituted with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

The compositions of the present invention may be administered by a variety of methods known in the art. The route and/or mode of administration will vary depending upon the desired result. Active compounds can be prepared using carriers that prevent rapid release of the compound, such as controlled release formulations, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable activators such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid may be used. Many methods of preparing such formulations are described, for example, in Sustained and Controlled Release Drug delivery systems, J.R.Robinson, ed., Marcel Dekker, Inc., New York, (1978). The pharmaceutical composition is preferably prepared under GMP conditions.

Pharmaceutical compositions may be prepared, packaged or sold as sterile injectable aqueous or oleaginous suspensions or solutions. Such suspensions or solutions may be formulated according to known techniques and may contain additional ingredients in addition to the active ingredient, such as dispersing, wetting or suspending agents as described herein. Such sterile injectable preparations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, for example, water or 1, 3-butanediol. Other acceptable diluents and solvents include, but are not limited to, ringer's solution, isotonic sodium chloride solution and fixed oils, such as synthetic mono-or diglycerides. Other useful parenteral formulations include those containing the active ingredient in microcrystalline form, in liposomal formulations, or as a component of a biodegradable activator system. The sustained release or implant composition may comprise a pharmaceutically acceptable polymer or hydrophobic material, such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.

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

The following non-limiting preparations and examples illustrate the preparation of the compounds and salts of the present invention.

General experiments

The following preparations and examples illustrate the invention, but do not limit it in any way. All starting materials are commercially available or described in the literature. All temperatures are in ℃. Flash column chromatography was performed using Merck silica gel 60 (9385). Thin Layer Chromatography (TLC) was performed using Merck silica gel 60 plates (5729). "R_f"indicates the distance traveled by the compound as the solvent front on the TLC plate. Melting points were determined using a Gallenkamp MPD350 instrument and were not calibrated. Using a VarianNMR spectroscopy at Unity Inova400MHz or Varian Mercury400 MHz. Mass spectrometry was performed using a Finnigan Navigator single quadrupole electrospray mass spectrometer or a Finnigan aQa APCI mass spectrometer.

When describing the preparation of compounds in the manner described in the earlier preparations or examples, the skilled person understands that the reaction time, the number of reagent equivalents and the reaction temperature may vary for each specific reaction, however, it is necessary or desirable to use different work-up or purification conditions.

The invention is illustrated by the following non-limiting examples, in which the following abbreviations and definitions are used: the following preparations and examples illustrate the invention, but do not limit it in any way. All starting materials are commercially available or described in the literature. All temperatures are in ℃. Flash column chromatography was performed using Merck silica gel 60(9385) or Redisep silica gel. NMR was performed using a Varian Mercury400MHz NMR spectrophotometer or Jeol ECX400MHz NMR.

Mass spectra were obtained using the following conditions:

Waters ZQ ESCI

API-20005min LC-MS of Applied Biosystem

Waters Alliance2795 with ZQ2000(ESI)

Agent 110HPLC5min (System 5)

Waters ZQ ESCI8min LC-MS

Waters Alliance269525min with ZQ2000(ESI)

HP1100HPLC12.5minLC-MS with Waters Micromass ZQ mass detector

UPLC Mass Spectroscopy using Waters Acquity ZQD (ESI), 1.5min LC-MS

WATERS ACQUITY UPLC/WATERS3100MSD/PL-ELS2100ICE ELSD

When singleton compounds were analyzed by LCMS, there were 6 methods of use. Examples of which are as follows.

System 1

6 min LC-MS gradient and Instrument conditions

A: 0.1% formic acid in water

B: 0.1% formic acid in acetonitrile

Column: c18 phase Waters Sunfire50x4.6mm with5 micron particle size

Gradient: 95-5% A, 3min, 1min hold, 2min rebalance, 1.5mL/min flow rate

UV：210nm-450nm DAD

Temperature: 50 deg.C

System 2

2min LC-MS gradient and Instrument conditions

A: 0.1% formic acid in water

B: 0.1% formic acid in acetonitrile

Column: c18 phase Phenomenex20x4.0mm with3 micron particle size

Gradient: 70-2% A, 1.5min, 0.3min hold, 0.2 rebalance, 1.8mL/min flow rate

UV：210nm-450nm DAD

Temperature: 75 deg.C

System 3

5min LC-MS gradient and Instrument conditions

A: 0.1% formic acid in water

B: 0.1% formic acid in acetonitrile

Column: c18 phase Waters Sunfire50x4.6mm with5 micron particle size

Gradient: 95-5% A, 3min, 1min hold, 1min rebalance, 1.5mL/min flow rate

UV：225nm–ELSD-MS

Temperature: environment(s)

System 4

5min LC-MS gradient and Instrument conditions

A: 0.1% aqueous ammonium hydroxide solution

B: 0.1% ammonium hydroxide in acetonitrile

Column: c18 phase XTerra50x4.6mm with5 micron particle size

Gradient: 95-5% A, 3min, 1min hold, 1min rebalance, 1.5mL/min flow rate

UV：225nm–ELSD-MS

Temperature: environment(s)

System 5

5min LC-MS gradient and Instrument conditions

A: 0.0375% TFA in water

B: 0.01875% TFA in acetonitrile

Column: c18 phase Welch XB50x2.1mm with5 micron particle size

Gradient: 99-0% A, 4min, 0.70min rebalancing, 0.8mL/min flow rate

UV：225nm–ELSD-MS

Temperature: 50 deg.C

System 6

5min LC-MS gradient and Instrument conditions

A: 0.0375% TFA in water

B: 0.01875% TFA in acetonitrile

Column: c18 phase Welch XB50x2.1mm with5 micron particle size

Gradient: 90-0% A, 4min, 0.70min rebalancing, 0.8mL/min flow rate

UV：225nm–ELSD-MS

Temperature: 50 deg.C

System 7

25 min LC-MS gradient and Instrument conditions

A: 10mmol ammonium bicarbonate in water

B: acetonitrile

Column: c18 phase XBridge150x3.0mm with5 micron particle size

Gradient: 95-5% A, 15min, 10min hold, 2min rebalance, 0.5mL/min flow rate

UV：200nm-350nm DAD

Temperature: 30 deg.C

System 8

3min LC-MS gradient and Instrument conditions

A: 0.05% formic acid in water

B: acetonitrile

Column: c18 phase Restek30x2.1mm with3 micron particle size

Gradient: 98-2% A, 2min, 0.25min hold, 0.75min rebalance, 1.5mL/min flow rate

UV：200nm-350nm DAD

Temperature: 50 deg.C

System 9

5min LC-MS gradient and Instrument conditions

A: 0.05% formic acid in water

B: acetonitrile

Column: c18 phase XBridge50x4.6mm with5 micron particle size

Gradient: 90-10% A, 3min, 1min hold, 1min rebalance, 1.2mL/min flow rate

UV：200nm-260nm DAD

Temperature: 25 deg.C

System 10

5min LC-MS gradient and Instrument conditions

A: 10mM ammonium acetate in water

B: acetonitrile

Column: c18 phase Gemini NX50x4.6mm with5 micron particle size

Gradient: 90-10% A, 3min, 1min hold, 1min rebalance, 1.2mL/min flow rate

UV：200nm-260nm DAD

Temperature: 25 deg.C

Unless otherwise indicated, when purifying a singleton compound by high performance liquid chromatography, one of 4 methods is used, and these 4 methods are now shown below.

Waters purification system with mass spectrometry or UV detection

Production system 1

10 min preparative LC-MS gradients and instrument conditions

A: 0.1% formic acid in water

B: 0.1% formic acid in acetonitrile

Column: c18 phase Sunfirex 100x19.0mm

Gradient: 95-2% A, 7min, 2min hold, 1min rebalance, 18mL/min flow rate

Temperature: ambient temperature

Preparation system 2

10 min preparative LC-MS gradients and instrument conditions

A: 0.1% DEA in water

B: 0.1% DEA in acetonitrile

Column: c18 phase Xterra100x19.0mm

Gradient: 95-2% A, 7min, 2min hold, 1min rebalance, 18mL/min flow rate

Temperature: ambient temperature

Preparation System 3

7min preparative LC-MS gradients and instrument conditions

A: 0.05% aqueous ammonia solution

B: acetonitrile

Column: c18 phase Xbridge50x19.0mm

Gradient: 90-20% A, 7min, 20mL/min flow rate

Temperature: ambient temperature

Preparation system 4

8min preparative LC-MS gradients and instrument conditions

A: aqueous 0.1% TFA

B: acetonitrile

Column: c18 phase Sepax BR100x21.2mm

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

Temperature: ambient temperature

If described, the compounds are prepared in the manner described in the initial preparations or examples, and those skilled in the art will understand that the reaction time, number of reagent equivalents, and reaction temperature may vary for each particular reaction, however, it is necessary or desirable to use different work-up or purification conditions. The invention is illustrated by the following non-limiting examples, in which the following abbreviations and definitions are used:

AcOH-acetic acid; APCI-atmospheric pressure chemical ionization; arbocel is a filtering agent; br s-broad singlet; BINAP-2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl; nBuLi-n-butyllithium; CDCl ₃-deuterated chloroform; cs₂CO₃Is cesium carbonate; CuI is copper (I) iodide;Cu(OAc)₂is copper (II) acetate; delta-chemical shift; d-doublet; a DAD-diode array detector; DCE-1, 2-dichloroethane; DCM-dichloromethane; DEA-diethylamine; DIBAL-diisobutylaluminum hydride; DIPEA-diisopropylethylamine; DMAP-4-dimethylaminopyridine; DME-dimethoxyethane; DMF-N, N-dimethylformamide; DMF-DMA-N, N-dimethylformamide-dimethylacetal; DMSO-dimethyl sulfoxide; DPPF-1, 1' -bis (diphenylphosphino) ferrocene; ELSD-evaporative laser scattering detector; ESI-electrospray ionization; et (Et)₂O-diethyl ether; EtOAc/EA-ethyl acetate; EtOH-ethanol; g-g; HATU-2- (7-azabenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate; HBTU is O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate; HCl is hydrochloric acid; HOBT is N-hydroxybenzotriazole hydrate; HPLC-high performance liquid chromatography; IPA-isopropyl alcohol; k₂CO₃Is potassium carbonate; KHSO₄Is potassium hydrogen sulfate; KOAc is potassium acetate; KOH is potassium hydroxide; k₃PO₄Is dipotassium hydrogen phosphate; KF-potassium fluoride; l is liter; LCMS-liquid chromatography mass spectrometry; LiHMDS-lithium hexamethyldisilazide; m-multiplet; mg-mg; mL-mL; M/Z-mass peak; MeCN-acetonitrile; MeOH-methanol; 2-MeTHF-2-methyltetrahydrofuran; MgSO (MgSO) ₄Is magnesium sulfate; MnO₂-manganese dioxide; NaClO₂-sodium chlorite; NaH-sodium hydride; NaHCO 2₃-sodium bicarbonate; na (Na)₂CO₃-sodium carbonate; NaH₂PO₄-sodium phosphate; NaHSO₃-sodium sulfite; NaHSO₄-sodium hydrogen sulphate; NaOH-sodium hydroxide; na (Na)₂SO₄-sodium sulphate; NH (NH)₃-ammonia; NH (NH)₄Cl-ammonium chloride; NMM-N-methylmorpholine; NMR-nuclear magnetic resonance; Pd/C-palladium on carbon; PdCl₂-palladium chloride; pd₂(dba)₃Is tris (dibenzylideneacetone) dipalladium (0); pd (PPh)₃)₄-tetrakis (triphenylphosphine) palladium; pd (OAc)₂-palladium acetate; PTSA-p-toluenesulfonic acid; prep-preparation; r_t-a retention time; q-quartet; s-singlet; TBDMS-tert-butyldimethylsilyl; TBME-Tert-ButyleneA dimethyl ether; TCP-1-propylphosphonic acid cyclic anhydride; TEA-triethylamine; TFA-trifluoroacetic acid; THF-tetrahydrofuran; TLC-thin layer chromatography; (R, S) -racemic mixture; WSCDI-1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.

For the avoidance of doubt, IUAPC, Chemdraw and/or Pro ACD Labs name software v7.11 is used^TMOr use other standard nomenclature to name the named compounds used herein. The NMR spectrum was determined with a deuterated solvent and was consistent with the name/structure given below.

Example 1: n- {5- [ (7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } -2- (5-fluoropyridin-2-yl) acetamide

2- (5-Fluoropyridin-2-yl) acetic acid (23.1mg, 0.149mmol) (see preparation 92) was added to (5-aminopyridin-3-yl) (7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (40mg, 0.135mmol) (see preparation 31), 1-propylphosphonic acid cyclic anhydride (0.2mL, 0.338mmol, 50% in EtOAc) and triethylamine (0.65mL, 0.474mmol) in THF (3 mL). The mixture was stirred at 25 ℃ for 18 h, evaporated in vacuo and partitioned between saturated aqueous sodium bicarbonate (5mL) and ethyl acetate (5 mL). The organic phase was dried over sodium sulfate, evaporated in vacuo, and the residue triturated with pentane: diethyl ether (3:1, 1mL) to give the title compound as an off-white solid in 65% yield, 38 mg.

¹H NMR (400MHz, DMSO). delta.: 1.79(s, 9H), 3.95(s, 2H), 7.50(m, 1H), 7.72(m, 1H), 8.21(s, 1H), 8.50(d, 1H), 8.76(d, 1H), 8.95(d, 1H), 9.00(s, 1H), 9.48(s, 1H), 10.72(s, 1H); LCMS (system 4): r_t=2.86min；m/z433[M+H]⁺。

Examples 2-8 were prepared according to the procedure described above for example 1 starting from (5-aminopyridin-3-yl) (7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (see preparation 31) and the appropriate acid.

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

4- (trifluoromethyl) phenylacetic acid (33.6g, 165mmol) was added to (5-aminopyridin-3-yl) {7- [ (1S) -2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone (45.2g, 110mmol) (see preparation 37), 1-propylphosphonic acid cyclic anhydride (194mL, 329mmol, 50% in EtOAc) and triethylamine (53.6mL, 384mmol) in THF (400 mL). The mixture was stirred at 25 ℃ for 2 hours, then saturated aqueous sodium bicarbonate (250mL) was added and the organic layer was separated. The aqueous phase was extracted with EtOAc (2 × 200mL) and all organic phases were combined, dried over sodium sulfate and evaporated in vacuo.

The brown solid residue was dissolved in THF (400mL) and aqueous HCl (200mL, 2M) was added. The mixture was stirred at room temperature for 2 hours, then cooled to 0 ℃ and sodium hydroxide (28g) was added. The mixture was stirred for 3 hours, then water (100mL) was added. The organic layer was separated, the aqueous phase was extracted with EtOAc (2 × 300mL), all organic phases were combined, dried over sodium sulfate, and evaporated in vacuo. The crude solid was recrystallized from ethyl acetate (150mL) to give the title compound as a white solid in 63% yield, 33.4 g.

¹H NMR (400MHz, DMSO). delta.: 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), 10.72(s, 1H); LCMS (system 1): rt =4.53 min; m/z484[ M + H ]]⁺。

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

1, 4-di containing 10% hydrochloric acidAn alkane solution (0.2mL) was added to preparation 66(59mg, 0.098mmol) in THF (2mL), and the mixture was stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and triturated with pentane: ether (3:1, 1mL) to give the title compound as an off-white solid in 86% yield, 41 mg.

LCMS (system 4): rt =2.85 min; m/z488.2[ M + H ]]⁺。

Examples 11-16 were prepared according to the procedure described above for example 10 starting from the appropriate protected alcohol.

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

(5-methyl-3-trifluoromethyl-pyrazol-1-yl) acetic acid (46.8mg, 0.225mmol) was added to (R, S) (5-aminopyridin-3-yl) {7- [ (1R) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone (66mg, 0.173mmol) (see preparation 36), 1-propylphosphonic acid cyclic anhydride (0.31mL, 0.519mmol), and DIPEA (0.09mL, 0.606mmol) in THF (5 mL). The mixture was heated at reflux for 48 h, evaporated in vacuo, partitioned between saturated aqueous sodium bicarbonate (5mL) and ethyl acetate (5mL), the organic phase dried over sodium sulfate, evaporated in vacuo and the residue purified by silica gel column chromatography (EtOAc: hexane 85: 15 gradient) to give intermediate as an off-white solid, 53% yield, 52 mg.

1, 4-di containing 10% hydrochloric acidAn alkane solution (0.4mL) was added to the intermediate (52mg, 0.091mmol) in THF (2mL) and the mixture was stirred at room temperature for 1.5 h. The mixture was evaporated in vacuo and triturated with pentane: diethyl ether (3:1, 1mL) to give the title compound as an off-white solid in 94% yield, 42 mg.

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

LCMS (system 4): r_t=2.86min；m/z488[M+H]⁺。

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

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

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

¹H NMR (400MHz, DMSO). delta.: 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_t=2.53min；m/z445[M+H]⁺。

Examples 26-33 were prepared according to the procedure described above for example 10 starting from the appropriate protected alcohol TBDMS ether.

Example 34: n- (5- { [ 2-amino-7- (2-hydroxy-1-methylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] carbonyl } pyridin-3-yl) -2- (4-chlorophenyl) acetamide (enantiomer 1)

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

LCMS (system 5): rt =2.90 min; m/z465[ M + H]⁺.

Examples 35-45 were prepared according to the procedure described above for example 34 starting from [ 2-amino-7- (2-hydroxy-1-methylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] (5-aminopyridin-3-yl) methanone (see preparation 57, enantiomer 1, or preparation 59, enantiomer 2) and the appropriate acid.

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

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

The brown solid residue was dissolved in trifluoroacetic acid (300mL), and the solution was stirred at 50 ℃ for 3 hours and then evaporated in vacuo. Methanol (1800mL) was added to the residue and the mixture was filtered. The filtrate was concentrated in vacuo, azeotroped with ethanol (3 × 200 mL).

Potassium carbonate (87.7g, mmol) was added to a methanol solution (300mL) of crude trifluoroacetamide, and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water (2000mL) and filtered. The solid was washed with water (200mL) then triturated with ethanol (2x200mL at room temperature then 380mL at 50 ℃) to give the title compound as a yellow solid in 48% yield, 29.9 g.

¹H NMR (400MHz, DMSO-d6) delta: 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), 10.71(s, 1H); LCMS (system 3): r_t=9.92min；m/z480[M+H]⁺。

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

The title compound was prepared according to the method described for example 46 using (5-aminopyridin-3-yl) {7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -2- [ (2, 4-dimethoxybenzyl) amino ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone (see preparation 51) and (5-methyl-3-trifluoromethyl-pyrazol-1-yl) acetic acid (46.8mg, 0.225mmol) to give the title compound as a brown solid in 79% yield, 82 mg.

LCMS (system 1): r_t=2.83min；m/z517[M+H]⁺。

Examples 48-53 were prepared according to the procedure described above for example 34 starting from [ 2-amino-7- (2-hydroxy-1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] (5-aminopyridin-3-yl) methanone (see preparation 48) and the appropriate acid.

Example 54: n- (5- { [ 2-amino-7- (2-hydroxy-1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] carbonyl } pyridin-3-yl) -2- [4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl ] acetamide

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

¹H NMR (400MHz, DMSO-d6) delta: 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_t=2.71min；m/z502[M-H]⁺。

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

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

¹H NMR(400MHz，DMSO-d6)δ：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/z486[M+H]⁺。

Example 56: n- (5- { [ 2-amino-7- (2-hydroxy-1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] carbonyl } pyridin-3-yl) -2- (4-cyclopropyl-1H-1, 2, 3-triazol-1-yl) acetamide

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

¹H NMR(400MHz，DMSO-D₆) δ: 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_t=2.42min；m/z476[M+H]⁺。

Examples 57-64 were prepared according to the procedure described above for example 1 starting from (2-amino-7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (5-aminopyridin-3-yl) methanone (see preparation 65) and the appropriate acid.

The following examples were prepared according to procedure a (example 34 at 50 ℃) or procedure b (example 1, using DIPEA), (5-aminopyridin-3-yl) (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 95) as described above and the appropriate acid as starting materials.

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

Zinc cyanide (28mg, 0.23mmol) was added to 2- (5-bromo-pyridin-2-yl) -N- [5- (7- (prop-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl) -pyridin-3-yl ] -acetamide (example 317, 75mg, 0.16mmol) in DMF (2mL) and the mixture was degassed for 10 min. Then tris (dibenzylideneacetone) dipalladium (3mg, 0.003mmol) and 1, 1' -bis (diphenylphosphino) ferrocene (7mg, 0.012mmol) were added and the mixture was heated at 100 ℃ for 40mins under microwave irradiation. The mixture was diluted with EtOAc (5mL), washed with water (2mL), brine (2mL), and dried over sodium sulfate. The filtrate was concentrated in vacuo and purified by preparative TLC (3% MeOH in dcm) to give the title compound as a light brown individual in 18% yield, 12 mg.

¹H NMR(400MHz，DMSO)δ：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_t=2.75min；m/z426[M+H]⁺。

Example 167: 2- [ 5-fluoro-2- (trifluoromethyl) phenyl ] -N- {5- [ (7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } acetamide

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl (150. mu.L, 0.5M in DMF) was added to 5-fluoro-2- (trifluoromethyl) phenylacetic acid (90. mu. mol), N-methylmorpholine (25. mu.L, 150. mu. mol), 1-hydroxybenzotriazole (15. mu. mol, 0.05M in DMF) and (5-aminopyridin-3-yl) (7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 110, 75. mu. mol, 0.25M in DMF). The mixture was stirred at 50 ℃ for 2 hours, then evaporated in vacuo and purified by preparative-HPLC (method 4) to give the title compound.

LCMS(system 5): r_t=2.66min；m/z458[M+H]⁺

The following examples were prepared according to the procedure described above for example 167 starting from (5-aminopyridin-3-yl) (7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 110) and the appropriate acid.

Example 198: 3- (2-chlorophenyl) -N- {5- [ (7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } propionamide

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

LCMS (system 5): r_t=2.66min；m/z420[M+H]⁺

The following examples were prepared according to procedure b (example 1, using DIPEA) as described above, starting from (5-aminopyridin-3-yl) (7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 31) and the appropriate acid.

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

1, 4-di containing 10% hydrochloric acidAn alkane solution (0.2mL) was added to N- (5- {7- [ (S) -2- (tert-butyl-dimethyl-silanyloxy) -1-methyl-ethyl in THF (2mL)]-7H-pyrrolo [2,3-d]Pyrimidine-5-carbonyl } -pyridin-3-yl) -2- (3-trifluoromethyl-phenyl) -acetamide (preparation 105, 59mg, 0.098mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and triturated with ether-pentane to give the title compound as an off white solid, 86% yield, 41 mg.

LCMS (system 9): rt =2.97 min; m/z484[ M + H ]]⁺。

The following examples were prepared according to the procedure described above for example 204 using the appropriate preparations.

The following examples were prepared according to the procedure described above for example 34 starting from [ 2-amino-7- (2-hydroxy-1-methylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] (5-aminopyridin-3-yl) methanone (enantiomer 1, preparation 57) and the appropriate acid at 50 ℃.

The following examples were prepared according to the procedure described above for example 34 starting from [ 2-amino-7- (2-hydroxy-1-methylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] (5-aminopyridin-3-yl) methanone (enantiomer 2, preparation 59) and the appropriate acid at 50 ℃.

The following examples were prepared according to the procedure described above for example 34 starting from (5-aminopyridin-3-yl) (7-oxetan-3-yl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 100) and the appropriate acid at 50 ℃.

The following examples were prepared according to the procedure described above for example 204 using the preparation described.

Example 229: racemic 2- {5- [ (5- { [ (4-chlorophenyl) acetyl ] amino } pyridin-3-yl) carbonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-7-yl } propionamide

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

LCMS (system 3): r_t=2.13min；m/z463[M+H]⁺。

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

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

LCMS (system 3): r_t=2.39min；m/z491[M+H]⁺。

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

The title compound was prepared according to the procedure described for example 34 using 2- {5- [ (5- { [ (4-chlorophenyl) acetyl ] amino } pyridin-3-yl) carbonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-7-yl } propanoic acid (example 354) and methylamine at 50 ℃. Purification by preparative HPLC (method 1) gave the title compound.

LCMS (system 3): r_t=2.31min；m/z477[M+H]⁺。

Example 232: 2- (4-cyanophenyl) -N- [5- ({7- [ 2-hydroxy-1- (hydroxymethyl) -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } carbonyl) pyridin-3-yl ] acetamide

4-cyanophenylacetic acid (19mg, 0.10mmol) was added to (5-aminopyridin-3-yl) {7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone (preparation 116, 54mg, 0.97mmol), 1-propylphosphonic acid cyclic anhydride (0.17mL, 0.291mmol), and triethylamine (0.047mL, 0.291mmol) in tetrahydrofuran (3 mL). The mixture was stirred at 50 ℃ for 16 hours. Saturated aqueous sodium bicarbonate (5mL) was added and then extracted with dichloromethane (3 × 7 mL). The combined organic phases were dried over magnesium sulfate and evaporated in vacuo.

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

LCMS (system 4): r_t=2.52min；m/z471[M+H]⁺

The following examples were prepared according to the procedure described above for example 232 starting from (5-aminopyridin-3-yl) {7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone (preparation 116) and the appropriate acid.

The following examples were prepared according to the procedure described above for example 1 using DIPEA and purification by preparative HPLC starting from (2-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (5-aminopyridin-3-yl) methanone (preparation 122) and the appropriate acid.

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

The procedure described for example 166 was followed using N- {5- [ (2-amino-7-isopropyl-7H-pyrrolo [2,3-d ] ]Pyrimidin-5-yl) carbonyl]Pyridin-3-yl } -2- (5-bromopyridin-2-yl) acetamide (example 318) the title compound was prepared in 45% yield 30 mg.¹H NMR (400MHz, DMSO-d6) delta: 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_t=2.49min；m/z441[M+H]⁺。

The following examples were prepared according to the procedure described for example 34 starting from [ 2-amino-7- (2-hydroxy-1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] (5-aminopyridin-3-yl) methanone (preparation 48) and the appropriate acid at 50 ℃.

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

2- (4-cyano-3- (trifluoromethyl) phenyl) acetic acid (preparation 164, 29.8mg, 0.13mmol) was added to a stirred (5-aminopyridin-3-yl) {7- [2- { [ tert-butyl (dimethyl) silyl]Oxy } -1- ({ [ tert-butyl (dimethyl) silyl)]Oxy } methyl) -1-methylethyl]-7H-pyrrolo [2,3-d]Pyrimidin-5-yl) methanone (preparation 116, 55.6mg, 0.10mmol) and 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate (57mg, 0.15mmol) in pyridine (0.5 mL). The mixture was stirred at 50 ℃ for 16 h, then cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate (5mL) and DCM (5 mL). The organic phase was separated and concentrated in vacuo to give a residue which was dissolved in 3mL THF and then treated with 3mL1N HCl aqueous solution. The mixture was stirred rapidly at room temperature for 4 hours, then basified by the addition of 4mL of 1N aqueous NaOH. The mixture was extracted with three separate portions of a 5mL95/5DCM/MeOH mixture. The crude residue was obtained by drying the combined organic extracts through a phase separator and then concentrating in vacuo. The residue was dissolved in 1mL DMSO and purified by preparative HPLC to give the title compound as an off white solid, 56% yield, 30 mg. ¹H NMR(400MHz，DMSO)δ：1.68(s，3H)，3.83(m，2H)，4.01(s，2H)，4.19(m，2H)，5.00(m，2H)，7.82(m，1H)，8.01(d，1H)，8.18(m，1H)，8.21(s，1H)，8.66(s，1H)，8.97(m，2H)，9.40(s，1H)，10.78(s，1H)。

LCMS (system 2): r_t=0.90min；m/z539[M+H]⁺。

The following examples were prepared according to the procedure described for example 261, starting from ((5-aminopyridin-3-yl) {7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 116) and the appropriate acid, followed by silyl deprotection.

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

Azetidine hydrochloride (10mg, 0.11mmol) was added to a stirred solution of 2- (3-formylphenyl) -N- {5- [ (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } acetamide (preparation 192, 23mg, 0.05mmol) in DCM (1mL) and acetic acid (0.04mL, 0.60 mmol). The reaction mixture was stirred at room temperature for 30min, then sodium triacetoxyborohydride (29mg, 0.14mmol) was added and stirring continued for 3 h. Water (1mL) was added and the mixture was concentrated in vacuo (azeotroped with toluene). The residue was purified by preparative HPLC to give the title compound as the acid salt in 12% yield, 3.4 mg.

LCMS：R_t=2.95min；m/z469[M+H]⁺。

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

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

LCMS：R_t=2.75min；m/z487[M+H]⁺。

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

The title compound was prepared according to the method described for example 266 using 2- (3-formylphenyl) -N- {5- [ (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } acetamide (preparation 192, 60mg, 0.14mmol) and morpholine to give the title compound as the formate salt in 30% yield, 21 mg.

LCMS：R_t=2.70min；m/z499[M+H]⁺

Example 269-283 general procedure:

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

Method A

The mixture was extracted with a mixture of DCM/MeOH (95/5, 5mL x3), and the combined organic layers were passed through a phase separator and concentrated in vacuo to give a crude residue. The residue was dissolved in DMSO (1mL) and purified by HPLC to give the desired compound.

Method B

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

Method C

The mixture was extracted with a mixture of EtOAc/MeOH (95:5, 5mL x3), and the combined organic layers were passed through a phase separator and concentrated in vacuo to give a crude residue. The residue was dissolved in DMSO (1mL) and purified by preparative HPLC to give the desired compound.

Example 284: 4-benzoyl-N-alpha- (tert-butyloxycarbonyl) -N- {5- [ (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } -L-phenylpropanamide

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

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

4-benzoyl-N alpha- (tert-butyloxycarbonyl) -N- {5- [ (7-isopropyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) carbonyl]Pyridin-3-yl } -D-phenylalanine amide (example 284, 20mg, 0.03mmol) with 10% hydrochloric acid in 1, 4-bisThe alkane solution (5mL) was stirred together at room temperature for 1 hour. The mixture was evaporated in vacuo and purified by preparative HPLC to give the title compound as a gum in 56% yield, 9 mg.

LCMS (system 5): r_t=2.89min；m/z533[M+H]⁺。

Example 286: 4-benzoyl-N-alpha- (tert-butyloxycarbonyl) -N- {5- [ (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } -L-phenylpropanamide

The title compound was prepared according to example 284 using (5-aminopyridin-3-yl) (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 95) and 4-benzoyl-N- (tert-butoxycarbonyl) -L-phenylalanine.

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

The title compound was prepared according to the method described for example 285 using 4-benzoyl-N α - (tert-butoxycarbonyl) -N- {5- [ (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } -L-phenylalanine amide (example 286) to give the title compound in 36% yield, 5 mg.

LCMS (system 4): r_t=2.30min；m/z533[M+H]⁺。

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

The title compound was prepared according to the procedure described for example 34 starting from (5-aminopyridin-3-yl) (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 95) and 2- (3-benzoylphenyl) acetic acid to give the title compound in 86% yield, 31 mg.

LCMS (system 3): r_t=3.05min；m/z504[M+H]⁺。

Example 2892- (4-benzoylphenyl) -N- (5- (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl) pyridin-3-yl) acetamide

The procedure described for example 34 was followed to synthesize (5-aminopyridin-3-yl) (7-isopropyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) methanone (preparation 95) and 2- (4-benzoylphenyl) acetic acid (JOC, 1961, 1635) were used as starting materials to prepare the title compound in 94% yield, 34 mg. LCMS (system 3): r_t=3.12min；m/z504[M+H]⁺。

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

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

¹H NMR(400MHz，d4-MeOH)δ: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 ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } -4- [3- (trifluoromethyl) -3H-diazacyclopropen-3-yl ] benzamide

The procedure described for example 34 was followed to synthesize (5-aminopyridin-3-yl) (7-isopropyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) methanone (preparation 95) and 4- [3- (trifluoromethyl) -3H-diazacyclopropen-3-yl]Benzoic acid the title compound was prepared as starting material to give the title compound as a white solid in 4% yield, 2 mg. LCMS (system 3): r_t=3.64min；m/z494[M+H]⁺。

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

The procedure described for example 34 was followed to synthesize (5-aminopyridin-3-yl) (7-isopropyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) methanone (preparation 95) and 3- (trifluoroacetyl) benzoic acid (preparation 200) were used as starting materials to prepare the title compound as a white solid in 80% yield, 41 mg. LCMS (system 3): r_t=2.52min；m/z482[M+H]⁺。

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

1-chloro-4-isocyanatobenzene (24mg, 0.15mmol) is added to (5-aminopyridin-3-yl) (7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (30mg, 0.12mmol) (preparation 232) in pyridine (1.0 mL). The mixture was stirred at room temperature overnight and then evaporated in vacuo. The product was obtained as a crude residue. The crude residue was purified by preparative HPLC to give the title compound in 49% yield, 24 mg.

LCMS：R_t=1.58min；m/z407[M+H]⁺

The following examples were prepared according to the procedure described above for example 293 starting from (5-aminopyridin-3-yl) (7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 232) and the appropriate isocyanates.

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

(4-chlorophenyl) acetic acid (22mg, 0.13mmol) was added to stirred (7-isopropyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) [5- (methylamino) pyridin-3-yl]Methanone (30mg, 0.10mmol) (preparation 149) andN- [ (dimethylamino) (3H- [1,2, 3)]Triazolo [4,5-b]Pyridin-3-yloxy) methylene]-N-Methylmethylammonium hexafluorophosphate (57mg, 0.15mmol) in a mixture of pyridine (1.0 mL). The mixture was heated to 50 ℃ for 16 h and evaporated in vacuo and partitioned between saturated aqueous sodium bicarbonate (10mL) and EtOAc (10 mL). The aqueous layer was washed with EtOAc (2 × 10 mL). With Na₂SO₄The combined organic layers were dried, filtered, concentrated in vacuo, and purified by preparative HPLC to give the title compound in 43% yield, 19mg,

¹H NMR(400MHz，DMSO)δ：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_t=2.99min；m/z448[M+H]⁺

the following examples were prepared according to the procedure described above for example 297, starting from (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) [5- (methylamino) pyridin-3-yl ] methanone (preparation 149) and the appropriate acid.

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

N- (5- {7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl ] -7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl } -pyridin-3-yl) -2- (4-chloro-phenyl) -acetamide (preparation 20335mg, 0.059mmoL) was dissolved in dry THF (0.5mL) and tetrabutylammonium fluoride (0.065mL of a 1M solution in THF, 0.065mmoL) was added. The reaction was stirred at room temperature for 30 min. The mixture was partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted 2 times with etoac. The combined organic layers were concentrated and purified by preparative HPLC to give the title compound in 28mg quantitative yield.

LCMS (system 4): r_t=3.03min；m/z478[M+H]⁺

Example 300: n- {5- [7- (3-hydroxymethyl-oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl ] -pyridin-3-yl } -2- (4-trifluoromethyl-phenyl) -acetamide:

n- (5- {7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl ] according to the procedure described for example 299]-7H-pyrrolo [2,3-d]Pyrimidine-5-carbonyl } -pyridin-3-yl) -2- (4-trifluoromethyl-phenyl) -acetamide (preparation 204) the title compound was prepared as a starting material to give the title compound as a white solid in quantitative yield, 30 mg. LCMS: r _t=2.74min；m/z512[M+H]⁺。

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

The process as described for example 299 was followed to obtain N- [5- ({7- [3- ({ [ tert-butyl (dimethyl) silyl)]Oxy } methyl) oxetane-3-Base of]-7H-pyrrolo [2,3-d]Pyrimidin-5-yl } carbonyl) pyridin-3-yl]Starting from (E) 2- (5-chloropyridin-2-yl) acetamide (preparation 223) the title compound was prepared as a pale yellow liquid in 87% yield, 23 mg. LCMS (system 4): r_t=1.57min；m/z479[M+H]⁺。

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

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

LCMS (System 5) R_t=1.57min；m/z502[M+H]⁺。

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

To a stirred solution of 2- (4-chlorophenyl) -N- [5- (7H-pyrrolo [2,3-d ]]Pyrimidin-5-ylcarbonyl) pyridin-3-yl]To a solution of acetamide (example 308, 50mg, 0.13mmol) in DMF (1ml) was added Cs₂CO₃(75mg, 0.23mmol) and then 2-bromoethyl acetate was addedAmide (21.3mg, 0.154 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with water (5mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with water (5mL) then brine (5mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification by preparative HPLC gave the title compound in 59% yield, 34 mg.

LCMS (system 4): r_t=1.56min；m/z449[M+H]⁺。

Example 304: 2- {5- [ (5- { [ (4-chlorophenyl) acetyl ] amino } pyridin-3-yl) carbonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-7-yl } -N, N-dimethylacetamide

Reacting {5- [ (5- { [ (4-chlorophenyl) acetyl group]Amino } pyridin-3-yl) carbonyl]-7H-pyrrolo [2,3-d]Pyrimidin-7-yl } acetic acid potassium salt (example 307, 50mg, 0.102mmol) was added to a stirred solution of dimethylamine HCl (12.5mg, 0.153mmol) and HATU (58.2mg, 0.153mmol) in pyridine (2mL), and the resulting solution was stirred at 50 deg.C (reaction vial) for 14 hours. The reaction was cooled to 25 ℃, diluted with DCM (5mL) and then saturated NaHCO ₃The reaction was stopped (aq) (5mL) and extracted with DCM (3 × 5 mL). The organic layers were combined, washed with saturated brine (5mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification by preparative HPLC gave the title compound in 55% yield, 26.6 mg.

LCMS：R_t=1.86min；m/z477[M+H]⁺。

Example 305: 2- (4-chlorophenyl) -N- [5- ({7- [2- (methylamino) -2-oxoethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } carbonyl) pyridin-3-yl ] acetamide

Reacting {5- [ (5- { [ (4-chlorophenyl) acetyl group]Amino } pyridin-3-yl) carbonyl]-7H-pyrrolo [2,3-d]Pyrimidin-7-yl } acetic acid potassium salt (example 307, 50mg, 0.102mmol) was added to a stirred solution of methylamine hydrochloride (10.3mg, 0.153mmol) and HATU (58.2mg, 0.153mmol) in pyridine (2 mL). Will obtainThe solution was stirred at 50 deg.C (reaction vial) for 14 hours. The reaction was cooled to 25 ℃, diluted with DCM (5mL) and then saturated NaHCO₃The reaction was stopped (aq) (5mL) and extracted with DCM (3 × 5 mL). The organic layers were combined, washed with saturated brine (5mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification by preparative HPLC gave the title compound in 65% yield, 30.5 mg.

LCMS：R_t=2.63min；m/z463[M+H]⁺。

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

To a stirred solution of 2- (4-chlorophenyl) -N- [5- (7H-pyrrolo [2,3-d ]]Pyrimidin-5-ylcarbonyl) pyridin-3-yl]To a solution of acetamide (example 308, 250mg, 0.638mmol) in DMF (4mL) was added Cs₂CO₃(374mg, 1.15mmol) followed by methyl bromoacetate (73uL, 0.766mmol) was added. The reaction was stirred at 25 ℃ for 3h, then quenched with water (10mL) and extracted with EtOAc (3 × 10 mL). The organic layers were combined, washed with water (10mL) and saturated brine (10mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a pale yellow oil (356mg) which solidified upon standing. Purification by silica gel column chromatography (gradient 0-100%90:10:1DCM/MeOH/NH3 in DCM) gave the title compound as a pale yellow solid in 70% yield, 208 mg.¹HNMR(400MHz，CDCl₃) δ 3.78(s, 2H), 3.81(s, 3H), 5.15(s, 2H), 7.29-7.41(m, 4H), 7.51(s, 1H), 7.88(s, 1H), 8.46(m, 1H), 8.78-8.82(m, 2H), 9.04(s, 1H), 9.65(s, 1H). LCMS (system 4): r_t=2.07min；m/z464[M+H]⁺。

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

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

LCMS (system 4): r_t=1.76min；m/z450[M+H]⁺。

Example 308: 2- (4-chlorophenyl) -N- [5- (7H-pyrrolo [2,3-d ] pyrimidin-5-ylcarbonyl) pyridin-3-yl ] acetamide

The title compound was prepared according to the method described for example 46 to give the title compound as a white solid in 87% yield 930 mg.

¹H NMR(400MHz，DMSO)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_t=2.87min；m/z392[M+H]⁺。

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

Reacting (5-aminopyridin-3-yl) [7- (3-methyloxetan-3-yl) -7H-pyrrolo [2,3-d]Pyrimidin-5-yl]Methanone (preparation 222, 15.5mg, 0.05mmol) was added to a stirred mixture of 4-chlorophenylacetic acid (11.1mg, 0.065mmol) and HATU (28.5mg, 0.075mmol) in pyridine (0.25 mL). The mixture was heated to 50 ℃ and stirred for 16 hours. The mixture was cooled to room temperature and saturated sodium bicarbonate solution (5mL) was added. The mixture was extracted with ethyl acetate (3 × 5mL), the combined organic portions were washed with brine, dried (MgSO)₄) The solvent was removed under reduced pressure to give the crude product, which was automatically purified.

LCMS (system 4): r_t=3.08min；m/z462[M+H]⁺。

The following examples were prepared in accordance with the procedures described above for example 309, starting from 5-aminopyridin-3-yl) [7- (3-methyloxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] methanone (preparation 222) and the appropriate acid.

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

Potassium carbonate (38mg, 0.275mmol) was added to the stirred 2- (4-chlorophenyl) -N- [5- (7H-pyrrolo [2,3-d ] at room temperature]Pyrimidin-5-ylcarbonyl)Pyridin-3-yl]A solution of acetamide (example 308, 60.0mg, 0.153mmol) in DMF (1.0 mL). After 10min, chloromethyl methyl sulfide (19 μ L, 0.23mmol) was added to the mixture and the reaction was stirred at room temperature for 24 h. Water (3mL) was added to the mixture and extracted with EtOAc (3 × 5 mL). The combined organic portions were washed with water (5mL), brine (5mL), dried over magnesium sulfate, and concentrated under reduced pressure to give a pale yellow oil. The crude material was purified by silica gel column chromatography (100% DCM-90: 10:1 DCM/MeOH/NH)₃Gradient) to give the title compound as a pale yellow solid, 36% yield, 25 mg.

¹H NMR(400MHz，CDCl₃) δ: 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 _t=1.97min；m/z452；454[M+H]⁺。

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

Potassium peroxymonosulfate (ozone, 67.2mg, 0.110mmol) was added to a stirred 2- (4-chlorophenyl) -N- [5- ({7- [ (methylthio) methyl ] thio) methyl ester at 0 deg.C]-7H-pyrrolo [2,3-d]Pyrimidin-5-yl } carbonyl) pyridin-3-yl]A solution of acetamide (example 313, 25.0mg, 0.055mmol) in methanol (1.0mL) and water (0.25 mL). After 1 hour, the reaction was warmed to room temperature and stirred for 24 hours. The reaction mixture was cooled to 0 ℃ and sodium metabisulphite (0.5M, 1ml) was added. The reaction mixture was evaporated under reduced pressure to remove methanol. Water (3mL) was added to the mixture and extracted with EtOAc (3 × 5 mL). The combined organic portions were washed with water (5mL), brine (5mL), dried over magnesium sulfate and the solvent removed under reduced pressure to give the crude product as an off-white solid. The crude material was purified by silica gel column chromatography (100% DCM-90: 10:1 DCM/MeOH/NH)₃Gradient) to give the title compound as a pale yellow solid in 17% yield, 27 mg. LCMS (system 4): r_t=1.91min；m/z484；486[M+H]⁺。

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

To (5-amino-pyridin-3-yl) - (7-isopropyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) -methanone (preparation 95, 50mg, 0.17mmol), (1-cyclopropyl-5-trifluoromethyl-1H-pyrazol-4-yl) -acetic acid (preparation 141, 47.1mg, 0.21mmol), and TEA (0.08mL, 0.62mmol) in THF (1mL) was added 1-propylphosphonic acid cyclic anhydride (50% in EtOAc, 0.26mL, 0.44mmol), and the mixture was stirred at rt for 14H. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and dried (Na)₂SO₄) And (4) evaporating in vacuum. Purification by silica gel column chromatography (EtOAc: hexanes 0: 100-80: 20 gradient) gave the title compound as a white solid, 76% yield, 67 mg.¹H NMR (400MHz, DMSO-D6) delta: 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_t=3.03min m/z498[M+H]⁺

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

[ 2-amino-7- (2-hydroxy-1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] was used at 50 ℃ according to the method described for example 34]Pyrimidin-5-yl](5-aminopyridine)-3-yl) methanone (preparation 48) and (5-bromopyridin-2-yl) acetic acid the title compound was prepared as a yellow solid in 60% yield, 75 mg. LCMS (system 10): r_t=2.69min；m/z524[M+H]⁺

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

Using DIPEA according to the procedure described in example 1, using (5-aminopyridin-3-yl) (7-isopropyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) methanone (preparation 95) and (5-bromopyridin-2-yl) acetic acid the title compound was prepared as a yellow solid in 45% yield, 75 mg. LCMS (system 9): r_t=2.97min；m/z479[M+H]⁺。

Example 318: n- {5- [ (2-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } -2- (5-bromopyridin-2-yl) acetamide

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

LCMS (system 10): r_t=2.81min；m/z494[M+H]⁺。

Library protocol 1

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

Preparation of a 0.25M solution of (5-amino-pyridin-3-yl) - (7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -methanone (preparation 110) in anhydrous DMF. Stock solutions (0.30M) of each acid monomer in anhydrous DMF were prepared. Stock solutions of EDCI (0.5M) and HOBT (0.05M) in anhydrous DMF were prepared. Mu.l (90. mu. mol.) of each acid monomer solution was dispensed into an 8mL vial, and then 300. mu.l (75. mu. mol) of (5-amino-pyridin-3-yl) - (7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -methanone solution was added. To each vial were added N-methylmorpholine (150. mu. mol, 2.0eq), 300. mu.l EDCI solution (150. mu. mol) and HOBT (15. mu. mol). The vial was capped and shaken at 50 ℃ for 2 hours. The solvent was removed using Speedvac and the final product was purified by HPLC under the conditions recited to give the final compound.

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

(5-amino-pyridin-3-yl) - (7-methyl-7H-pyrrolo [2, 3-d) according to the methods described for library protocol 1]Pyrimidin-5-yl) -methanone (preparation 110) and 1-phenylcyclopropanecarboxylic acid were used as starting materials to prepare the title compound. LCMS: r _t=2.61min；m/z398[M+H]^+.

Example 337: n- {5- [ (7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } indan-2-carboxamide

(5-amino-pyridin-3-yl) - (7-methyl-7H-pyrrolo [2, 3-d) according to the methods described for library protocol 1]Pyrimidin-5-yl) -methanone (preparation 110) and indan-2-carboxylic acid were used as starting materials to prepare the title compound. LCMS: r_t=2.58min；m/z398[M+H]^+.

Example 338: (2R) -N- {5- [ (7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } -2-phenylpropanamide

(5-amino-pyridin-3-yl) - (7-methyl-7H-pyrrolo [2, 3-d) according to the methods described for library protocol 1]Pyrimidin-5-yl) -methanone (preparation 110) and (2R) -2-phenylpropionic acid the title compound was prepared as starting materials. LCMS: r_t=2.52min；m/z386[M+H]^+.Example 339: 3-hydroxy-2-phenyl-N- (5- { [7- (propan-2-yl) -7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl]Carbonyl } pyridin-3-yl) propionamide

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

¹H NMR(400MHz，DMSO-d6)δ：1.57(d，6H)，3.16-3.22(m，1H)，3.37-3.41(m，1H)，3.60-3.64(m，1H)，5.10(m，1H)，6.30(t，1H)，7.10(t，1H)，7.20(t，2H)，7.30-7.32(m，3H)，8.12(s，1H)，8.15(d，1H)，8.61(s，1H)，8.96(s，1H)，9.44(s，1H)。

LCMS (system 10): r_t=2.36min；m/z430[M+H]⁺.

The following examples were prepared according to methods a and b of examples 1 and 34 as described above.

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

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

To (1- (4-chlorophenyl) -2- ((5- (7-isopropyl-7H-pyrrolo [2, 3-d)]Pyrimidine-5-carbonyl) pyridin-3-yl) amino) -2-oxoethyl) carbamic acid tert-butyl ester (preparation 299, 64mg, 0.11mmol) to which was added 4M HCl/bisAlkane (5mL), the reaction was 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 light brown solid in 8% yield, 4mg.

¹H NMR(400MHz，MeOD)δ：1.59(d，6H)，4.63(s，1H)，5.16(m，1H)，7.35(d，2H)，7.47(d，2H)，8.33(s，1H)，8.62(s，1H)，8.69(s，1H)，8.88(s，1H)，8.92(s，1H)，9.47(s，1H)。

LCMS R_t=2.81min；MS m/z449[M+H]⁺

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

To N- {5- [ 2-amino-7- (2-hydroxy-1, 1-dimethyl-ethyl) -7H-pyrrolo [2,3-d]Pyrimidine-5-carbonyl]-pyridin-3-yl } -2- (5-bromo-pyridin-2-yl) -acetamide (example 316, 75mg, 0.143mmol) in DMF (2mL) was added Zn (CN)₂(25mg, 0.215mmol), the reaction mixture was degassed with argon for 10 min. Then Pd is added ₂(dba)₃(3mg, 0.002mmol) and 1,1' -bis (diphenylphosphino) ferrocene 6mg, 0.011mmol), the resulting reaction mixture was heated at 100 ℃ for 40 minutes under microwave irradiation. The reaction mixture was diluted with EtOAc (20mL), washed with water (2 × 10mL) and brine (10 mL). Drying the organic layer (Na)₂SO₄) And (4) evaporating in vacuum. The crude material was purified by preparative TLC (7% MeOH in DCM) to give the title compound as a yellow solid in 31% yield, 21 mg.

¹H NMR(400MHz，DMSO-D6)δ：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_t=2.50min MS m/z471[M+H]⁺

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

To (5-amino-pyridin-3-yl) - (7-isopropyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) -methanone (preparation 95, 50mg, 0.17mmol), (1-cyclopropyl-3-trifluoromethyl-1H-pyrazol-4-yl) -acetic acid (preparation 148, 47.1mg, 0.21mmol), and TEA (0.08mL, 0.62mmol) in THF (1mL) was added 1-propylphosphonic acid cyclic anhydride (50% in EtOAc, 0.26mL, 0.44mmol), and the mixture was stirred at rt for 18H. The reaction mixture was evaporated under reduced pressure and the residue partitioned between water and EtOAc. The organic layer was washed with saturated sodium bicarbonate solution and dried (Na)₂SO₄) And (4) evaporating in vacuum. Purification by silica gel column chromatography (EtOAc) afforded the title compound as a white solid, 77% yield, 68 mg.

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

LCMS (system 10): r_t=3.02min MS m/z498[M+H]⁺.

Example 353: racemic methyl 2- {5- [ (5- { [ (4-chlorophenyl) acetyl ] amino } pyridin-3-yl) carbonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-7-yl } 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 ] pyrimidin-5-ylcarbonyl) pyridin-3-yl ] acetamide (example 308), methyl 2-bromopropionate and cesium carbonate. Purification using preparative HPLC (method 1) gave the title compound.

LCMS (system 2): r_t=1.42min MS m/z478[M+H]⁺

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

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

LCMS (system 2): r_t=1.40min；m/z464[M+H]⁺.

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

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

LCMS (system 8): r_t=1.55min；m/z458[M+H]

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

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

LCMS (system 8): r_t=1.56min；m/z492[M+H]⁺

The following examples were prepared according to one of the methods of example 355 (method d) and 356 (method e) using (5-aminopyridin-3-yl) (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 95).

Example 517: 2- (5, 8-dihydro-6H- [1,7] naphthyridin-7-yl) -N- [5- (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl) -pyridin-3-yl ] -acetamide

To (5, 8-dihydro-6H- [1, 7)]Naphthyridin-7-yl) -acetic acid hydrochloride (preparation 235) (34.2mg, 0.18mmol) in DMF was added (5-amino-pyridin-3-yl) - (7-isopropyl-7H-pyrrolo [2, 3-d) ]Pyrimidin-5-yl) -methanone (preparation 95) (50mg, 0.18mmol), HATU (136.4mg, 0.36mmol) and Hunig's base (0.092ml, 0.54 mmol). The mixture was heated at 50 ℃ for 20 h, then diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and evaporated to dryness in vacuo. The crude solid was purified by preparative TLC eluting with 5% MeOH/EtOAc to give the title compound as an off-white solid, 26% yield, 21 mg.¹H NMR (400MHz, DMSO-D6) delta: 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 (system 9): r_t=1.77min；m/z456[M+H]⁺。

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

Stirring of N- [5- (7-isopropyl-7H-pyrrolo [2, 3-d) at 0 deg.C]Pyrimidine-5-carbonyl) -pyridin-3-yl]-2-phenyl-2- (tetrahydro-pyran-2-yloxy) -acetamide (60mg, 0.12mmol) (preparation 237) in bisTo a solution in alkane (1mL) was added dialkane-HCl (1mL of 4N solution). The mixture was stirred at room temperature for 2 hours. All volatiles were removed in vacuo and the resulting solid triturated with ether to give the title compound as a pale yellow solid in 78% yield, 42mg. ¹H NMR(400MHz，DMSO-D6)δ：1.55(d，6H)，5.08-5.12(m，1H)，5.19(s，1H)，7.30(t，1H)，7.37(t，2H)，7.53(d，2H)，8.56(s，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_t=2.81min；m/z416[M+H]⁺。

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

The title compound was prepared according to the method described for example 1 using (5-amino-6-ethoxy-pyridin-3-yl) - (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -methanone (preparation 242) and (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetic acid to give the title compound as an off-white solid in 50% yield, 40mg.

¹H NMR (400MHz, CDCl3) delta: 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_t=3.48min；m/z516[M+H]⁺。

Example 520: n- [5- (2-amino-7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl) -pyridin-3-yl ] -2- (4-cyano-phenyl) -acetamide

The title compound was prepared according to the method described for example 1 using (2-amino-7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) - (5-amino-pyridin-3-yl) -methanone (see preparation 65) and 4-cyanophenylacetic acid. The title compound was obtained as an off-white solid, 58%, 23mg.

LCMS (system 10): r_t=2.78min；m/z454[M+H]⁺.

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

2- (4-chloro-phenyl) -3-hydroxy-propionic acid (570mg, 2.84mmol) (preparation 244) was added to a solution of (5-amino-pyridin-3-yl) - (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -methanone (200mg, 0.71mmol) (preparation 95) in THF (5mL), di-isopropylethylamine (0.64mL, 3.56mmol), EDCI.HCl (273mg, 1.42mmol), and HOBT (193mg, 1.42mmol) were added and the mixture was stirred at 25 ℃ for 48H. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (2mL), extracted with ethyl acetate (3 × 15mL), the combined organic layers were washed with water (5mL), brine (5mL), dried over sodium sulfate, and evaporated in vacuo. The crude material was purified by preparative TLC (dichloromethane: methanol 93:7) to give the title compound as a yellow solid in 3% yield, 10mg.

¹H NMR (400MHz, DMSO-D6) delta: 1.55(d, 6H), 3.58-3.61(m, 1H), 3.88-3.91(m, 1H), 4.04(t, 1H), 5.07-5.13(m, 2H), 7.41(s, 4H), 8.47(s, 1H), 8.50(s, 1H), 8.72(s, 1H), 8.99(s, 2H), 9.43(s, 1H), 10.65(s, 1H); LCMS (system 10): r _t=2.99min；m/z464[M+H]⁺。

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

(4-cyano-phenyl) -acetic acid (6.1mg, 0.04mmol) was added to a solution of (5-amino-pyridin-3-yl) - {7- [1- (tetrahydro-pyran-2-yloxymethyl) -cyclopropyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } -methanone (15mg, 0.04mmol) (preparation 251) in THF (1 mL). 1-Propylphosphonic acid cyclic anhydride (0.07mL, 0.11mmol) and triethylamine (0.02mL, 0.13mmol) were then added and the mixture was stirred at 25 ℃ for 4 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (2mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with water (5mL), brine (5mL), dried over sodium sulfate and evaporated in vacuo. The crude product was dissolved in methanol (1mL), added to a solution in PTSA (5mg), and stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (2mL) and extracted with dichloromethane (5 × 5 mL). The combined organic layers were washed with brine (5mL), dried over sodium sulfate and evaporated in vacuo. The crude material was purified by preparative TLC (dichloromethane: MeOH 95:5) to give the title compound as a white solid in 58% yield, 10 mg.

¹H NMR (400MHz, DMSO-D6) delta: 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_t=2.57min；m/z453[M+H]⁺.

The following examples were prepared according to the procedure described above for example 522 starting from (5-amino-pyridin-3-yl) - [7- (3-methyl-oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -methanone (preparation 251) and the appropriate acid.

Example 526: 1- (3-cyclopropyl-1 ' -methyl-1 ' H- [1,4' ] bipyrazolyl-5-yl) -3- [5- (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl) -pyridin-3-yl ] -urea

Phenyl chloroformate (0.03mL, 0.24mmol) was added slowly to 3-cyclopropyl-1 '-methyl-1' H- [1,4 'at 0 deg.C']Dipyrazol-5-ylamine (preparation 297, 40mg, 0.19mmol) and pyridine (0.03mL) in THF (2mL) and the mixture was stirred at room temperature for 4 hours. Then (5-amino-pyridin-3-yl) - (7-isopropyl-7H-pyrrolo [2, 3-d) is added]Pyrimidin-5-yl) -methanone (preparation 95) (55.4mg, 0.19mmol) in DMF (1mL) and the reaction mixture was heated at 100 ℃ for 16 h. The mixture was cooled, diluted with ethyl acetate (15mL) and saturated NaHCO ₃Aqueous solution (2 × 10mL), water (10mL), brine (10mL), dried over sodium sulfate and evaporated to dryness in vacuo. The crude material was purified by preparative TLC plate eluting with 5% methanol in DCM to give the title compound as an off white solid in 15% yield, 15 mg.¹H NMR (400MHz, DMSO-d6) delta: 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(brs, 1H), 8.65(s, 1H), 8.78(s, 1H), 8.99(s, 1H), 9.45(s, 2H); LCMS (system 10): r_t=2.75min；m/z511[M+H]⁺。

Example 527: 1- (3-tert-butyl-1 ' -methyl-1 ' H- [1,4' ] bi pyrazolyl-5-yl) -3- [5- (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl) -pyridin-3-yl ] -urea

According to the method described for the example 526, (5-amino-pyridin-3-yl) is used) - (7-isopropyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) -methanone (preparation 95) and 3-tert-butyl-1 ' -methyl-1 ' H- [1,4']Bipyrazol-5-ylamine (preparation 296) the title compound was prepared as a yellow solid in 35% yield, 17mg. lcms (system 10): r_t=3.01min；m/z527[M+H]⁺。

The following examples were prepared according to the procedure described above for example 1 starting from (2-amino-7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (5-aminopyridin-3-yl) methanone (preparation 65) and the appropriate acid.

The following examples were prepared according to the procedure described above for example 522 using (5-amino-pyridin-3-yl) - {7- [ (S) -1-methyl-2- (tetrahydro-pyran-2-yloxy) -ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } -methanone (preparation 33) and the appropriate acid.

The following examples were prepared according to the procedures described for d ] pyrimidin-5-yl ] methanone (preparation 186) and the appropriate acid.

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

Stirring of N- [5- (7-tert-butyl-7H-pyrrolo [2, 3-d) at 0 ℃ in a nitrogen atmosphere]Pyrimidine-5-carbonyl) -pyridin-3-yl]To a solution of-2- (4-fluoro-phenyl) -acetamide (example 546, 115mg, 0.27mmol) in anhydrous THF (4.5mL) was added NaH (60% solution in paraffin oil, 10.7mg, 0.27mmol) and the resulting mixture was stirred for 10 min. MeI (0.017mL, 0.27mmol) was then added and the reaction mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride (5mL) was added and the mixture was extracted with ethyl acetate (2 × 10 mL). The organic phase was washed with water (10mL), brine (10mL), dried over sodium sulfate and evaporated to dryness in vacuo. The crude material was purified by preparative TLC (eluting with 5% methanol in DCM) to give the title compound as an off-white solid in 46% yield, 55 mg. ¹H NMR (400MHz, DMSO-D6) delta: 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_t=3.08min；m/z446[M+H]⁺.

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

To a stirred mixture of (5-amino-pyridin-3-yl) - (7-tert-butyl-7H-pyrrolo [2, 3-d)]To a solution of pyrimidin-5-yl) -methanone (preparation 31) (200mg, 0.68mmol) in DCM (4mL) was added boc-anhydride (0.155mL, 0.68mmol) and Hunig's base (0.24mL, 1.36mmol), and the reaction mixture was stirred at room temperature for 16 h. Diluted with DCM (15mL),washed with water (2 × 10mL), brine (10mL), dried over sodium sulfate and evaporated to dryness in vacuo. The crude material was purified by silica gel column chromatography (methanol: DCM2:98) to give the title compound as a pale brown gum in 41% yield, 110 mg. LCMS (system 10): r_t=3.16min；m/z396[M+H]⁺.

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

The procedure described for example 540 was followed using [5- (7-tert-butyl-7H-pyrrolo [2,3-d ]]Pyrimidine-5-carbonyl) -pyridin-3-yl ]Tert-butyl carbamate (example 541) the title compound was prepared as a yellow solid in 79% yield, 90 mg. LCMS (system 10): r_t=3.83min；m/z410[M+H]⁺.

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

According to the method described for example 1, (7-tert-butyl-7H-pyrrolo [2, 3-d) is used]Pyrimidin-5-yl) - (5-methylamino-pyridin-3-yl) -methanone (preparation 187) and (5-chloro-pyridin-2-yl) -acetic acid (see preparation 90) the title compound was prepared as an off-white solid in 21% yield, 25 mg.¹H NMR (400MHz, DMSO-D6) delta: 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_t=3.29min；m/z463.2[M+H]⁺.

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

The title compound was prepared according to the method described for example 1 using (7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) - (5-methylamino-pyridin-3-yl) -methanone (preparation 187) and (4-chloro-phenyl) -acetic acid to give the title compound as an off-white solid in 45% yield, 21mg.

LCMS (system 10): r_t=3.28min；m/z462[M+H]⁺.

The following examples were prepared according to the procedure described above for example 1 starting from (5-aminopyridin-3-yl) (7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 31) and the appropriate acid.

The following examples were prepared according to the procedure described above for example 1 starting from [ 2-amino-7- (2-methoxy-1, 1-dimethyl-ethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] - (5-amino-pyridin-3-yl) -methanone (preparation 261) and the appropriate acid.

The following examples were prepared according to the procedure described above for example 522 using (5-amino-pyridin-3-yl) - {7- [ (S) -1-methyl-2- (tetrahydro-pyran-2-yloxy) -ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } -methanone (preparation 49) and the appropriate acid.

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

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

According to the method described for example 343, 2- (4-cyano-phenyl) -N- {5- [7- (2-trimethylsilyl-ethoxymethyl) -7H-pyrrolo [2,3-d ] is used ]Pyrimidine-5-carbonyl]Pyridin-3-yl } -acetamide (preparation 277) the title compound was prepared as a white solid in 99% yield,¹H NMR(400MHz，DMSO-d₆) δ: 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_t=2.48min；m/z383[M+H]⁺.

The following examples were prepared according to the procedure described above for example 1 starting from (5-amino-pyridin-3-yl) - [7- (3-methyl-oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -methanone (preparation 222) and the appropriate acid.

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

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

LCMS (system 10): r_t=2.62min；m/z475[M+H]⁺.

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

According to the method described for example 1, (2-amino-7-tert-butyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl)- (5-amino-pyridin-3-yl) -methanone (see preparation 65) and (4-cyclopropyl-pyrazol-1-yl) -acetic acid the title compound was prepared as a light yellow solid in 16% yield, 12mg. lcms (system 10): r_t=2.80min；m/z459[M+H]⁺.

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

To (5-amino-pyridin-3-yl) - [ 7-bicyclo [1.1.1] at room temperature]Pent-1-yl-2- (4-methoxy-benzylamino) -7H-pyrrolo [2,3-d]Pyrimidin-5-yl]To a solution of methanone (preparation 287) (50mg, 0.11mmol) in THF (5mL) was added 5-fluoropyridin-2-yl acetic acid (27mg, 0.17mmol), TEA (0.08mL, 0.56mmol) and 1-propylphosphonic acid cyclic anhydride (50% in EtOAc, 0.20mL, 0.34 mmol). The mixture was then stirred for 18 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between saturated sodium bicarbonate solution (10mL) and ethyl acetate (25 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. TFA (1.5mL) was added and the resulting mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and the residue was partitioned between saturated sodium bicarbonate (10mL) and ethyl acetate (30 mL). The organic phase was dried over sodium sulfate, concentrated under reduced pressure, and purified by preparative TLC (MeOH: DCM 5: 95) to give the title compound as an off-white solid in 31% yield, 16 mg. ¹H NMR(400MHz，DMSO-d₆) δ: 2.32(s, 6H), 2.66(s, 1H), 3.94(s, 2H), 6.57(s, 2H), 7.49(m, 1H), 7.69-7.73(m, 2H), 8.38(s, 1H), 8.50(d, 1H), 8.65(d, 1H), 8.92(s, 1H), 8.96(d, 1H), 10.67(s, 1H); LCMS (system 10): r_t=2.85min；m/z458[M+H]⁺.

The following examples were prepared according to the procedure described above for example 578 starting from ((5-amino-pyridin-3-yl) - [ 7-bicyclo [1.1.1] pent-1-yl-2- (4-methoxy-benzylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -methanone (preparation 287) and the appropriate acid.

Example 584-:

it belongs to formula (I) according to the tautomerism of pyridones.

Preparation 1: 7- [ (1S) -2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl ] -4-chloro-7H-pyrrolo [2,3-d ] pyrimidine

(S) -2-tert-Butyldimethylsilyloxy-1-methylethylamine (120g, 636mmol) was added to (4, 6-dichloropyrimidin-5-yl) acetaldehyde (52.8g, 276mmol) in ethanol (500 mL). The mixture was heated to reflux for 45 minutes. The reaction mixture was evaporated in vacuo, then the residue was diluted with water (400mL) and extracted with ethyl acetate (600 mL). The organic extracts were evaporated in vacuo and the crude material was purified by silica gel column chromatography (pentane: EtOAc90: 10-80: 20 gradient) to give the title compound as a yellow liquid in 67% yield, 60.4g.

¹H NMR(400MHz，CDCl3)δ：-0.92(s，6H)，0.80(s，9H)，1.58(d，3H)，3.86(m，2H)，5.04(m，1H)，6.59(d，1H)，7.40(d，1H)，8.60(s，1H)。

Preparation 2: 7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -4-chloro-7H-pyrrolo [2,3-d ] pyrimidine

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

¹H NMR(400MHz，CDCl₃)δ：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 ] pyrimidin-7-yl) propan-1-ol

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

LCMS (system 2): r_t=0.89min；m/z212[M+H]⁺.

Preparation of DL 3: (R, S)7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl ] -4-chloro-7H-pyrrolo [2,3-d ] pyrimidine

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

¹H NMR(400MHz，CDCl3)δ：-0.90(s，6H)，0.82(s，9H)，1.58(d，3H)，3.84(m，2H)，5.05(m，1H)，6.59(d，1H)，7.42(d，1H)，8.60(s，1H)。

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

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

¹H NMR(400MHz，DMSO-D6)δ：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-butyl-4-chloro-7H-pyrrolo [2,3-d ] pyrimidine

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

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

Preparation 6: 4-chloro-7- [ (1R) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidine

2, 3-dihydropyran (25.0mL, 270mmol) was added to (2R) -2- (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) propan-1-ol (11.00g, 51.97mmol) (see preparation 3) and pyridinium toluene-4-sulfonate (3.92g, 15.6mmol) in DCM (150 mL). The reaction mixture was washed with water (200mL) and extracted with DCM (2 × 150 mL). The combined organic phases were dried over magnesium sulfate and evaporated in vacuo. The crude material was purified by silica gel column chromatography (heptane: EtOAc100: 0-70: 30 gradient) to give the title compound as a yellow oil in 100% yield, 15.65g.

LCMS (system 2): r_t=1.30min；m/z296[M+H]⁺.

Preparation 7: 4-chloro-7- [ (1S) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidine

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

¹H NMR(400MHz，CDCl₃)δ：1.43-1.71(m，9H)，3.42(m，1H)，3.57(m，1H)，3.69(m，1H)，4.00(m，1H)，4.52(m，1H)，5.19(m，1H)，6.60(d，1H)，7.44(d，1H)，8.61(s，1H)。

Preparation 8: 7- [ (1S) -2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidine

Palladium (10%/carbon, 18g) was added to 7- [ (1S) -2- { [ tert-butyl (dimethyl) silyl]Oxy } -1-methylethyl]-4-chloro-7H-pyrrolo [2,3-d]Pyrimidine (182g, 558mmol) (see preparation 1) was hydrogenated (60psi, 20 ℃ C.) in ethanol (900mL) and concentrated ammonia solution (100mL) for 18 h. By Arbocel^TMThe reaction mixture was filtered and the filtrate was concentrated in vacuo. Diethyl ether (300mL) was added to the residue and the mixture was filtered. The filtrate was concentrated in vacuo to give the title compound as an orange oil in 94% yield, 162.7g.

¹H NMR(400MHz，CDCl3)δ：-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)。

Preparation 9: 7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared according to the procedure described for preparation 8 using 7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (see preparation 2) to give the title compound as a white solid in 97% yield of 327 mg.

¹H NMR(400MHz，CDCl₃)δ：0.01(s，6H)，0.94(s，9H)，2.02(s，6H)，4.30(s，2H)，6.92(d，1H)，7.84(d，1H)，9.13(s，1H)，9.21(s，1H)。

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

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

¹H NMR(400MHz，DMSO-D6)δ：0.01(s，6H)，0.88(s，9H)，1.69(d，3H)，4.09(m，2H)，5.20(m，1H)，6.84(d，1H)，7.92(d，1H)，8.96(s，1H)，9.18(s，1H)。

Preparation 11: 7- [ (1R) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [23-d ] pyrimidine

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

LCMS (system 2): r_t=0.73min；m/z262[M+H]⁺.

Preparation 12: 7- [ (1S) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidine

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

¹H NMR(400MHz，CDCl₃)δ：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

The title compound was prepared according to the procedure described for preparation 8 using 7-tert-butyl-4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (see preparation 5) to give the title compound as a yellow liquid in 94% yield, 1.27g.

¹H NMR(400MHz，DMSO-D6)δ：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 } -1-methylethyl ] -5-iodo-7H-pyrrolo [2,3-d ] pyrimidine

N-iodosuccinimide (124g, 553mmol) was added to 7- [ (1S) -2- { [ tert-butyl (dimethyl) silyl ] in acetonitrile (700mL) ]Oxy } -1-methylethyl]-7H-pyrrolo [2,3-d]Pyrimidine (153.4g, 526mmol) (see preparation 8). The mixture was stirred at room temperature for 16 hours, then saturated aqueous sodium thiosulfate solution (700mL) was added. The mixture was extracted with EtOAc (800mL) and the organic extracts were dried over magnesium sulfate and evaporated in vacuo. The crude material was purified by silica gel column chromatography (pentane: EtOAc90: 10-80: 20 gradient) to give the title compound as a yellow solid in 66% yield, 145g.¹H NMR(400MHz，CDCl₃)δ：-0.90(d，6H)0.80(s，9H)1.58(d，3H)3.84(m，2H)5.07(m，1H)7.48(s，1H)8.73(s，1H)8.86(s，1H)。

Preparation 15: 7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -5-iodo-7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared according to the procedure described for preparation 14 using 7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidine (see preparation 9) to give the title compound as a brown oil in 59% yield of 270 mg.

¹H NMR(400MHz，CDCl₃)δ：0.01(s，6H)，0.92(s，9H)，2.00(s，6H)，4.20(s，2H)，7.95(s，1H)，9.02(s，1H)，9.16(s，1H)。

Preparation 16: (R, S)7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl) -5-iodo-7H-pyrrolo [2,3-d ] pyrimidine

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

LCMS (system 1): r_t=4.03min；m/z418[M+H]⁺.

Preparation 17: 5-iodo-7- [ (1R) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidine

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

¹H NMR(400MHz，CDCl₃)δ：1.43-1.74(m，9H)，3.42(m，1H)，3.54(m，1H)，3.67(m，1H)，3.99(m，1H)，4.54(m，1H)，5.23(m，1H)，7.51(s，1H)，8.74(s，1H)，8.88(s，1H)。

Preparation 18: 5-iodo-7- [ (1S) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidine

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

¹H NMR(400MHz，CDCl₃)δ：1.44-1.65(m，9H)，3.45(m，1H)，3.56(m，1H)，3.67(m，1H)，3.99(m，1H)，4.54(m，1H)，5.24(m，1H)，7.51(s，1H)，8.76(s，1H)，8.89(s，1H)。

Preparation 19: 7-tert-butyl-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine

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

LCMS (system 1): r_t=3.12min；m/z302[M+H]⁺.

Preparation 20: (R, S) methyl 2- (5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) propionate

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

¹H NMR(400MHz，CDCl₃)δ：1.82(d，3H)，3.76(s，3H)，5.72(q，1H)，7.48(s，1H)，8.76(s，1H)，8.89(s，1H)。

Preparation 21: 2- (5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-methylpropanoic acid methyl ester

A solution of potassium tert-butoxide (71.3mL, 71.3mmol, 1.0M in THF) was added to methyl (R, S)2- (5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) propionate (16.9g, 50.9mmol) (see preparation 20) and iodomethane (4.44mL, 71.3mmol) in THF (100 mL). The mixture was stirred at room temperature for 15 minutes, then water (20mL) and aqueous HCl (0.3mL, 2M) were added. THF was removed by evaporation in vacuo, and 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 silica gel column chromatography (80:20 pentane: EtOAc) to give the title compound as a white solid in 51% yield, 8.92g.

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

Preparation 22: 2- (5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-methylpropan-1-ol

Lithium borohydride (32.3mL, 64.6mmol, 2.0M in THF) was added to methyl 2- (5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-methylpropionate (8.92g, 25.9mmol) (see preparation 21) in ethanol (70 mL). The mixture was stirred at room temperature for 17 hours, then water (70mL) was added. The mixture was evaporated in vacuo and the residue was partitioned between DCM (250mL) and water (50 mL). The aqueous phase was extracted with DCM: MeOH (90:10, 2X250mL) and the combined organic phases were dried over magnesium sulfate and evaporated in vacuo to give the title compound as an off-white solid in 100% yield, 8.20g.

¹H NMR(400MHz，DMSO-d6)δ：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

Benzophenone imine (205mL, 1.22mol) was added to 5-bromo-N-methoxy-N-methylisonicotinamide (250g, 1.02mol), tris (dibenzylideneacetone) dipalladium (28.0g, 31.0mmol), 2-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (34.7g, 82.0mmol), and freshly ground tripotassium phosphate (541g, 2.55mol) in 1, 2-dimethoxyethane (2500 mL). The mixture was stirred at 50 ℃ for 17 hours. By Arbocel^TMThe reaction mixture was filtered and the pad was washed with EtOAc (500 mL). The filtrate was concentrated in vacuo and the crude material was purified by silica gel column chromatography (heptane: EtOAc70: 30-0: 100 gradient) to give the title compound as an orange gum in 51% yield, 180.0g.

¹H NMR(400MHz，DMSO-D6)δ：3.19(s，3H)，3.37(s，3H)，7.18-7.23(m，2H)，7.29(m，1H)，7.32-7.39(m，3H)，7.46-7.53(m，2H)，7.57(m，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 } -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } {5- [ (diphenylmethylene) amino ] pyridin-3-yl } methanone

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

R_t=7.94min；m/z576[M+H]⁺.

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

The title compound was prepared according to the procedure described for preparation 24 using 7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (see preparation 15) and 5- [ (diphenylmethylene) amino ] -N-methoxy-N-methylnicotinamide (see preparation 23) to give the title compound as a colorless gum in 56% yield, 1.49g.

¹H NMR(400MHz，CDCl₃)δ：0.21(s，6H)，0.67(s，9H)，1.80(s，6H)，4.10(s，2H)，7.14(d，2H)，7.33(m，3H)，7.45(m，2H)，7.54(m，1H)，7.58(t，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-Bromopyridin-3-yl) {7- [ (1R) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone

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

LCMS (system 2): r_t=1.27min；m/z447[M+H]⁺.

Preparation 27: (5-Bromopyridin-3-yl) {7- [ (1S) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone

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

LCMS (system 2): r_t=1.27min；m/z447[M+H]⁺.

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

N-butyllithium (0.57mL, 1.31mmol, 2.3M in hexane) was added to (R, S)7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl) -5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (500mg, 1.19mmol) (see preparation 16) in dry ether (20mL) at-78 deg.C and the reaction mixture was stirred for 30 minutes. 5- [ (diphenylmethylene) amino ] -N-methoxy-N-methylnicotinamide (372mg, 1.07mmol) in dry ether (25mL) was then added dropwise at the same temperature (see preparation 23). After 15 min, the mixture was quenched with saturated aqueous ammonium chloride (50mL) and extracted with ethyl acetate (70 mL). The organic extract was dried over sodium sulfate, evaporated in vacuo and purified by silica gel column chromatography (hexanes: EtOAc 70: 30) to give the title compound as an off-white solid in 19% yield, 134 mg.

LCMS (system 4): r_t=4.53min；m/z576[M+H]⁺.

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

The title compound was prepared according to the procedure described for preparation 28 using 7-tert-butyl-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (see preparation 19) and 5-bromo-pyridine-3-carbaldehyde to give the title compound as a colorless oil in 37% yield of 486 mg.

LCMS (system 4): r_t=2.94min；m/z362[M+H]⁺.

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

2-Iodoylbenzoic acid (909mg, 3.25mmol) was added to (R, S) (5-bromopyridin-3-yl) (7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanol (405mg, 1.34mmol) (see preparation 29) in ethyl acetate (30mL), and the mixture was refluxed for 4 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid in 95% yield, 554 mg.

LCMS (system 4): r_t=3.28min；m/z360[M+H]⁺.

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

Copper sulfate pentahydrate (55mg, 0.24mmol) was added to (5-bromopyridin-3-yl) (7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (292mg, 0.81mmol) (see preparation 30) and concentrated ammonia solution (20 mL). The mixture was heated at 140 ℃ for 17 hours in a sealed container. The reaction mixture was evaporated in vacuo and the residue stirred in aqueous brine (10mL, 2M) at room temperature for 17 h. The reaction mixture was basified to pH9 using saturated aqueous sodium carbonate solution and then extracted with DCM (3 × 20 mL). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound as a white solid in 49% yield, 240 mg.

LCMS (system 4): r_t=2.68min；m/z296[M+H]⁺.

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

The title compound was prepared according to the procedure described for preparation 31 using (5-bromopyridin-3-yl) {7- [ (1S) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone (see preparation 27) to give the title compound as a white solid in 10% yield, 134 mg.

LCMS (system 2): r_t=0.59min；m/z298[M+H]⁺.

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

Benzophenoimines (0.40mL, 2.4mmol) were added to (5-bromopyridin-3-yl) {7- [ (1S) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl in 1, 2-dimethoxyethane (4mL)]-7H-pyrrolo [2,3-d]Pyrimidin-5-yl } methanone (891mg, 2.0mmol) (see preparation 27), tris (dibenzylideneacetone) dipalladium (55mg, 0.06mmol), 2-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (68mg, 0.16mmol), and freshly ground tripotassium phosphate (1.06g, 5.0 mmol). The mixture was stirred at 50 ℃ for 17 hours. The reaction mixture was diluted with DCM (10mL) and passed through Arbocel ^TMFilter and wash the pad with DCM (5 mL). The filtrate was concentrated in vacuo and the crude material was dissolved in THF (10 mL). Aqueous citric acid (5mL, 2M) was added and the mixture was stirred at room temperature for 16 h. Water (40mL) was added, followed by sodium hydroxide to basify the mixture. The mixture was extracted with EtOAc (3 × 40mL) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (EtOAc: MeOH100: 0-80: 20 gradient) to give the title compound as a white solid in 70% yield, 506 mg.

LCMS (system 1): r_t=3.27min；m/z382[M+H]⁺.

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

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

LCMS (system 5): r_t=2.98min，m/z541[M+H]⁺.

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

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

LCMS (system 5): r_t=3.08min，m/z536[M+H]⁺.

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

Copper (I) oxide (9.2mg, 0.06mmol) was added to (5-bromopyridin-3-yl) {7- [ (1R) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone (285mg, 0.64mmol) (see preparation 26) and concentrated ammonia solution (2mL) in 1-methyl-2-pyrrolidone (0.5 mL). The mixture was heated in a sealed container at 80 ℃ for 17 hours. Ethyl acetate (5mL) and water (5mL) were added to the reaction mixture, which was then filtered through a glass fiber filter. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The crude solid was purified by silica gel column chromatography (EtOAc: MeOH: cNH3100:0: 0-95: 5:0.5 gradient) to give the title compound as a colorless oil, 70% yield, 171 mg.

LCMS (system 2): r_t=0.78min；m/z382[M+H]⁺.

Preparation 37: (5-Aminopyridin-3-yl) {7- [ (1S) -2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone

An aqueous solution of citric acid (120mL, 2.0M) was added to {7- [ (1S) -2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } {5- [ (diphenylmethylene) amino ] pyridin-3-yl } methanone (63.2g, 110mmol) (see preparation 24) in THF (274mL) and the mixture was stirred at room temperature for 17 hours. The mixture was cooled to 0 ℃, water (200mL) was added, and the mixture was basified using sodium hydroxide (28 g). The mixture was extracted with ethyl acetate (150mL), then the aqueous phase was extracted with ethyl acetate (2 × 200 mL). The combined organic phases were washed with brine (600mL), dried over sodium sulfate and evaporated in vacuo to give the title compound as a semi-solid in quantitative yield, 45.2g.

LCMS (system 2): r_t=1.16min；m/z412[M+H]⁺.

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

The title compound was prepared according to the procedure described for preparation 37 using [7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] {5- [ (diphenylmethylene) amino ] pyridin-3-yl } methanone (see preparation 25) to give the title compound as a white solid in 81% yield, 872 mg.

¹H NMR(400MHz，DMSO-d6)δ：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)。

Preparation 39: (R, S) (5-Aminopyridin-3-yl) {7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone

The title compound was prepared according to the procedure described for preparation 37 using (R, S) {7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } {5- [ (diphenylmethylene) amino ] pyridin-3-yl } methanone (see preparation 28) to give the title compound as a white solid in 89% yield, 86 mg.

LCMS (system 4): r_t=1.37min；m/z412[M+H]⁺.

Preparation 40: 2-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine

N-iodosuccinimide (742g, 3.30mol) was added to 2-chloro-7H-pyrrolo [2,3-d ] pyrimidine (482.5g, 3.14mol) in acetonitrile (2500mL) at 12 ℃. The mixture was stirred at room temperature for 1 hour, then sodium metabisulfite (650g in 4500mL water) was added. The mixture was stirred for 1 hour then filtered to give the title compound as an orange solid, 82% yield 716.2g.

¹H NMR(400MHz，DMSO-D6)δ：7.83(s，1H)，8.63(s，1H)，12.73(s，1H)。

Preparation 41: 2- (2-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-methylpropionic acid methyl ester

Methyl 2-bromo-2-methylpropionate (663mL, 5.13mmol) was added to 2-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (358.1g, 1.28mol) (see preparation 40), potassium iodide (21.3g, 128mmol) and cesium carbonate (1670g, 5.13mol) in DMF (7162 mL). The mixture was heated at 60 ℃ for 19 hours. The reaction mixture was diluted with water (7000mL) and stirred at room temperature for 42 h. The mixture was filtered and the solid washed with water (500mL) to give the title compound as a light brown solid in 92% yield, 445.8g.

¹H NMR(400MHz，CDCl₃)δ：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 ] pyrimidin-7-yl) -2-methylpropionic acid

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

LCMS (System 5) R_t=2.24min；m/z366[M+H]⁺.

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

Pathway a

Isobutyl chloroformate (6.6mL, 50.02mmol) was added to 2- (2-chloro-5-iodo-7H-pyrrolo [2,3-d ] in THF (300mL) at 0 ℃ under a nitrogen atmosphere]Pyrimidin-7-yl) -2-methylpropionic acid (16.6g, 45.48mmol) (see preparation 42) and triethylamine (12.64mL, 90.9 mmol). The mixture was stirred at room temperature for 3 hours and then passed through short Celite^TMThe pad is filtered. The filtrate was cooled to 0 deg.C and a solution of sodium borohydride (8.6g, 227.6mmol) in water (300mL) was added. The mixture was stirred at 0 ℃ for 10 min, extracted with ethyl acetate (3 × 150mL), the organic extracts were washed with brine (150mL) and dried over sodium sulfate. The solution was evaporated in vacuo and the residue triturated with hexanes to give the title compound as a white solid in 63% yield, 10.0g.

¹H NMR(400MHz，DMSO-D₆)δ：1.64(s，6H)，3.85(d，2H)，4.99(t，1H)，7.82(s，1H)，8.63(s，1H)。

Pathway b

Diisobutylaluminum hydride (300mL, 300mmol, 1M in THF) was added dropwise to methyl 2- (2-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-methylpropionate (51.8g, 136mmol) (see preparation 41) in THF (150mL) at 0 ℃. The mixture was stirred for 90 minutes, then methanol (27.9mL) and aqueous HCl (20mL, 2M) were heated. Water (100mL), aqueous HCl (280mL, 2M) and EtOAc (150mL) were added and the mixture was stirred at room temperature for 30 min. The mixture was filtered and the solid washed with water (150mL) and tert-butyl methyl ether (150mL) to give the title compound as a white solid in 56% yield, 26.8g.

LCMS (System 1) R_t=4.88min；m/z352[M+H]⁺.

Preparation 44: 7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -2-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine

Tert-butyldimethylsilyl chloride (78.8g, 518mmol) was added to 2- (2-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-methylpropan-1-ol (140g, 398mmol) (see preparation 43) and imidazole (67.8g, 996mmol) in DMF (996mL) at 0 ℃. The mixture was stirred at room temperature for 16 hours. The mixture was poured into saturated aqueous sodium bicarbonate (1500mL) and extracted with heptane: EtOAc (1:1, 1500 mL). The organic extracts were washed with brine (2x900mL) then dried over magnesium sulfate and evaporated in vacuo to give the title compound as a brown gum in 96% yield, 178.2g.

LCMS (System 1) R_t=8.32min；m/z466[M+H]⁺.

Preparation 45: 2-chloro-7- [1, 1-dimethyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -5-iodo-7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared according to the procedure described for preparation 6 using 2- (2-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-methylpropan-1-ol (see preparation 43) to give the title compound as a yellow oil in 74% yield, 7.3g.

LCMS (System 5) R_t=4.01min；m/z436[M+H]⁺.

Preparation 46: (5-Bromopyridin-3-yl) [7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -2-chloro-7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] methanone

The title compound was prepared according to the procedure described for preparation 28 using 7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -2-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (see preparation 44) and 5-bromo-N-methoxy-N-methylnicotinamide to give the title compound as a yellow solid in 42% yield, 1.40g.

¹H NMR(400MHz，CDCl₃)δ：-0.18(s，6H)，0.63(s，9H)，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)。

Preparation 47: (5-Bromopyridin-3-yl) { 2-chloro-7- [1, 1-dimethyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone

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

¹H NMR(400MHz，CDCl₃)δ：1.42-1.62(m，6H)，1.83(s，6H)，3.35-3.39(m，1H)，3.53-3.56(m，1H)，3.85(d，1H)，4.22(d，1H)，4.47(m，1H)，7.98(s，1H)，8.25(s，1H)，8.87(s，1H)，8.94(s，1H)，9.45(s，1H)。

Preparation 48: [ 2-amino-7- (2-hydroxy-1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] (5-aminopyridin-3-yl) methanone

The method according to preparation 36

The title compound was prepared using (5-bromopyridin-3-yl) [7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -2-chloro-7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] methanone (see preparation 46) as a yellow solid in 48% yield, 300 mg.

¹H NMR(400MHz，DMSO-D₆)δ：1.64(s，6H)，3.90(d，2H)，5.07(t，1H)，5.60(s，2H)，6.50(s，2H)，7.23(s，1H)，7.61(s，1H)，8.11(m，2H)，8.93(s，1H)。

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

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

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

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

LCMS (System 5) R_t=2.72min；m/z411[M+H]⁺.

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

Isopropylmagnesium chloride (105mL, 210mmol, 2.0M in THF) was added to 7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -2-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (89.0g, 190mmol) (see preparation 44) in THF (450mL) at 0 deg.C under nitrogen. The mixture was stirred at 0 ℃ for 1 h, then a solution of 5- [ (diphenylmethylene) amino ] -N-methoxy-N-methylnicotinamide (72.6g, 210mmol) (see preparation 23) in THF (200mL) was added dropwise at 0 ℃. The mixture was warmed to room temperature and stirred at that temperature for 16 hours. The reaction mixture was quenched with 10% aqueous ammonium chloride (500mL) and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (2 × 300 mL). The combined organic extracts were washed with brine (400mL), dried over sodium sulfate, evaporated in vacuo and the crude material was purified by silica gel column chromatography (heptane: EtOAc100: 0-60: 40 gradient) to give the title compound as a colorless gum in 66% yield, 78.9g.

LCMS (System 1) R_t=8.60min；m/z624[M+H]⁺.

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

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

The crude residue was dissolved in THF (200mL) and aqueous citric acid (200mL, 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 (300mL) and the aqueous extract was washed with aqueous potassium carbonate (300mL, 2M). The organic phase was dried over magnesium sulfate, evaporated in vacuo and the residue purified by silica gel column chromatography (pentane: EtOAc100: 0-0: 100 gradient then EtOAc: MeOH95:5) to give the title compound as a colorless oil, 78% yield, 39.0g.

LCMS (System 1) R_t=5.97min；m/z591[M+H]⁺.

Preparation 52: n- [5- ({ 2-amino-7- [1, 1-dimethyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } carbonyl) pyridin-3-yl ] -2- (4-cyclopropyl-1H-1, 2, 3-triazol-1-yl) acetamide

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

LCMS (system 5): r_t=2.87min；m/z560[M+H]⁺.

Preparation 53: (R, S) methyl 2- (2-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) propionate

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

¹H NMR(400MHz，CDCl₃)δ：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-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) propan-1-ol

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

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

Preparation 55: 7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl) -2-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine

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

¹H NMR(400MHz，CDCl₃)δ：-0.09(s，6H)，0.80(s，9H)，1.53(d，3H)，3.80(d，2H)，5.04(m，1H)，7.46(s，1H)，8.55(s，1H)。

The enantiomers were separated using Chiralpak IC20X250mm, 98:2:0.1 heptane: IPA: diethylamine (flow-rate-18.0 mL/min).

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

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

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

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

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

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

The method according to preparation 36

The title compound was prepared using (5-bromopyridin-3-yl) [7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl) -2-chloro-7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] methanone (see preparation 56) as a yellow solid in 51% yield, 450 mg.

¹H NMR(400MHz，DMSO-D₆)δ：141(d, 3H), 3.66(m, 2H), 4.74(m, 1H), 5.01(t, 1H), 5.59(s, 2H), 6.55(s, 2H), 7.22(s, 1H), 7.83(s, 1H), 8.11-8.13(m, 2H), 8.91(s, 1H); LCMS (System 5) R_t=1.72min；m/z313[M+H]⁺.

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

The title compound was prepared according to the procedure described for preparation 28 using 7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl) -2-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (see preparation 55, enantiomer 2) and 5-bromo-N-methoxy-N-methylnicotinamide to give the title compound as a yellow solid in 30% yield, 1.4g.

Preparation 59: [ 2-amino-7- (2-hydroxy-1-methylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] (5-aminopyridin-3-yl) methanone (enantiomer 2)

The method according to preparation 36

The title compound was prepared using (5-bromopyridin-3-yl) [7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl) -2-chloro-7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] methanone (see preparation 58) as a yellow solid in 51% yield, 450 mg.

LCMS (System 5) R _t=1.70min；m/z313[M+H]⁺.

Preparation 60: 5-bromo-N-tert-butyl-2-chloropyrimidin-4-amine

Tert-butylamine (5.28g, 72mmol) was added to 5-bromo-2, 4-dichloropyrimidine (15g, 66mmol) and triethylamine (19.9g, 197mmol) in acetonitrile (450mL) at room temperature and the mixture was stirred at room temperature for 16 h. The mixture was then evaporated in vacuo and the crude residue partitioned between EtOAc (450mL) and water (400 mL). The organic layer was separated, washed with brine (400mL), then dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane: EtOAc88:12) to give the title compound as a yellow oil, 52% yield, 8.8g.

LCMS (system 5): r_t=3.46min；m/z265[M+H]⁺.

Preparation 61: n-tert-butyl-2-chloro-5- [ (E) -2-ethoxyvinyl ] pyrimidin-4-amine

Catechol borane (7.8g, 65.4mmol) in THF (50mL) was added dropwise to a 40% solution of ethoxyacetylene in hexane (12.8mL, 72.5mmol) at 0-5 ℃ under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours and then heated at 70 ℃ for 2 hours. The mixture was then cooled to room temperature and a solution of 5-bromo-N-tert-butyl-2-chloropyrimidin-4-amine (10g, 37.8mmol) (see preparation 60) in THF (50mL) was added. The solution was degassed with argon for about 25 minutes, then Pd (PPh) was added ₃)₄(1.3g, 1.13mmol) and sodium hydroxide powder (4.53g, 113 mmol). Subjecting the mixture to a temperature of 70 deg.CHeated for 16 hours and then cooled to room temperature. EtOAc (200mL) was added and passed through Celite^TMThe pad filters the mixture. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (hexanes: EtOAc93: 7-90: 10 gradient) to give the title compound as a yellow oil in 55% yield, 5.3g.

LCMS (system 5): r_t=3.65min；m/z256[M+H]⁺.

Preparation 62: 7-tert-butyl-2-chloro-7H-pyrrolo [2,3-d ] pyrimidine

Concentrated HCl (25mL) was added to N-tert-butyl-2-chloro-5- [ (E) -2-ethoxyvinyl) in isopropanol (210mL)]To pyrimidin-4-amine (5.3g, 20.72mmol) (see preparation 61) the mixture was heated at reflux for 4 hours. The reaction mixture was then evaporated in vacuo and saturated NaHCO₃The residue was basified with aqueous solution and extracted with EtOAc (200 mL). The organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexanes: EtOAc93: 7-90: 10 gradient) to give the title compound as a yellow oil in 85% yield, 3.7g.

LCMS (system 5): r_t=3.42min；m/z210[M+H]⁺.

Preparation 63: 7-tert-butyl-2-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared according to the procedure described for preparation 14 using 7-tert-butyl-2-chloro-7H-pyrrolo [2,3-d ] pyrimidine (see preparation 62) to give the title compound as a brown solid in 87% yield, 4.7g.

¹H NMR(400MHz，CDCl₃)δ：1.55(s，9H)，7.39(s，1H)，8.54(s，1H)。

Preparation of 64: (5-Bromopyridin-3-yl) (7-tert-butyl-2-chloro-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone

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

¹H NMR(400MHz，CDCl3)δ：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-amino-7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (5-aminopyridin-3-yl) methanone

The title compound was prepared according to the procedure described for preparation 36 using (5-bromopyridin-3-yl) (7-tert-butyl-2-chloro-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (see preparation 64) to give the title compound as a white solid in 55% yield of 870 mg.

LCMS (system 5): r_t=2.42min；m/z311[M+H]⁺.

Preparations 66-70 were prepared according to example 1 starting from (5-aminopyridin-3-yl) {7- [ (1S) -2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone of the formula (see preparation 37) and the appropriate acid:

preparations 71-78 were prepared according to example 1 starting from (5-aminopyridin-3-yl) [7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] methanone of the formula (see preparation 38):

Preparation of 79: (3-cyclopropyl-1H-pyrazol-1-yl) acetic acid ethyl ester

Potassium carbonate (7.67g, 55.56mmol) was added to 3-cyclopropyl-1H-pyrazole (2.0g, 18.52mmol) in dry DMF (20mL) at 25 ℃ and the mixture was stirred for 20 min. Ethyl bromoacetate (2.06mL, 18.52mmol) was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was neutralized with aqueous HCl (1.0M), extracted with ether (40mL), and the organic extracts were washed with brine (30mL), dried over sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane: EtOAc88:12) to give the title compound as a yellow oil, 42% yield, 1.50g.

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

Preparation 80: (3-cyclopropyl-1H-pyrazol-1-yl) acetic acid

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

LCMS (system 4): r_t=1.16min；m/z167[M+H]⁺.

Preparation 81: [4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl ] acetic acid

Trifluoromethylacetylene (22.0g, 0.234mol) in THF (210mL) was added to a solution of sodium ascorbate (2.77g, 14.0mmol), ethyl azidoacetate (27.1g, 0.210mol) and copper sulfate (4.76mL, 0.3M in water) in water (105 mL). The mixture was stirred at room temperature for 240 hours and then evaporated in vacuo. The residue was taken up in EtOAc (500mL) and the organic phase was dried over magnesium sulfate and evaporated in vacuo. A solution of sodium hydroxide (7.32g, 0.183mol) in water (30mL) was added to the residue (32.7g, 0.146mol) in methanol (50mL) and the mixture was stirred at room temperature for 17 h. The methanol was evaporated in vacuo and the residue diluted with water (10 mL). A solution of potassium bisulfate (26.6g, 0.195mol) in water (70mL) was added. The solution was evaporated in vacuo and the crude solid was purified by crystallization using water to give the title compound as a white solid in 75% yield, 25.8g.

¹H NMR(400MHz，DMSO-d6)δ：5.40(s，2H)，8.85(s，1H)，13.50(br s，1H)。

Preparation 82: (4-cyclopropyl-1H-1, 2, 3-triazol-1-yl) acetic acid ethyl ester

Cyclopropylacetylene (15g, 0.116mol), ethyl azidoacetate (11.5g, 0.174mol), triethylamine (0.32mL, 2.33mmol) and copper iodide (442mg, 2.33mmol) in acetonitrile (100mL) were stirred at 25 ℃ for 18 h. The mixture was evaporated in vacuo, the residue partitioned between water (100mL) and ethyl acetate (100mL), the organic phase dried over sodium sulfate, evaporated in vacuo and purified by silica gel column chromatography (EtOAc: hexane 40: 60) to give the title compound as a colorless liquid in 95% yield, 21.6g.

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

Preparation 83: (4-cyclopropyl-1H-1, 2, 3-triazol-1-yl) acetic acid

The title compound was prepared according to the procedure described for preparation 42 using ethyl (4-cyclopropyl-1H-1, 2, 3-triazol-1-yl) acetate (see preparation 82) to give the title compound as a yellow solid in 63% yield, 13.0g.

LCMS (system 4): r_t=1.86min；m/z186[M+H]⁺.

Preparation 84: [4- (trifluoromethyl) -1H-pyrazol-1-yl ] acetic acid tert-butyl ester

The title compound was prepared according to the procedure described for preparation 79 using 4- (trifluoromethyl) -1H-pyrazole and tert-butyl bromoacetate to give the title compound as a yellow solid in 24% yield, 1.32g.

LCMS (system 4): r_t=3.64min；m/z251[M+H]⁺.

Preparation 85: [4- (trifluoromethyl) -1H-pyrazol-1-yl ] acetic acid

A solution in trifluoroacetic acid (10mL) was added to tert-butyl [4- (trifluoromethyl) -1H-pyrazol-1-yl ] acetate (1.3g, 5.2mmol) (see preparation 84) in dry DCM (10mL), the mixture was stirred at 25 ℃ for 18H, then the mixture was evaporated in vacuo and the residue was purified by trituration with ether pentane (1:9, 2mL) to give the title compound as a white solid in 79% yield, 800 mg.

LCMS (system 4): r_t=1.39min；m/z193[M+H]⁺.

Preparation 86: [ 4-bromo-1H-pyrazol-1-yl ] acetic acid tert-butyl ester

The title compound was prepared according to the procedure described for preparation 79 using 4-bromo-1H-pyrazole and tert-butyl bromoacetate to give the title compound as a yellow solid in 34% yield, 48.0g.

¹H NMR(400MHz，CDCl3)δ：1.42(s，9H)，4.70(s，2H)，7.40(s，2H)。

Preparation 87: (4-cyclopropyl-1H-pyrazol-1-yl) acetic acid tert-butyl ester

Palladium acetate (215mg, 0.957mmol) was added to the reaction solution in toluene: [ 4-bromo-1H-pyrazol-1-yl ] in water (60mL:15mL)]Tert-butyl acetate (5g, 19.14mmol) (cf. preparation 86), cyclopropylboronic acid (8.22g, 95.74mmol), potassium phosphate (8.12g, 38.29mmol) and tricyclohexylphosphine (537mg, 1.91 mmol). The mixture was degassed for 20 minutes and then refluxed for 18 hours. Through Celite^TMThe reaction mixture was filtered, the filtrate concentrated in vacuo, and the residue purified by silica gel column chromatography (EtOAc: hexane 15: 85 gradient) to give the title compound as an off-white solid, 21% yield, 1.3g.

LCMS (system 4): r_t=3.17min；m/z223[M+H]⁺.

Preparation 88: (4-cyclopropyl-1H-pyrazol-1-yl) acetic acid

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

LCMS (system 4): r_t=1.13min；m/z165[M+H]⁺.

Preparation 89: (5-Chloropyridin-2-yl) acetic acid ethyl ester

Cesium carbonate (71g, 218mmol) was added to dry 1, 4-bisIn 2-bromo-5-chloropyridine (14g, 73mmol) and diethyl malonate (22mL, 145mmol) in an alkane (280mL), the solution was degassed with argon for 30 minutes, copper (I) oxide (2.8g, 14.55mmol) and picolinic acid (3.6g, 29mmol) were then added, and the mixture was stirred in a sealed vessel at 130 ℃ for 24 hours. The mixture was cooled to room temperature, quenched with water (100mL), and extracted with EtOAc (3 × 100 mL). The organic extracts were washed with water (200mL), brine (200mL), dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (EtOAc: hexane 92: 8) to give the title compound as a yellow oil, 54% yield, 8.0g.

¹H NMR(400MHz，DMSO-d₆)δ：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-Chloropyridin-2-yl) acetic acid

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

LCMS (system 4): r_t=1.00min；m/z172[M+H]⁺.

Preparation 91: (5-Fluoropyridin-2-yl) acetic acid ethyl ester

The title compound was prepared according to the procedure described for preparation 89 using 2-bromo-5-fluoropyridine to give the title compound as a yellow oil in 20% yield, 5g.

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

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

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

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

Preparation 93: 5-iodo-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine

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

¹H NMR(400MHz，CDCl₃) δ: 1.53(d, 6H), 5.15(m, 1H), 7.40(s, 1H), 8.73(s, 1H), 8.88(s, 1H); LCMS (system 2): r_t=1.02min；m/z288[M+H]⁺.

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

To a stirred solution of 5-iodo-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine (preparation 93, 4.85g, 16.9mmol) in THF (90mL) was added isopropylmagnesium chloride (9.28mL, 18.6mmol, 2.0M in ether) at 0 deg.C under a nitrogen atmosphere. The mixture was stirred at 0 ℃ for 1 hour, then a solution of 5-bromo-N-methoxy-N-methylnicotinamide (preparation 227, 4.55g, 18.6mmol) in THF (10mL) was added dropwise at 0 ℃. The mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (200mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were concentrated under reduced pressure and purified by silica gel column chromatography eluting with a gradient of EtOAc: DCM95: 5-50: 50 to give a light brown oil. The crude material was recrystallized using EtOAc: heptane (15:200mL) to give the title compound as a white solid in 33% yield, 2.16g.

¹H NMR(400MHz，CDCl₃) δ: 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_t=1.36min；m/z346[M+H]⁺.

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

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

¹H NMR(400MHz，CDCl₃) δ: 1.58(d, 6H), 3.98(br s, 2H), 5.18(m, 1H), 7.39(dd, 1H), 7.89(s, 1H), 8.29(br s, 1H), 8.43(br s, 1H), 9.01(s, 1H), 9.59(s, 1H); LCMS (system 2): r_t=0.50min；m/z282[M+H]⁺.

Preparation 96: 4-chloro-7-oxetan-3-yl-7H-pyrrolo [2,3-d ] pyrimidine

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

LCMS (system 1): r_t=1.92min；m/z210，212[M+H]⁺.

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

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

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

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

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

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

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

The title compound was prepared according to the procedure described for preparation 94 using 5-iodo-7-oxetan-3-yl-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(400MHz，DMSO-d₆)δ：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)。

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

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

¹H NMR(400MHz，DMSO-d₆)δ：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-iodo-7- { [2- (trimethylsilyl) ethoxy ] methyl } -7H-pyrrolo [2,3-d ] pyrimidine

To a stirred solution of 5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (preparation 201, 735mg, 3.00mmol) in DMF (5mL) at 0 deg.C was added sodium hydride (132mg, 3.30mmol, 60% in oil). The mixture was stirred at room temperature for 30 minutes, cooled to-20 ℃ and 2- (trimethylsilyl) ethoxymethyl chloride (0.58mL, 3.30mmol) was added. The reaction mixture was stirred at-20 ℃ for 3 hours, then water (30mL) was added. The mixture was extracted with EtOAc (2 × 50mL), the combined organic phases were dried over magnesium sulfate, evaporated under reduced pressure, and the crude solid was purified by silica gel column chromatography eluting with a gradient of heptane: EtOAc100: 0-50: 50) to give the title compound as a white solid in 61% yield, 691 mg.

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

Preparation 102: {5- [ (diphenylmethylene) amino ] pyridin-3-yl } (7- { [2- (trimethylsilyl) ethoxy ] methyl } -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone

The title compound was prepared according to the procedure described for preparation 28 using 5-iodo-7- { [2- (trimethylsilyl) ethoxy ] methyl } -7H-pyrrolo [2,3-d ] pyrimidine (preparation 101) and 5- [ (diphenylmethylene) amino ] -N-methoxy-N-methylnicotinamide (preparation 23) to give the title compound as a yellow oil in 32% yield, 460 mg.

¹H NMR(400MHz，DMSO-d₆) δ: -0.11(s, 9H), 0.84(m, 2H), 3.59(m, 2H), 5.71(s, 2H), 7.27(m, 2H), 7.37(m, 3H), 7.51(m, 2H), 7.59(m, 2H), 7.73(d, 2H), 8.22(d, 1H), 8.38(s, 1H), 8.56(d, 1H), 9.00(s, 1H), 9.45(s, 1H); LCMS (system 9): r_t=2.36min；m/z534[M+H]⁺.

Preparation 103: (5-Aminopyridin-3-yl) (7- { [2- (trimethylsilyl) ethoxy ] methyl } -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone

The title compound was prepared according to the procedure described for preparation 37 using {5- [ (diphenylmethylene) amino ] pyridin-3-yl } (7- { [2- (trimethylsilyl) ethoxy ] methyl } -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 102) to give the title compound as a colorless oil in 73% yield, 2.10g.

¹H NMR(400MHz，DMSO-d₆) δ: 0.09(s, 9H), 0.84(t, 2H), 3.60(t, 2H), 5.66(m, 4H), 7.30(s, 1H), 8.18(s, 2H), 8.55(s, 1H), 9.02(s, 1H), 9.47(s, 1H); LCMS (system 9): r_t=3.25min；m/z370[M+H]⁺.

Preparation 104: 2- (4-chlorophenyl) -N- (5- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl) pyridin-3-yl) acetamide

The title compound was prepared according to the method described for examples 73-87 using (5-aminopyridin-3-yl) (7- { [2- (trimethylsilyl) ethoxy ] methyl } -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 103) and 4-chlorophenylacetic acid to give the title compound as a white solid in 66% yield, 223 mg.

¹H NMR(400MHz，DMSO-d₆)δ：-0.11(s，9H)，0.82(t，3H)，3.60(t，2H)，3.74(s，2H)，5.70(s，2H)，7.37(t，4H)，8.47(s，1H)，8.60(s，2H)，8.72(s，1H)，8.98(s，1H)，9.03(s，1H)，9.48(s，1H)；

LCMS (system 9): r_t=3.50min；m/z522[M+H]⁺.

Preparation 105: n- [5- ({7- [ (1S) -2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } carbonyl) pyridin-3-yl ] -2- [3- (trifluoromethyl) phenyl ] acetamide

Prepared according to example 1 using (S) (5-aminopyridin-3-yl) {2- { [ tert-butyl (dimethyl) silyl ] oxy } -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone (preparation 37) and 3-trifluoromethylphenyl acetic acid with DIPEA as base.

¹H NMR(400MHz，DMSO)δ：-0.24(s，3H)，-0.18(s，3H)，0.56(s，9H)，1.52(d，3H)，3.86(m,3H)，3.94(m，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_t=3.89min；m/z598[M+H]⁺.

Preparation 106: 5- [ (diphenylmethylene) amino ] nicotinamide

To a stirred solution of 5- [ (diphenylmethylene) amino ] -N-methoxy-N-methylnicotinamide (preparation 23, 7.50g, 0.021mol) in THF (150mL) was added diisopropylaluminum hydride (42mL, 0.042mol, 1.0M solution in THF) at-70 deg.C, and the resulting mixture was stirred at-70 deg.C for 2 hours. Water (20mL) and ethyl acetate (100mL) were added. The organic phase was separated, concentrated under reduced pressure and purified by silica gel column chromatography using EtOAc: petroleum ether 1:10 elution gave the title compound as a brown solid in 65% yield, 4g.

The title compound can also be prepared according to the following method:

mixing 5-bromonicotinaldehyde (2790mg, 15.0mmol), diphenylmethylamine (3.01mL, 18mmol) and Pd₂(dba)₃(412mg, 0.45mmol), di-tert-butyl (2',4',6 '-triisopropyl- [1,1' -biphenyl)]-2-yl) phosphine (510mg, 1.2mmol) and K₃PO₄(7960mg, 37.5mmol) was stirred in DME (30.0mL) at 50 deg.C for 16 h. After cooling to room temperature, the reaction was quenched with dilute DCM (50mL) and the mixture was passed through a pad of arbocel. The filter cake was washed with DCM (50mL) and the filtrate was concentrated under reduced pressure.The crude material was recrystallized from ethyl acetate/heptane to give the desired compound as a solid in 78% yield of 3341mg.

1H NMR(400MHz，DMSO-d₆)δ：7.18-7.26(m，2H)，7.30-7.39(m，3H)，7.47-7.54(m，2H)，7.55-7.62(m，2H)，7.68-7.75(m，2H)，8.25(d，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-disilaundecane-6-ol

To a stirred solution of glycerol (4.01mL, 55mmol) and imidazole (18.7g, 275mmol) in DMF (150mL) was added tert-butyldimethylsilyl chloride (17.2g, 113mmol) in DMF (33mL) at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 16 hours. Water (500mL) was added to the reaction mixture and the resulting mixture was extracted with heptane (500mL x 3). The combined organic layers were washed with water (300mL) and MgSO₄Drying, and concentrating under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient of heptane to EtOAc100: 0-80: 20 eluent to give the title compound as a colorless oil, 68% yield, 11.9g.

1H NMR(400MHz，DMSO-d₆)δ：0.03(s，12H)，0.86(s，18H)，3.40-3.59(m，5H)，4.58(d，1H)。

Preparation 108: trifluoromethanesulfonic acid 2,2,3,3,9,9,10, 10-octamethyl-4, 8-dioxa-3, 9-disilaundecan-6-yl ester

To a stirred solution of 2,2,3,3,9,9,10, 10-octamethyl-4, 8-dioxa-3, 9-disilaundecan-6-ol (preparation 107, 6410mg, 20mmol) and pyridine (2.42mL, 30mmol) in DCM (40mL) was added trifluoromethanesulfonic anhydride (5.05mL, 30mmol) at-50 deg.C and the reaction was stirred for 2 hours at-30 deg.C. 1N aqueous HCl (40mL) was added to the reaction and the mixture was extracted with DCM (40mL x 3). The combined organic layers were concentrated under reduced pressure to give a colorless gel that was used in the next step without further purification (preparation 196).

Preparation 109: 4-chloro- [ 7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] {5- [ (diphenylmethylene) amino ] pyridin-3-yl } methanone

The title compound was prepared according to the procedure described for preparation 28, then preparation 30, using 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine (preparation 226) and 5- [ (diphenylmethylene) amino ] nicotinaldehyde (preparation 106) to afford the title compound as a yellow solid (11.0g, 48%).

¹H NMR(400MHz，CDCl₃)δ：3.87(s，3H)，7.06(m，2H)，7.28(m，2H)，7.37(m，2H)，7.45(m，3H)，7.70(m，3H)，8.15(d，1H)，8.49(d，1H)，8.69(s，1H)。

Preparation 110: (5-Aminopyridin-3-yl) (7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone

Citric acid (2M, 200mL) was added to 4-chloro- [ 7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] {5- [ (diphenylmethylene) amino ] pyridin-3-yl } methanone (preparation 109, 30g, 0.066mol) in THF (200mL) and the mixture was stirred at room temperature for 30 min. Ether (200mL) was added and the phases separated. The aqueous layer was neutralized with aqueous sodium carbonate solution, then the solid was collected by filtration and dried in vacuo to give (5-aminopyridin-3-yl) (4-chloro-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone as a brown solid, 18g, 95%

Methanethiol sodium salt (15.5g, 0.22mol) was added to 5-aminopyridin-3-yl) (4-chloro-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (21g, 0.073mol) in methanol (300mL) and the mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into ice-water (200mL) and the precipitate was filtered. The filter cake was washed with water (100mL) and then acetone (20mL) to give (5-aminopyridin-3-yl) [ 7-methyl-4- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] methanone as a brown solid, 15g, 69%

Raney nickel (10g) was added to the reaction mixture at 1,4(5-Aminopyridin-3-yl) [ 7-methyl-4- (methylthio) -7H-pyrrolo [2,3-d ] in an alkane (150mL)]Pyrimidin-5-yl]Methanone (1.5g, 5.0mmol) and concentrated ammonia (150 mL). The mixture was refluxed for 6 hours and then filtered. The filtrate was concentrated in vacuo and purified by preparative HPLC (method 4) to give the title compound as a brown solid in 100% yield, 1.9g.

¹H NMR(400MHz，DMSO-D6)δ：3.88(s，3H)，5.63(s，2H)，7.27(m，1H)，8.14-8.18(m，2H)，8.40(s，1H)，8.97(s，1H)，9.42(s，1H)。

Preparation 111: 2,2,3,3,6,9,9,10, 10-nonamethyl-4, 8-dioxa-3, 9-disilaundecane-6-amine

The title compound was prepared according to the procedure described for preparation 44, using 2-amino-2-methyl-1, 3-propanediol to give the title compound as a colorless oil in 100% yield, 23.0g.

¹H NMR(400MHz，CDCl₃)δ：0.05(s，12H)，0.87-0.99(m，21H)，3.36-3.42(m，4H)。

Preparation of 112: 7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -1-methylethyl ] -4-chloro-7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared according to the procedure described for preparation 1 using 2,2,3,3,6,9,9,10, 10-nonamethyl-4, 8-dioxa-3, 9-disilaundecane-6-amine (preparation 111) to give the title compound as a colorless gum in 75% yield, 8.91g.

¹H NMR(400MHz，CDCl₃)δ：0.09-0.11(m，12H)，0.78-0.79(m，18H)，1.74(s，3H)，4.06-4.09(m，2H)，4.29-4.31(m，2H)，6.52(m，1H)，7.44-7.45(m，1H)，8.56(m，1H)。

Preparation 113: 7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared according to the procedure described for preparation 8 using 7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -1-methylethyl ] -4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (preparation 112) to give the title compound as a yellow oil in 99% yield, 8.14g.

¹H NMR(400MHz，CDCl₃)δ：-0.13(s,6H)，-0.10(s,6H)，0.78(s,18H)，1.75(s，3H)，4.11(d，2H)，4.33(d，2H)，6.45(d，1H)，7.41(d，1H)，8.78(s,1H)，8.90(s，1H)。

Preparation of 114: 7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -1-methylethyl ] -5-iodo-7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared according to the procedure described for preparation 14 using 7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidine (preparation 113) to give the title compound as a yellow oil in 88% yield, 7.98g.

¹H NMR(400MHz，CDCl₃)δ：-0.10(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: {7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } {5- [ (diphenylmethylene) amino ] pyridin-3-yl } methanone

The title compound was prepared according to the procedure described for preparation 28 using 7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -1-methylethyl ] -5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (preparation 114) and 5- [ (diphenylmethylene) amino ] -N-methoxy-N-methylnicotinamide (preparation 23) to give the title compound as a yellow foam in 69% yield, 1.76g.

¹H NMR(400MHz，CDCl₃)δ：0.10-0.12(m，12H)，0.73-0.76(m，18H)，1.77(s，3H)，4.06-4.09(m，2H)，4.34-4.36(m，2H)，7.11-7.16(m，2H)，7.28-7.33(m，3H)，7.42-7.47(m，2H)，7.50-7.54(m，2H)，7.78-7.80(m，2H)，7.93(s，1H)，8.15-8.16(m，1H)，8.56(m，1H)，8.94(s，1H)，9.58(s，1H)。

Preparation 116: (5-Aminopyridin-3-yl) {7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone

The title compound was prepared according to the procedure described for preparation 37 using {7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -1-methylethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } {5- [ (diphenylmethylene) amino ] pyridin-3-yl } methanone (preparation 115) to give the title compound as a yellow foam in 85% yield, 1.15g.

LCMS (system 1): r_t=4.01min；m/z556[M+H]⁺.

Preparation 117: 1-isopropyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester

To a suspension of ethyl 5-trifluoromethyl-1H-pyrazole-4-carboxylate (13g, 62.5mmol) and cesium carbonate (61.1g, 187.5mmol) in DMF (70mL) was added 2-iodo-propane (6.86mL, 68.75mmol) and the resulting mixture was stirred at rt for 16H. The crude reaction mixture was poured onto water (100mL) and extracted with EtOAc (100mL × 3). The combined organic layers were washed with water (50mL x2), brine (50mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as an off-white solid in 65% yield, 10.2g.

¹H NMR(400MHz，CDCl₃) δ: 1.33(t, 3H), 1.53(d, 6H), 4.30(q, 2H), 4.50-4.57(m, 1H), 8.00(s, 1H); LCMS (system 9): r_t=3.55min；m/z251[M+H]⁺.

Preparation 118: (1-isopropyl-3-trifluoromethyl-1H-pyrazol-4-yl) -methanol

The title compound was prepared according to the procedure described for preparation 183 using ethyl 1-isopropyl-3-trifluoromethyl-1H-pyrazole-4-carboxylate (preparation 117) to give the title compound as an off-white solid in 97% yield, 8.3g.

¹H NMR(400MHz，CDCl₃) δ: 1.50(d, 6H), 1.72(t, 1H), 4.47-4.54(m, 1H), 4.65(d, 2H), 7.50(s, 1H); LCMS (system 9): r_t=2.77min；m/z209[M+H]⁺.

Preparation 119: (1-isopropyl-3-trifluoromethyl-1H-pyrazol-4-yl) -acetonitrile

The title compound was prepared according to the procedure described for preparation 184 using (1-isopropyl-3-trifluoromethyl-1H-pyrazol-4-yl) -methanol (preparation 118) to give the title compound as an off-white solid in 58% yield, 5g.

¹H NMR(400MHz，DMSO-d₆)δ：1.42(d，6H)，3.92(s，2H)，4.56-4.63(m，1H)，8.06(s，1H)。

Preparation 120: 2-chloro-5-iodo-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared as a white solid in 87% yield 5.5g according to the procedure described for preparation 93 using 2-chloro-5-iodo-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine (preparation 40).

¹H NMR(400MHz，CDCl₃) δ: 1.50(d, 6H), 5.10(m, 1H), 7.36(s, 1H), 8.55(s, 1H); LCMS (System 10) R _t=3.6min；m/z322[M+H]⁺.

Preparation 121: (5-Bromopyridin-3-yl) (2-chloro-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone

The title compound was prepared according to the procedure described for preparation 28 using 2-chloro-5-iodo-7-isopropyl-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, 1.2g.

¹H NMR(400MHz，DMSO-D₆)δ：1.54(d，6H)，5.02(m，1H)，8.41(d，1H)，8.63(s，1H)，9.0(m，2H)，9.33(s，1H)。

Preparation 122: (2-amino-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (5-aminopyridin-3-yl) methanone

The title compound was prepared according to the procedure described for preparation 31 using (5-bromopyridin-3-yl) (2-chloro-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 121) to give the title compound as a yellow solid in 58% yield, 500 mg.

¹H NMR(400MHz，DMSO-D₆) δ: 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_t=0.99min；m/z297[M+H]⁺.

Preparation 123: (1-isopropyl-3-trifluoromethyl-1H-pyrazol-4-yl) -acetic acid

The title compound was prepared according to the procedure described for preparation 185 using (1-isopropyl-3-trifluoromethyl-1H-pyrazol-4-yl) -acetonitrile (preparation 119) to give the title compound as an off-white solid in 82% yield, 4.5g.

¹H NMR(400MHz，DMSO-d₆) δ: 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 _t=1.56min；m/z235[M-H]^-.

Preparation 124: (3-cyclopropyl-1-methyl-1H-pyrazol-4-yl) -acetonitrile

To a suspension of potassium tert-butoxide (8.95g, 79.9mmol) in DME (250mL) at-78 deg.C under a nitrogen atmosphere was added a solution of 1- (isocyanomethylsulfonyl) -4-methylbenzene (9.36g, 47.94mmol) in DME (50 mL). After stirring for 10 min, a solution of 3-cyclopropyl-1-methyl-1H-pyrazole-4-carbaldehyde (6g, 39.95mmol) in DME (100mL) was added. The resulting mixture was stirred at-78 ℃ for 1 hour, then at room temperature for 1 hour. Methanol (50mL) was added and the resulting mixture was refluxed for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (200mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (2 × 50mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with hexanes: EtOAc90:10 to give the title compound as an off-white solid in 67% yield, 4.3g.

¹H NMR(400MHz，DMSO-d₆) δ: 0.67-0.7(m, 2H), 0.79-0.83(m, 2H), 1.75-1.80(m, 1H), 3.68(s, 3H), 3.79(s, 2H), 7.54(s, 1H); LCMS (system 9): r_t=2.53min；m/z162[M+H]⁺.

Preparation of 125: (3-cyclopropyl-1-methyl-1H-pyrazol-4-yl) -acetic acid

The title compound was prepared as a solid in 83% yield, 4g according to the procedure described for preparation 141 using (3-cyclopropyl-1-methyl-1H-pyrazol-4-yl) -acetonitrile (preparation 124).

¹H NMR(400MHz，DMSO-d₆) δ: 0.62-0.66(m, 2H), 0.73-0.77(m, 2H), 1.67-1.74(m, 1H), 3.38(s, 2H), 3.66(s, 3H), 7.40(s, 1H), 12.22(br, 1H); LCMS (system 9): r_t=1.97min；m/z181[M+H]⁺.

Preparation 126: (3-cyano-4-fluoro-phenyl) -acetic acid

To a solution of (3-bromo-4-fluoro-phenyl) -acetic acid (10g, 42.9mmol) in DMF (65mL) was added copper (I) cyanide (7.7g, 85.8mmol) and heated at 130 ℃ for 24 hrs. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (250 mL). The organic layer was washed with water (5 × 50mL), brine (50mL), dried over sodium, filtered, and concentrated under reduced pressure. The crude material was recrystallized from ether and hexane to give the title compound as a yellow solid in 65% yield, 5g.

¹H NMR(400MHz，DMSO-d₆) δ: 3.68(s, 2H), 7.48(t, 1H), 7.66-7.71(m, 1H), 7.82(dd, 1H), 12.53(br s, 1H); LCMS (system 10): r_t=1.39min；m/z178[M-H]^-.

Preparation 127: (3-cyano-4-fluoro-phenyl) -acetic acid ethyl ester

To a suspension of (3-cyano-4-fluoro-phenyl) -acetic acid (500mg, 2.79mmol) (preparation 126) and potassium carbonate (770mg, 5.58mmol) in DMF (5mL) was added iodoethane (0.89mL, 11.16mmol), and the reaction mixture was stirred at room temperature for 4 h. The crude reaction mixture was poured onto water (10mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with water (5 × 10mL), brine (10mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as an off-white solid in 87% yield, 500mg.

¹H NMR(400MHz，CDCl₃)δ：1.26(t，3H)，3.61(s，2H)，4.16(q，2H)，7.17(t，1H)，7.49-7.55(m，2H)。

Preparation of 128: (3-amino-benzo [ d ]]Different from each otherAzol-5-yl) -acetic acid ethyl ester

To a solution of (3-cyano-4-fluoro-phenyl) -acetic acid ethyl ester (preparation 127, 400mg, 1.93mmol) and acetylhydroxamic acid (362mg, 4.83mmol) in DMF (40mL) and water (15mL) was added potassium carbonate (1.6g, 11.58mmol), and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water (100mL) and the resulting white precipitate was collected by filtration. The crude material was purified by silica gel column chromatography, eluting with dichloromethane: a gradient elution of methanol 100: 0-97: 3 gave the title compound as an off-white solid in 59% yield, 250mg.

LCMS (system 9): r_t=2.87min；m/z221[M+H]⁺.

Preparation of 129: (3-amino-benzo [ d ]]Different from each otherAzol-5-yl) -acetic acid

According to the method described for the preparation of 141, (3-amino-benzo [ d ] is used]Different from each otherOxazol-5-yl) -ethyl acetate (preparation 128) to give the title compound as an off-white solid in 69% yield, 30mg.

¹H NMR(400MHz，DMSO-d₆) δ: 3.65(s, 2H), 6.36(br s, 2H), 7.36-7.42(m, 2H), 7.69(s, 1H), 12.37(br s, 1H); LCMS (system 10): r_t=1.65min；m/z193[M+H]⁺.

Preparation 130: imidazo [1,2-a ] pyridin-7-yl-acetic acid ethyl ester

To stirred 7-bromo-imidazo [1,2-a ]]Pyridine (600mg, 3.0mmol) and diethyl malonate (0.93mL, 6.1mmol) in dry dioxane To a solution in alkane (15mL) was added cesium carbonate (3gm, 9.1 mmol). Argon was bubbled through the mixture for 10 min, then copper (I) iodide (116mg, 0.61mmol) and picolinic acid (150mg, 1.22mmol) were added. The resulting mixture was heated in a sealed tube at 130 ℃ for 24 hours. The reaction mixture was cooled to room temperature, quenched with water (10mL), and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 10mL), brine (10mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography, eluting with dichloromethane: methanol gradient elution 100: 0-98: 2 gave the title compound as an off-white gum in 29% yield, 180mg.

LCMS (system 10): r_t=2.61min；m/z205[M+H]⁺.

Preparation of 131: n- (5- { [7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] carbonyl } pyridin-3-yl) -2- (4-cyanophenyl) acetamide

Prepared as described for example 1 using (5-aminopyridin-3-yl) [7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] methanone (preparation 38) and 4-cyanophenylacetic acid with DIPEA.

¹H NMR(400MHz，DMSO)δ：-0.26(s，6H)，0.58(s，9H)，1.75(s，6H)，3.86(s，2H)，4.10(s，2H)，7.54(d，2H)，7.82(d，2H)，8.16(s，1H)，8.51(s，1H)，8.68(s，1H)，8.88(s，1H)，8.98(s，1H)，9.47(s，1H)，10.73(s，1H)；

LCMS (system 9): r_t=3.80min；m/z569[M+H]⁺.

Preparation 132: imidazo [1,2-a ] pyridin-7-yl-acetic acids

To imidazo [1,2-a ] at 0 DEG C]Pyridin-7-yl-acetic acid ethyl ester (180mg, 0.65mmol) (preparation 130) in dioxaneTo the solution in alkane (4mL) was added 2N aqueous sodium hydroxide (4mL) and the reaction mixture was heated at 90 ℃ for 6 hours. After cooling to 0 ℃, the mixture was acidified to pH4 with 2N aqueous hydrochloric acid and extracted with 20% isopropanol in dichloromethane (8 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound as an off-white solid in 70% yield, 80mg.

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

Preparation 133: pyrazolo [3,4-b ] pyridin-1-yl-acetic acid ethyl ester

To a solution of 7-azaindazole (250mg, 2.1mmol) and ethyl bromoacetate (0.47mL, 4.2mmol) in DMF (8mL) was added K₂CO₃(1.16gm, 8.4mmol) and the resulting mixture was stirred at 70 ℃ for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic layer was washed with water (2 × 5mL), brine (5mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the crude material using silica gel columnMass, eluted with EtOAc: hexanes 10:90 to give the title compound as an off-white solid, 49% yield, 210 mg.

¹H NMR(400MHz，DMSO-d₆)δ：1.19(t，3H)，4.14(q，2H)，5.35(s，2H)，7.25-7.28(m，1H)，8.22(s，1H)，8.29(d，1H)，8.55(d，1H)。

Preparation of 134: pyrazolo [3,4-b ] pyridin-1-yl-acetic acids

Pyrazolo [3,4-b ] stirred at 0 deg.C ]Pyridin-1-yl-acetic acid ethyl ester (210mg, 1.02mmol) (preparation 133) to a solution in THF (4mL) and water (1mL) was added LiOH₂O (129mg, 3.06 mmol). The reaction mixture was stirred at room temperature for 2 hours. The pH of the mixture was adjusted to pH4 with 2N aqueous brine solution and extracted with 20% isopropanol in dichloromethane (8x5 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as an off-white solid in 40% yield, 70 mg.

¹H NMR(400MHz，DMSO-d₆) δ: 5.22(s, 2H), 7.25(dd, 1H), 8.19(s, 1H), 8.27(dd, 1H), 8.55(dd, 1H), 13.15(brs, 1H); LCMS (system 9): r_t=1.93min；m/z178[M+H]⁺.

Preparation of 135: 1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester

Ethyl 4,4, 4-trifluoro-3-oxo-butanoate (16g, 86.4mmol) was dissolved in acetic anhydride (33.6g, 329.6mmol) and triethyl orthoformate (38.4g, 260mmol) was added to the mixture. The resulting mixture was refluxed for 18 hours. Concentrating under reduced pressureThe mixture was mixed to give 20g of 2- [ 1-ethoxy-methyl- (E) -ylidene ] idene]-4,4, 4-trifluoro-3-oxo-butyric acid ethyl ester as crude product. This was dissolved in EtOH (50mL) and added to a suspension of cyclopropylhydrazine hydrochloride (9.95g, 91.7mmol) and DIPEA (28.3mL, 166.7mmol) in EtOH (150mL) at-20 ℃. The resulting mixture was slowly warmed to room temperature and stirred for 16 hours. The mixture was concentrated under reduced pressure and the resulting residue partitioned between EtOAc (50mL) and water (50 mL). The organic layer was washed with 2N HCl (25mL), water (25mL), brine (25mL) and dried (Na) ₂SO₄) And (4) evaporating in vacuum. The crude material was purified by silica gel column chromatography (EtOAc: hexane 5:95) to give the title compound as an off-white viscous solid in 7% yield, 1.4g.

¹H NMR(400MHz，DMSO-D6)δ：1.10-1.21(m，4H)，1.26(t，3H)，3.90(m，1H)，4.26(q，2H)，7.98(s，1H)。

Preparation of 136: n- (5- { [7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] carbonyl } pyridin-3-yl) -2- [3- (trifluoromethyl) phenyl ] acetamide

Prepared according to the method described for example 1 using (5-aminopyridin-3-yl) [7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] methanone (preparation 38) and 3-trifluoromethylphenylacetic acid with DIPEA.

¹H NMR(400MHz，DMSO)δ：-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: (1-cyclopropyl-5-trifluoromethyl-1H-pyrazol-4-yl) -methanol

A solution of ethyl 1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylate (preparation 135, 1.4g, 5.64mmol) in dry toluene (25mL) was cooled to-78 deg.C, to which DIBAL-H (11.8mL of a 1.2M solution in toluene, 14.1mmol) was added dropwise. The reaction mixture was stirred at-78 ℃ for 2 hours and poured into 2N HCl (10 mL). It was stirred at rt for 4 h, then extracted with EtOAc (2x25mL), the combined organic layers were washed with water (2x10mL), brine (10mL), dried (Na)₂SO₄) Evaporation in vacuo gave the title compound as an off-white solid in 100% yield, 1.2g.

¹H NMR (400MHz, DMSO-D6) delta: 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_t=2.68min；m/z207[M+H]⁺

Preparing 138: n- (5- { [7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] carbonyl } pyridin-3-yl) -2- (4-isopropyl-1H-1, 2, 3-triazol-1-yl) acetamide.

Prepared according to the procedure described for example 1 using (5-aminopyridin-3-yl) [7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] methanone (preparation 38) and [4- (trifluoromethyl) -1H-pyrazol-1-yl ] acetic acid (preparation 85) with DIPEA as base.

LCMS (system 9): r_t=3.67min；m/z577[M+H]⁺.

Preparation 139: (1-cyclopropyl-5-trifluoromethyl-1H-pyrazol-4-yl) -acetonitrile

A solution of (1-cyclopropyl-5-trifluoromethyl-1H-pyrazol-4-yl) -methanol (preparation 137, 1.2g, 5.82mmol) in DCM (15mL) was cooled to 0 deg.C and thionyl chloride (0.85mL, 11.7mmol) was added. The reaction mixture was stirred at 0 ℃ for 2 hours and diluted with DCM. The organic layer was washed with water, brine and dried (Na)₂SO₄) And (4) evaporating in vacuum. The crude residue was dissolved in IIAlkane (25mL) and water (25mL), tert-butylammonium bromide (1.38g, 4.28mmol) was added. The reaction mixture was stirred for 10mins, then KCN (1.28g, 19.82mmol) was added and the resulting mixture was stirred at room temperature for a further 16 h. The mixture was diluted with EtOAc (50mL), washed with water (1x10mL), brine (1x10mL), and dried (Na) ₂SO₄) And (4) evaporating in vacuum. The crude material was purified by silica gel column chromatography (hexanes: EtOAc10:90) to give the title compound as a light yellow solid, 56% yield, 700mg.

¹H NMR(400MHz，CDCl3)δ：1.06-1.13(m，2H)，1.24-1.29(m，2H)，3.61-3.62(m，1H)，3.66(s，2H)，7.49(s，1H)。

Preparation 140: n- (5- { [7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] carbonyl } pyridin-3-yl) -2-quinolin-7-yl acetamide

Prepared according to the procedure described for example 1 using (5-aminopyridin-3-yl) [7- (2- { [ tert-butyl (dimethyl) silyl ] oxy } -1, 1-dimethylethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] methanone (preparation 38) and 2-quinolin-7-ylacetic acid with DIPEA as base.

¹H NMR(400MHz，DMSO)δ：-0.28(s，6H)，0.55(s，9H)，1.74(s，6H)，3.98(s，2H)，4.09(s，2H)，7.51(m，1H)，7.60(m，1H)，7.94(m，1H)，8.00(s，1H)，8.16(s，1H)，8.33(m，1H)，8.54(m，1H)，8.67(s，1H)，8.84(m，1H)，8.91(s，1H)，8.98(s，1H)，9.47(s，1H)，10.77(s，1H)；

LCMS (system 9): r_t=3.72min；m/z595[M+H]⁺.

Preparation 141: (1-cyclopropyl-5-trifluoromethyl-1H-pyrazol-4-yl) -acetic acid

To a solution of (1-cyclopropyl-5-trifluoromethyl-1H-pyrazol-4-yl) -acetonitrile (preparation 139, 700mg, 3.25mmol) in EtOH (15mL) was added 1N aqueous NaOH (15 mL). The resulting solution was heated at 60 ℃ for 16 hours. The mixture was concentrated and the residue was dissolved in water (10mL) and washed with EtOAc. The pH of the aqueous layer was adjusted to 5 using 1N HCl and extracted with 10% IPA in DCM (4 × 30 mL). Drying the organic layer (Na)₂SO₄) Evaporation in vacuo gave the title compound as a solid in 85% yield, 650mg.

¹H NMR (400MHz, DMSO-D6) delta: 1.04-1.07(m, 2H), 1.11-1.16(m, 2H), 3.55(s, 2H), 3.69-3.73(m, 1H), 7.47(s, 1H), 12.45(br, 1H); LCMS (system 10): r_t=1.50min；m/z233[M-H]⁺.

Preparation of 142N- [5- ({7- [ (1R) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } carbonyl) pyridin-3-yl ] -2- [3- (trifluoromethyl) phenyl ] acetamide

Prepared according to the procedure described above for example 1 using (5-aminopyridin-3-yl) {7- [ (1R) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone (preparation 36) and 3-trifluoromethylphenylacetic acid with DIPEA as base.

¹H NMR(400MHz，DMSO-d₆)δ：1.29-1.42(m，5H)，1.54(d，3H)，3.50(m，1H)，3.71(m，1H)，3.86(s，2H)，3.93(m，1H)，4.05(m，1H)，4.44(s，1H)，4.58(s，1H)，5.17(m，1H)，7.56(m，1H)，7.63(m，2H)，7.72(s，1H)，8.47(m，2H)，8.70(s，1H)，8.96(m，2H)，9.45(s，1H)，10.72(s，1H)；

LCMS (system 9): r_t=3.56min；m/z568[M+H]⁺.

Preparation 143: 5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester

DIPEA (45.3mL, 267mmol) was added slowly to a suspension of hydrazine hydrochloride (10g, 147mmol) in EtOH (500mL) at-20 deg.C, stirred for 10mins, and then 2- [ 1-ethoxy-methyl- (E) -ylidene]-4,4, 4-trifluoro-3-oxo-butyric acid ethyl ester (preparation 135, 32g, 133.33mmol) was added to the above solution, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between EtOAc (200mL) and water (50 mL). The organic layer was washed with water (25mL) and dried (Na) ₂SO₄) And (4) evaporating in vacuum. The crude material was purified by silica gel column chromatography (hexanes: EtOAc90:10) to give the title compound as an off-white solid in 43% yield, 13g.

¹H NMR(400MHz，DMSO-D6)δ：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-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } carbonyl) pyridin-3-yl ] -2- (4-isopropyl-1H-1, 2, 3-triazol-1-yl) acetamide

Prepared according to the procedure described above for example 1 using (5-aminopyridin-3-yl) {7- [ (1R) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone (preparation 36) and (4-isopropyl-1H-1, 2, 3-triazol-1-yl) acetic acid with DIPEA as base.

¹H NMR(400MHz，DMSO-d₆)δ：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_t=2.86min；m/z533[M+H]⁺.

Preparation 145: 1-cyclopropyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester

Cyclopropylboronic acid (11g, 127mmol), copper acetate (17.4g, 95.7mmol), pyridine (17.7g, 223mmol) and triethylamine (22.4mL, 160mmol) were added in that order to a solution of 5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (preparation 143, 6.63g, 31.9mmol) in THF (70mL), and the resulting mixture was stirred at 60 ℃ for 36 hours. The reaction mixture was filtered through a celite bed, and the filtrate was concentrated in vacuo and diluted with EtOAc (200 mL). The organic layer was washed with 1N HCl (1X25mL), brine (1X25mL) and dried (Na) ₂SO₄) And (4) evaporating in vacuum. By silica gel column chromatographyThe crude material was purified by method (hexane: EtOAc85:15) to give the title compound as a brown solid in 29% yield, 2.3g.

¹H NMR (400MHz, CDCl3) delta: 1.08-1.14(m, 2H), 1.17-1.21(m, 2H), 1.33(t, 3H), 3.62-3.67(m, 1H), 4.30(q, 2H), 8.01(s, 1H); LCMS (system 10): r_t=3.39min；m/z249[M+H]⁺.

Preparation of 146: (1-cyclopropyl-3-trifluoromethyl-1H-pyrazol-4-yl) -methanol

A solution of 1-cyclopropyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (preparation 145, 3.5g, 14.11mmol) in dry toluene (70mL) was cooled to-78 deg.C, to which DIBAL-H (29.4mL of a 1.2M solution in toluene, 35.3mmol) was added dropwise. The reaction mixture was stirred at-78 ℃ for 2 hours, then poured into 2N HCl (25mL), then stirred at room temperature for an additional 2 hours. The mixture was extracted with EtOAc (2x50mL), the combined organics were washed with water (2x15mL), brine (15mL), dried (Na)₂SO₄) Evaporation in vacuo gave the title compound as an off-white solid in 100% yield, 3g.

¹H NMR (400MHz, CDCl3) delta: 1.02-1.07(m, 2H), 1.11-1.16(m, 2H), 1.68(t, 1H), 3.57-3.63(m, 1H), 4.64(d, 2H), 7.53(s, 1H); LCMS (system 10): r_t=2.57min；m/z207[M+H]⁺.

Preparation 147: (1-cyclopropyl-3-trifluoromethyl-1H-pyrazol-4-yl) -acetonitrile

The title compound was prepared according to the procedure described for preparation 139 using (1-cyclopropyl-3-trifluoromethyl-1H-pyrazol-4-yl) -methanol (preparation 146) to give the title compound as a yellow solid in 70% yield, 2.2g.

¹H NMR (400MHz, DMSO-D6) delta: 0.98-1.03(m, 2H), 1.06-1.11(m, 2H), 3.83-3.88(m, 1H), 3.91(s, 2H), 8.08(s, 1H); LCMS (system 10): r_t=3.10min；m/z216[M+H]⁺.

Preparation of 148: (1-cyclopropyl-3-trifluoromethyl-1H-pyrazol-4-yl) -acetic acid

The title compound was prepared according to the procedure described for preparation 141 using (1-cyclopropyl-3-trifluoromethyl-1H-pyrazol-4-yl) -acetonitrile (preparation 147) to give the title compound as a solid in 79% yield, 1.9g.

¹H NMR (400MHz, DMSO-D6) delta: 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_t=1.41min；m/z233[M-H]⁺.

Preparation 149: (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) [5- (methylamino) pyridin-3-yl ] methanone

The title compound was prepared according to the procedure described for preparation 31 using (5-bromopyridin-3-yl) (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 94) and methylamine (20mL), 13% yield, 78mg.

LCMS (system 2): r_t=0.91min；m/z296[M+H]⁺

The following preparations were prepared according to the procedure described above for example 1 using (5-aminopyridin-3-yl) {7- [ (1R) -1-methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone (preparation 36) and the corresponding carboxylic acid with DIPEA. All carboxylic acids are commercially available unless otherwise noted.

Preparation 154: (2-cyclopropyl-1, 3-Oxazol-4-yl) acetic acid ethyl ester

A solution of ethyl 4-chloroacetoacetate (20.0g, 122.0mmol) in toluene (100mL) and 1, 4-bisCyclopropanecarboxamide (3.52g, 41.5mmol) in an alkane (100 mL). The mixture was refluxed at 120 ℃ for 17 hours and then evaporated in vacuo. The crude solid was purified by silica gel column chromatography (80:20 petroleum ether: EtOAc) to give the title compound as a white solid in 50% yield, 4.00g.

¹H NMR(300MHz，DMSO-d₆)δ：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: (2-cyclopropyl-1, 3-Azol-4-yl) acetic acid

Lithium hydroxide monohydrate (7.83g, 186.7mmol) was added to (2-cyclopropyl-1, 3-Oxazol-4-yl) acetic acid ethyl ester (preparation 154, 7.00g, 35.9 mmol). The mixture was stirred at room temperature for 2 hours, then the reaction mixture was reduced in volume to one third by evaporation in vacuo. The aqueous residue was acidified with aqueous HCl (1.0M) and then extracted with EtOAc (200 mL). The organic phase was evaporated in vacuo and the crude material was triturated with ether (100mL) to give the title compound as a white solid in 66% yield, 4.00g.

¹H NMR(300MHz，CDCl₃)δ：1.05(m，4H)，2.10(m，1H)，3.60(s，2H)，7.40(s，1H)，10.00(br s，1H)。

Preparation 156: [2- (Vinyloxy) phenyl ] acetic acid methyl ester

Copper acetate (1.42g, 7.82mmol) was added to DCM (6mL) and stirred for 20 min, where a dry tube was attached. Trivinyl cyclooxoane (1.24g, 5.16mmol), cesium carbonate (2.55g, 7.82mmol) and methyl 2-hydroxyphenylacetate (1.30g, 7.82mmol) were added and the mixture was stirred at room temperature for 17 hours. Saturated aqueous sodium bicarbonate (25mL) was added and the mixture was extracted with DCM (20 mL). The organic phase was filtered, dried over magnesium sulfate and evaporated in vacuo to give the title compound as a black oil in 52% yield, 784 mg. This material was used as crude in the next step.

¹H NMR(400MHz，CDCl₃)δ：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: [4- (Vinyloxy) phenyl ] acetic acid methyl ester

The title compound was prepared according to the procedure described for preparation 156 using methyl 4-hydroxyphenylacetate to give the title compound as a colorless oil in 70% yield of 914 mg.

¹H NMR(400MHz，CDCl₃)δ：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 of 158: [3- (Vinyloxy) phenyl ] acetic acid methyl ester

The title compound was prepared according to the procedure described for preparation 156 using methyl 3-hydroxyphenylacetate to give the title compound as a colorless oil in 56% yield, 835 mg.

¹H NMR(400MHz，CDCl₃)δ：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: [5- (Vinyloxy) pyridin-3-yl ] acetic acid methyl ester

The title compound was prepared according to the procedure described for preparation 156 using methyl (5-hydroxypyridin-3-yl) acetate to give the title compound as a yellow oil in 25% yield, 76 mg.

LCMS (system 2): r_t=0.85min；m/z194[M+H]⁺.

Preparation of 160: [2- (Cyclopropoxy) phenyl ] acetic acid

Diethyl zinc (2.34mL, 2.34mmol, 1M in heptane) was cooled to 0 ℃ under a nitrogen atmosphere, then chloroiodomethane (0.35mL, 4.68mmol) in DCE (1mL) was added dropwise. The mixture was stirred at 0 ℃ for 20 minutes under a nitrogen atmosphere, then methyl [2- (vinyloxy) phenyl ] acetate (preparation 156, 150mg, 0.78mmol) in DCE (1mL) was added. The reaction mixture was stirred at 0 ℃ for 30 minutes and then at room temperature for 17 hours. Saturated aqueous ammonium chloride (10mL) was added and the mixture was extracted with DCM (4 × 8 mL). The combined organic phases were dried over magnesium sulfate and evaporated in vacuo. Sodium hydroxide (3.28mL, 3.28mmol, 1M) was added to the residue in THF (3 mL). The mixture was heated at 80 ℃ for 17 hours and then evaporated in vacuo. Hydrochloric acid (10mL, 1M) was added to the residue, which was then extracted with EtOAc (10 mL). The organic phase was evaporated in vacuo to give the title compound as a yellow oil, 53% yield, 83 mg.

¹H NMR(400MHz，CDCl₃)δ：0.65-0.71(m，4H)，3.54(s，2H)，3.71(m，1H)，6.82-6.87(m，2H)，7.05-7.23(m，2H)。

Preparation 161: [4- (Cyclopropoxy) phenyl ] acetic acid

Prepared according to the method described for preparation 160 using methyl [4- (vinyloxy) phenyl ] acetate (preparation 157) to give the title compound as a colorless oil in 44% yield, 360 mg.

¹H NMR(400MHz，CDCl₃)δ：0.65-0.71(m，4H)，3.59(s，2H)，3.71(m，1H)，6.99-7.02(m，2H)，7.16-7.20(m，2H)。

Preparation 162: [3- (Cyclopropoxy) phenyl ] acetic acid

The title compound was prepared according to the procedure described for preparation 160 using methyl [3- (vinyloxy) phenyl ] acetate (preparation 158) to give the title compound as a colorless oil in 33% yield, 50 mg.

¹H NMR(400MHz，CDCl₃)δ：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: [5- (Cyclopropoxy) pyridin-3-yl ] acetic acid

The title compound was prepared according to the method described for preparation 160 using methyl [5- (vinyloxy) pyridin-3-yl ] acetate (preparation 159) to give the title compound as a yellow oil in 38% yield, 28mg.

LCMS (system 2): r_t=0.55min；m/z194[M+H]⁺.

Preparation of 164: [ 4-cyano-3- (trifluoromethyl) phenyl ] acetic acid

Lithium diisopropylamide (13.8mL, 24.8mmol, 1.8M in THF) was added to 4-methyl-2- (trifluoromethyl) benzonitrile (2.30g, 12.4mmol) in THF (20mL) at-78 deg.C and stirred for 5 min at-78 deg.C. Excess solid carbon dioxide was added and the mixture was then stirred at room temperature for 17 hours. Saturated aqueous ammonium chloride (10.5mL) and EtOAc (20mL) were added, and the aqueous layer was acidified with HCl acid solution (1M). Extraction with EtOAc (3 × 15mL) and drying of the combined organic phases over magnesium sulphate and evaporation in vacuo gave the title compound as a brown oil in 88% yield, 2.52g.

¹H NMR(400MHz，CDCl₃)δ：3.81(s，2H)，7.62(d，1H)，7.73(s，1H)，7.83(d，1H)。

Preparation 165: (2-methylquinolin-7-yl) acetic acid

Crotonaldehyde (33.0mL, 0.40mol) was added to 3-aminophenylacetic acid (30.0g, 0.20mmol) in concentrated hydrochloric acid (400mL) and toluene (100mL) at 110 ℃. The mixture was heated at 110 ℃ for 90 minutes. The aqueous layer was separated, washed with ether (350mL), and then neutralized with aqueous ammonia. The aqueous solution was washed with chloroform (3 × 500mL) and the organic phase was evaporated in vacuo. The solid residue was refluxed with chloroform (900mL) and methanol (100mL), then the solution was decanted and purified by silica gel column chromatography (chloroform: MeOH9: 1-4: 1 gradient) to give a mixture of isomeric acids. Purification by fractional crystallization using isopropanol gave the title compound as a white solid in 12% yield, 4.90g.

¹H NMR(400MHz，DMSO-d6)δ：2.64(s，3H)，3.78(s，2H)，7.37(d，1H)，7.44(dd，1H)，7.80(s，1H)，7.84(d，1H)，8.19(d，1H)，12.40(br s，1H)。

Preparation 166: (3-isopropyl-5-methyl-1H-pyrazol-1-yl) acetic acid ethyl ester

Ethyl bromoacetate (1.00mL, 9.03mmol) was added to 5-isopropyl-3-methyl-1H-pyrazole (1.07g, 8.60mmol) and potassium carbonate (3.57g, 25.9mol) in DMF (10 mL). The mixture was stirred at room temperature for 17 h, then EtOAc (20mL) and aqueous HCl (20mL, 1M) were added. The organic phase was dried over magnesium sulfate and then evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane: EtOAc4:1) to give the title compound as a yellow oil, 34% yield, 607 mg.

¹H NMR(400MHz，CDCl₃)δ：1.26(m，9H)，2.03(s，3H)，2.96(m，1H)，4.21(q，2H)，4.78(s，2H)，7.13(s，1H)。

Preparation 167: (3-isopropyl-5-methyl-1H-pyrazol-1-yl) acetic acid

A solution of lithium hydroxide (342mg, 8.15mmol) in water (4mL) was added to ethyl 3-isopropyl-5-methyl-1H-pyrazol-1-yl) acetate (preparation 166, 571mg, 2.72mmol) in methanol (4mL), and the mixture was stirred at room temperature for 30 minutes. Aqueous hydrochloric acid (2M) was added to acidify the mixture, then the solution was extracted with EtOAc (10 mL). The organic phase was dried over magnesium sulfate and evaporated in vacuo to give the title compound as a cream-like solid in 66% yield, 328 mg.

m/z183[M+H]⁺.

Preparation 168: (6-chloro-1H-indazol-3-yl) acetic acid ethyl ester

Concentrated sulfuric acid (0.25mL) was added to a solution of 2- (6-chloro-1H-indazol-3-yl) acetic acid (2.024g, 9.60mmol) in EtOH (10 mL). The mixture was heated at 80 ℃ for 4 hours and then evaporated in vacuo. The residue was partitioned between EtOAc (30mL) and 5% aqueous sodium bicarbonate (30 mL). The organic phase was dried over sodium sulfate, evaporated in vacuo and purified by silica gel column chromatography (DCM: MeOH99:1) to give compound 3 as a white solid in 83% yield, 1.90g.

¹H NMR(400MHz，DMSO-d₆)δ：1.17(t，3H)，4.00(s，2H)，4.10(q，2H)，7.11(d，1H)，7.56(s，1H)，7.74(d，1H)，13.00(s，1H)。

Preparation 169: (6-chloro-1-methyl-1H-indazol-3-yl) acetic acid ethyl ester

Sodium hydride (24mg, 0.602mmol, 60% in oil) was added to ethyl (6-chloro-1H-indazol-3-yl) acetate (preparation 168, 120mg, 0.502mmol) in THF (4mL) at 0 ℃, the mixture was stirred for 30 minutes, and methyl iodide (0.09mL, 1.508mmol) was then added. The mixture was stirred at room temperature for 30mins, then water (4mL) was added. The mixture was evaporated in vacuo and the aqueous residue was acidified with aqueous HCl (6M). Extraction with ethyl acetate (10mL) and drying of the organic phase over sodium sulfate followed by evaporation in vacuo afforded the title compound as a white solid in 100% yield, 150 mg.

¹H NMR(400MHz，DMSO-d₆)δ：1.18(t，3H)，3.89(s，3H)，4.07(s，2H)，4.13(q，2H)，7.15(d，1H)，7.56(s，1H)，7.74(d，1H)；

LCMS (system 9): r_t=3.48min；m/z253[M+H]⁺.

Preparation 170: (6-chloro-1-methyl-1H-indazol-3-yl) acetic acid

Aqueous potassium hydroxide (5.93mL, 10%) was added to ethyl (6-chloro-1-methyl-1H-indazol-3-yl) acetate (preparation 169, 1.78g, 0.704mol) in MeOH (30 mL). The mixture was stirred at 25 ℃ for 1 hour, then methanol was evaporated in vacuo. The aqueous residue was washed with diethyl ether (30mL) and then acidified with aqueous HCl (6M). The mixture was extracted with ethyl acetate (30mL), the organic phase was dried over sodium sulfate, evaporated in vacuo and purified by silica gel column chromatography (DCM: MeOH 95: 5) to give the title compound as a white solid in 56% yield, 865 mg.

¹H NMR(400MHz，DMSO-d6)δ：3.79(s，2H)，4.14(s，3H)，7.12(d，1H)，7.73(d，1H)，7.83(s，1H)。12.51(s，1H)。

Preparation 171: (5-fluoro-1H-indazol-1-yl) acetic acid ethyl ester

The title compound was prepared according to the procedure described for preparation 93 using 5-fluoro-1H-indazole and ethyl bromoacetate to give the title compound as an off-white solid in 53% yield, 260 mg.

¹H NMR(400MHz，CDCl₃) δ: 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_t=3.14min；m/z223[M+H]⁺.

Preparation 172: (5-fluoro-1H-indazol-1-yl) acetic acid

The title compound was prepared according to the method described for preparation 155 using ethyl (5-fluoro-1H-indazol-1-yl) acetate (preparation 171) to give the title compound as a yellow solid in 62% yield, 140 mg.

¹H NMR(400MHz，DMSO-d₆)δ：5.26(s，2H)，7.28(m，1H)，7.54(dd，1H)，7.68(dd，1H)，8.06(s，1H)，13.11(br s，1H)。

LCMS (system 9): r_t=1.49min；m/z193[M-H]^-

Preparation 173: (5-fluoro-2H-indazol-2-yl) acetic acid ethyl ester

The title compound was prepared according to the procedure described for preparation 93 using 5-fluoro-1H-indazole and ethyl bromoacetate to give the title compound as an off-white solid in 27% yield, 130 mg.

¹H NMR(400MHz，CDCl₃) δ: 1.26(t, 3H), 4.25(q, 2H), 5.17(s, 2H), 7.06-7.11(m, 1H), 7.21-7.24(m, 1H), 7.64-7.68(m, 1H), 7.96(s, 1H); LCMS (system 9): r_t=3.04min；m/z223[M+H]⁺

Preparation 174 (5-fluoro-2H-indazol-2-yl) acetic acid

The title compound was prepared according to the method described for preparation 155 using ethyl (5-fluoro-2H-indazol-2-yl) acetate (preparation 173) to give the title compound as a yellow solid in 100% yield, 160 mg.

LCMS (system 9): r_t=1.49min；m/z193[M-H]^-

Preparation 175: (7-fluoro-1H-indazol-1-yl) acetic acid ethyl ester

The title compound was prepared according to the procedure described for preparation 93 using 7-fluoro-1H-indazole and ethyl bromoacetate to give the title compound as an off-white solid in 41% yield, 200 mg.

¹H NMR(400MHz，CDCl₃)δ：1.29(t，3H)，4.22(q，2H)，5.28(s，2H)，6.98-7.07(m，2H)，7.49(m，1H)，8.02(d，1H)。

Preparation 176: (7-fluoro-1H-indazol-1-yl) acetic acid

The title compound was prepared according to the method described for preparation 155 using ethyl (7-fluoro-1H-indazol-1-yl) acetate (preparation 175) to give the title compound as a yellow solid in 68% yield, 120 mg.

¹H NMR(400MHz，DMSO-d₆) δ: 5.27(s, 2H), 7.12(m, 1H), 7.23(m, 1H), 7.60(d, 1H), 8.17(d, 1H), 13.18(br s, 1H); LCMS (system 9):

R_t=1.38min；m/z195[M+H]⁺

preparation 177: (7-fluoro-2H-indazol-2-yl) acetic acid ethyl ester

The title compound was prepared according to the procedure described for preparation 93 using 7-fluoro-1H-indazole and ethyl bromoacetate to give the title compound as an off-white solid in 35% yield, 175 mg.

¹H NMR(400MHz，CDCl3)δ：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-indazol-2-yl) acetic acid

The title compound was prepared according to the procedure described for preparation 155 using ethyl (7-fluoro-2H-indazol-2-yl) acetate (preparation 177) to give the title compound as a yellow solid in 75% yield, 110 mg.

¹H NMR(400MHz，DMSO-d₆) δ: 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_t=1.40min；m/z195[M+H]⁺

Preparation 179: 1H-pyrazolo [3,4-b ] pyridin-1-ylacetic acid ethyl ester

The title compound was prepared according to the procedure described for preparation 93 using 1H-pyrazolo [3,4-b ] pyridine and ethyl bromoacetate to give the title compound as an off-white solid in 49% yield, 210 mg.

¹H NMR(400MHz，DMSO-d₆)δ：1.19(t，3H)，4.14(q，2H)，5.35(s，2H)，7.27(m，1H)，8.27(s，1H)，8.29(d，1H)，8.55(d，1H)。

Preparation 180: 1H-pyrazolo [3,4-b ] pyridin-1-yl acetic acid

The title compound was prepared according to the procedure described for preparation 155 using ethyl 1H-pyrazolo [3,4-b ] pyridin-1-ylacetate (see preparation 179) to give the title compound as a yellow solid in 40% yield, 70 mg.

¹H NMR(400MHz，DMSO-d₆)δ：5.22(s，2H)，7.25(dd，1H)，8.19(s，1H)，8.27(dd，1H)，8.55(dd，1H)，13.15(br s，1H)。

Preparation 181: 1H-indazol-6-ylacetic acid tert-butyl ester

6-bromo-1H-indazole (1.3g, 6.6mmol) and tert-butyl acetate (1.33mL, 9.9mmol) in toluene were degassed with argon for 15mins, then the mixture was cooled to 0 ℃ and LiHMDS (16.5mL, 16.5mmol, 1M in hexane) was added dropwise. Bis (dibenzylideneacetone) palladium (380mg, 0.66mmol) and tri-tert-butylphosphine tetrafluoroborate (383mg, 1.32mmol) were added and the mixture was evaporatedStirred at 10 ℃ for 2 hours. The mixture was quenched with water (10mL) and then extracted with EtOAc (3 × 25 mL). The combined organic phases were washed with water (2X10mL), brine (10mL), and sodium sulfate (Na)₂SO₄) And (5) drying. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (hexanes: EtOAc80:20) to give the title compound as a white solid (65%, 1.00 g).

¹H NMR(400MHz，CDCl₃)δ：1.43(s，9H)，3.64(s，2H)，7.08(dd，1H)，7.39(s，1H)，7.69(d，1H)，8.03(s，1H)，10.05(br s，1H)。

Preparation 182: 1H-indazol-6-yl acetic acid

Hydrochloric acid (10mL, 4M of 1.4 bis)Alkane solution) to 1,4 bisTo tert-butyl 1H-indazol-6-ylacetate (preparation 181, 1.00g, 4.3mmol) in an alkane (5mL) the mixture was stirred at room temperature for 16H. The mixture was evaporated in vacuo and the residue triturated with dry ether to give the title compound as a white solid in 100% yield, 800mg.

¹H NMR(400MHz，CDCl₃)δ：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-isopropyl-5- (trifluoromethyl) -1H-pyrazol-4-yl ] methanol

Diisobutylaluminum hydride (99mL, 120mmol, 1.2M in toluene) was added to ethyl 1-isopropyl-5- (trifluoromethyl) -1H-pyrazole-4-carboxylate (WO2007071900, 12g, 48mmol) in toluene (220mL) at-78 ℃. The reaction mixture was stirred at-78 ℃ for 2 hours and then poured into aqueous HCl (100mL, 2M). The mixture was stirred at room temperature for 4 hours, then extracted with EtOAc (400 mL). The organic phase was washed with water (200mL), brine (200mL) and dried over sodium sulfate. The filtrate was concentrated in vacuo to give the title compound as a colorless oil in 100% yield, 10.5g.

¹H NMR(400MHz，CDCl₃)δ：1.51(d，6H)，4.57-4.66(m，3H)，7.58(s，1H)。

¹H NMR (400MHz, CDCl3) delta: 1.26(s, 4H), 3.83(s, 2H), 6.47(d, 1H), 7.26(d, 1H), 8.83(s, 1H), 8.88(s, 1H); LCMS (system 10): r_t=1.67min；m/z189.9[M+H]⁺.

Preparation 184: [ 1-isopropyl-5- (trifluoromethyl) -1H-pyrazol-4-yl ] acetonitrile

Thionyl chloride (5.26mL, 72mmol) was added to [ 1-isopropyl-5- (trifluoromethyl) -1H-pyrazol-4-yl ] methanol (preparation 183, 7.5g, 36mmol) in DCM (75mL) at 0 deg.C and the mixture was stirred for 2H. The mixture was diluted with DCM (30mL), and the organic phase was washed with water (75mL), brine (75mL) and dried over sodium sulfate. The filtrate was concentrated in vacuo to give 4- (chloromethyl) -1-isopropyl-5- (trifluoromethyl) -1H-pyrazole in 86% yield, 7g.

Tetrabutylammonium bromide (7.95gm, 24.7mmol) was added to the solution in bis4- (chloromethyl) -1-iso-ethanol in alkane (75mL) and water (75mL)Propyl-5- (trifluoromethyl) -1H-pyrazole (7g, 31mmol), and the mixture was stirred for 10 min. Potassium cyanide (7.42g, 114mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was diluted with EtOAc (100mL), then the organic phase was washed with water (100mL), brine (100mL) and dried over sodium sulfate. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (hexanes: EtOAc90:10) to give the title compound as a white solid in 100% yield, 7.00g.

¹H NMR(400MHz，DMSO-d₆)δ：1.43(d，6H)，3.99(s，2H)，4.61(m，1H)，7.71(s，1H)。

Preparation 185: [ 1-isopropyl-5- (trifluoromethyl) -1H-pyrazol-4-yl ] acetic acid

Aqueous sodium hydroxide (150mL of 1M solution) was added to [ 1-isopropyl-5- (trifluoromethyl) -1H-pyrazol-4-yl ] acetonitrile (preparation 184, 6.2g, 28.6mmol) in EtOH (150mL), and the mixture was heated at 60 ℃ for 16 hours. The mixture was evaporated in vacuo and the residue was dissolved in water (50mL) and washed with EtOAc (100 mL). The aqueous was acidified to pH5 using 1N HCl and extracted with 10% IPA in DCM (4x100 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo to give the title compound as a white solid in 75% yield, 5.0g.

¹H NMR(400MHz，DMSO-d₆)δ：1.42(d，6H)，3.56(s，2H)，4.58(m，1H)，7.57(s，1H)，12.28(br s，1H)。

Preparation 186: (5-amino-pyridin-3-yl) - [7- (2-methoxy-1, 1-dimethyl-ethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -methanone

The title compound was prepared according to the procedure described for preparation 65 using (5-bromo-pyridin-3-yl) - [7- (2-methoxy-1, 1-dimethyl-ethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -methanone (preparation 263) to give the title compound as an off-white solid in 41% yield of 650mg.

¹H NMR (400MHz, DMSO-D6) Δ 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_t=2.56min；m/z327[M+H]⁺.

Preparation 187: (7-tert-butyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) - (5-methylamino-pyridin-3-yl) -methanone

Di (4N HCl) at room temperatureThe alkyl solution is prepared by reacting [5- (7-tert-butyl-7H-pyrrolo [2,3-d ]]Pyrimidine-5-carbonyl) -pyridin-3-yl]Methyl-carbamic acid tert-butyl ester (example 542) for 2 hours. The solvent was removed in vacuo and the resulting solid triturated with ether to give the title compound as a white solid in 100% yield, 76mg.

¹H NMR (400MHz, DMSO-D6) delta: 1.80(s, 9H), 2.84(s, 3H), 7.27(br s, 1H), 8.21(d, 1H), 8.29(s, 1H), 8.41(s, 1H), 9.03(s, 1H), 9.49(s, 1H); LCMS (system 10): r _t=2.74min；m/z310[M+H]⁺.

Preparation 188: 1, 5-naphthyridin-3-ylacetic acid

3-bromo-1, 5-naphthyridine (540mg, 2.58mmol), diethyl malonate (0.8mL, 5.17mmol), and cesium carbonate (2.53g, 7.75mmol) were given under argon in 1, 4-bisThe mixture in alkane (6mL) was degassed for 15min, then picolinic acid (64mg, 0.517mmol) and CuI (50mg, 0.258mmol) were added. The mixture was heated at 110 ℃ for 24 hours in a sealed tube, then cooled to room temperature, diluted with ethyl acetate (10mL), washed with water (10mL) and brine (10 mL). The organic phase was dried over sodium sulfate and then evaporated in vacuo and purified by silica gel column chromatography (hexane: EtOAc70:30) to give 450mg of 1, 5-naphthyridin-3-ylacetic acid ethyl ester.

Sodium hydroxide (10mL, 2.0M) was added to the solution in 1, 4-bisIn 1, 5-naphthyridin-3-ylacetic acid ethyl ester in an alkane (10mL), the mixture was heated at 100 ℃ for 6 hours. The reaction mixture was cooled to room temperature, acidified to pH4 with 2M aqueous HCl, and evaporated in vacuo. The residue was azeotroped with toluene (2 × 15mL) and then dissolved in THF (50mL) and stirred at 40 ℃ for 30 min. The mixture was filtered, the filtrate concentrated in vacuo, and the residue triturated with ether to give the title compound as an off-white solid, 200 mg.

¹H NMR(400MHz，DMSO-d₆) δ: 3.94(s, 2H), 7.76(m, 1H), 8.31(s, 1H), 8.42(d, 1H), 8.91(d, 1H), 8.99(dd, 1H), 12.65(brs, 1H); LCMS (system 10): r _t=1.49min；m/z187[M-H]⁺

Preparation 189: 1H-pyrazolo [4,3-b ] pyridin-1-ylacetic acid tert-butyl ester

Ethyl tert-butyl bromoacetate (0.55mL, 3.69mmol) was added to 1H-pyrazolo [4,3-b ] in anhydrous DMF (7mL)]Pyridine (220mg, 1.85mmol) and Cs₂CO₃(723mg, 2.22 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50mL), washed with water (3 × 30mL), brine (30mL), dried over sodium sulfate, evaporated in vacuo and purified by silica gel column chromatography (hexanes: EtOAc80:20) to give a colorless gum in 51% yield, 220mg.

¹H NMR(400MHz，DMSO-D₆)δ：1.39(s，9H)，5.32(s，2H)，7.42(dd，1H)，8.14(d，1H)，8.32(s，1H)，8.55(d，1H)。

Preparation 190: 1H-pyrazolo [4,3-b ] pyridin-1-yl acetic acid

1H-pyrazolo [4,3, b)]pyridin-1-Ylacetic acid tert-butyl ester (preparation 189, 220mg, 0.944mmol) was dissolved in HCl (4mL, 4.0M of 1,4 bisAlkane solution) was stirred at room temperature for 4 hours under a nitrogen atmosphere. The mixture was evaporated in vacuo and the residue triturated with ether to give the title compound as an off-white solid in 60% yield, 120mg.

¹H NMR(400MHz，DMSO-D₆) δ: 5.36(s, 2H), 7.51(dd, 1H), 8.30(d, 1H), 8.36(s, 1H), 8.62(d, 1H); LCMS (system 10): r_t=1.39min；m/z176[M-H]⁺.

Preparation 192: 2- (3-formylphenyl) -N- {5- [ (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } acetamide

Des-Martin periodinane (392mg, 0.93mmol) was added to a solution of (2- [3- (hydroxymethyl) phenyl ] -N- {5- [ (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } acetamide (preparation 193, 265mg, 0.62mmol) in dichloromethane (15mL), the mixture was stirred at room temperature for 18H, water (10mL) was added, and the aqueous layer was extracted with a 95:5 mixture of dichloromethane/methanol, 3X10 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography using silica gel (dichloromethane-dichloromethane/methanol gradient (10: 1-9: 1) to give the title compound as a brown solid in 80% yield, 211mg.

LCMS (system 4): r_t=2.11min；m/z428[M+H]⁺.

Preparation 193: 2- [3- (hydroxymethyl) phenyl ] -N- {5- [ (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) carbonyl ] pyridin-3-yl } acetamide

A mixture of (5-aminopyridin-3-yl) (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 95, 250mg, 0.89mmol), [4- (hydroxymethyl) phenyl ] acetic acid (177mg, 1.06mmol) and HATU (505mg, 1.33mmol) in pyridine (7mL) was stirred at 50 ℃ for 3H, then at room temperature for 18H. The mixture was concentrated in vacuo and azeotroped with toluene. The residue was purified by column chromatography using silica gel (dichloromethane-dichloromethane/methanol gradient (10: 1-9: 1) to give the title compound as a gum, this material was dissolved in a 9:1 mixture of dichloromethane/methanol (1.5mL), added dropwise to diethyl ether (100mL), the resulting precipitate filtered off, dried in vacuo to give the title compound as a white solid, 412mg, which was used for the subsequent reaction.

LCMS (system 2): r_t=1.33min；m/z430[M+H]⁺.

Preparation 194: (5- ((diphenylmethylene) amino) pyridin-3-yl) (7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanol

A mixture of 7H-pyrrolo [2,3-d ] pyrimidine (preparation 202, 953mg, 8.0mmol), 5- [ (diphenylmethylene) amino ] nicotinaldehyde (preparation 106, 3340mg, 11.7mmol) and KOH (1350mg, 24mmol) in MeOH (16mL) was toluene at room temperature for 16H. The reaction was neutralized with saturated aqueous ammonium chloride and the mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a crude residue. The crude material was purified by silica gel column chromatography (EtOAc: MeOH =100: 0-80: 20) to give the desired compound as a solid, 62% yield, 2003mg.

1H NMR(400MHz，DMSO-d6)δ：5.88-5.99(m，2H)，6.96-6.99(m，1H)，7.04-7.14(m，3H)，7.16-7.27(m，3H)，7.43-7.51(m，2H)，7.51-7.58(m，1H)，7.64-7.69(m,2H)，7.89(d，1H)，8.21(d，1H)，8.72(s，1H)，8.73(s，1H)，11.92(br s，1H)

Preparation of 195: (5- ((diphenylmethylene) amino) pyridin-3-yl) (7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone

To a stirred (5- ((diphenylmethylene) amino) pyridin-3-yl) (7H-pyrrolo [2, 3-d)]To a solution of pyrimidin-5-yl) methanol (preparation 194, 1820mg, 4.5mmol) in MeCN (45mL) was added gradually MnO₂(1960mg, 22.5mmol) and the resulting mixture was stirred at 50 ℃ overnight. Then part of MnO is added₂(1960mg, 22.5mmol) was added to the reaction system and the mixture was heated to reflux for 5 hr. Cooling to room temperature, and introducingThe reaction mixture was filtered through a pad of arbocel, the filter cake was rinsed with DCM (100mL), and the resulting filtrate was concentrated in vacuo. The resulting material was purified by silica gel column chromatography (EtOAc: MeOH100: 0-90: 10 gradient) to give the desired compound as a solid in 61% yield, 1120mg.

1H NMR(400MHz，DMSO-d6)δ：7.24-7.33(m，2H)，7.37-7.64(m，7H)，7.64-7.78(m，3H)，8.28(d，1H)，8.53(d，1H)，8.94(s，1H)，9.41(s，1H)，13.09(br s，1H)

Preparation of 196: (5-Aminopyridin-3-yl) {7- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -1- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } methanone

Reacting (5- ((diphenylmethylene) amino) pyridin-3-yl) (7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) methanone (preparation 195, 1120mg, 2.77mmol) and Cs₂CO₃A mixture of (2710mg, 8.31mmol) in DMF (10mL) 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-disilaundecan-6-yl trifluoromethanesulfonate (preparation 108) in DMF (3.8mL) was then added to the reaction system, and the resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride (100mL) and the mixture was extracted with EtOAc (100mLx 3). The combined organic layers were washed with water (200mL), dried over sodium sulfate and concentrated in vacuo. The resulting material was purified by silica gel column chromatography (heptane: EtOAc100: 0-50: 50 gradient) to give (5- ((diphenylmethylene) amino) pyridin-3-yl) (7- (2,2,3,3,9,9,10, 10-octamethyl-4, 8-dioxa-3, 9-disilaundecan-6-yl) -7H-pyrrolo [2,3-d ]Pyrimidin-5-yl) methanone.

The above was dissolved in THF (20mL), and 1N aqueous citric acid solution (20mL) was added to the solution. The reaction mixture was stirred at room temperature for 4 hours, diluted with water (100mL) and basified with NaOH to pH 7.The resulting mixture was extracted with EtOAc (3 × 150mL), over Na₂SO₄The combined organic portions were dried and concentrated in vacuo. The resulting material was purified by silica gel column chromatography (heptane: EtOAc =40: 60-0: 100) to give the desired compound as a white solid, 49% yield, 739mg.

1H NMR(400MHz，DMSO-d6)δ：-0.11(s，6H)，-0.07(s，6H)，0.68(s，18H)，3.99-4.16(m，4H)，5.01-5.11(m，1H)，5.65(brs，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-diazirin-3-yl) benzoic acid

Ethyl 3- (3- (trifluoromethyl) -3H-diazirin-3-yl) benzoate (preparation 198, 60mg, 0.23mmol) was stirred in a mixture of 2:1THF: water (2 mL). Lithium hydroxide (5 mg.0.23mmol) was added and the mixture was stirred at 25 ℃ for 18 h. The reaction mixture was acidified to pH1 using 6M aqueous hydrochloric acid and then extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound as a solid in 75% yield, 40 mg. The material was used in the next step without further purification.

Preparation of 1983- (3- (trifluoromethyl) -3H-diazirin-3-yl) benzoic acid methyl ester

Ethyl 3- (3- (trifluoromethyl) diaziridin-3-yl) benzoate (preparation 199, 226mg, 0.87mmol) and triethylamine (0.36mL, 2.61mmol) were stirred in methanol (10 mL). Iodine (662mg, 2.61mmol) was dissolved in 2mL of methanol and added stepwise until orange-brown continued to appear. The reaction mixture was evaporated in vacuo and the residue diluted with 1M aqueous NaOH (30mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were dried (MgSO)₄) Evaporation in vacuo gave the title compound as a gum in 27% yield, 60 mg. The material was used in the next step without further purification.

¹H NMR(400MHz，CDCl₃)δ：1.40(t，3H)，4.38(q，2H)，7.46-7.51(m，2H)，7.83(s，1H)，8.08(d，1H)。

Preparation 199: 3- (3- (trifluoromethyl) diaziridin-3-yl) benzoic acid ethyl ester

To a solution of ethyl 3- (2,2, 2-trifluoroacetyl) benzoate (500mg, 2.15mmol) in ethanol was added pyridine (5mL) and hydroxylamine hydrochloride (500mg, 7.2mmol), and the resulting mixture was stirred at 57 ℃ for 3 hours. The reaction mixture was cooled, passed through an ion exchange column, and eluted with methanol (30 mL). The methanol solution was evaporated in vacuo to give ethyl (E) -3- (2,2, 2-trifluoro-1- (hydroxyimino) ethyl) benzoate as an oil in 71% yield, 401mg, which was used in the next step without further purification. To a stirred solution of ethyl (E) -3- (2,2, 2-trifluoro-1- (hydroxyimino) ethyl) benzoate (401mg, 1.54mmol) in dichloromethane (10mL) was added DMAP (17mg, 0.14mmol) and the mixture was cooled to 0 ℃. 4-Methylbenzene-1-sulfonyl chloride (331mg, 1.74mmol) was added stepwise as a solution in dichloromethane (5 mL). The reaction mixture was then allowed to stand at room temperature for 18 hours. The mixture was diluted with water (10mL), the organic layer was separated, dried over magnesium sulfate and evaporated in vacuo to give ethyl (E) -3- (2,2, 2-trifluoro-1- ((tosyloxy) imino) ethyl) benzoate as an oil in 78% yield, 500 mg. The material was used in the next step without further purification. A mixture of ethyl (E) -3- (2,2, 2-trifluoro-1- ((tosyloxy) imino) ethyl) benzoate (500mg, 1.2mmol) in diethyl ether (5mL) in a 3-necked flask equipped with an internal thermometer and condenser was cooled to-78 ℃. Ammonia gas was introduced for 5min and then stirring was continued for 45 min. The reaction mixture was warmed to-33 ℃ and stirred for 2 hours, after which it was warmed to room temperature overnight with stirring. The mixture was evaporated in vacuo and the crude material was purified by silica gel column chromatography (dichloromethane: ethyl acetate 100: 0-90: 10 gradient) to give the title compound as a gum in 76% yield, 240mg.

¹H NMR(400MHz,CDCl₃)δ：1.31(t，3H)，4.31(q，2H)，7.40-7.44(m，1H)，7.74(d，1H)，8.02(d，1H)，8.20(s，1H)。

Preparation of 200: 3- (2,2, 2-trifluoroacetyl) benzoic acid

The title compound was prepared according to the procedure described for preparation 42 starting from ethyl 3- (2,2, 2-trifluoroacetyl) benzoate to give the title compound as a white solid in 26% yield 23 mg.

¹H NMR(400MHz,CDCl₃)δ：7.71(t，1H)，8.32(d，1H)，8.45(d，1H)，8.80(s，1H)。

Preparation 201: 5-iodo-7H-pyrrolo [2,3-d ] pyrimidines

A mixture of 7H-pyrrolo [2,3-d ] pyrimidine (preparation 202, 28.0g, 235mmol) and N-iodosuccinimide (55.4g, 246mmol) in acetonitrile (470mL) was stirred at room temperature for 16H. The solid was filtered, rinsed with acetonitrile (150mL) and dried in vacuo. The solid was dissolved in 1.5L of 1N aqueous sodium hydroxide solution, to which was added 2N aqueous hydrogen chloride solution to a pH of 9. The resulting precipitate was filtered, washed with water (300mL), and dried under vacuum at 70 deg.C and 10mbar for 16 hours to give the title compound in 81% yield, 46.84g.

¹H NMR(400MHz，DMSO-d₆) δ: 7.82(s, 1H), 8.73(s, 1H), 8.80(s, 1H), 12.56(br s, 1H); LCMS (system 1): r_t=0.87min；m/z246[M+H]⁺.

Preparation 202: 7H-pyrrolo [2,3-d ] pyrimidines

In each of 4 separate reaction vessels, 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (50.0g, 260mmol) was suspended in ethanol (1.4L) and concentrated ammonium hydroxide solution (140 mL). 10% palladium on carbon (2.5g) was added to each vessel and the mixture was pressurized to 20psi hydrogen and stirred at room temperature overnight. An additional 1g of 10% palladium on charcoal column was added to those reaction systems still containing the starting material, pressurized to 20psi of hydrogen, and stirred until the starting material was consumed. The reaction mixture was filtered through Arbocel, washed with ethanol and the filtrate was evaporated to give a white solid. The 4 crude reaction products were combined, suspended in 500mL of water and extracted with (3 × 500mL) ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated on an array to give 122g of a white solid. The aqueous layer was extracted with 5% methanol in ethyl acetate (3 × 500mL) and the organic layers were combined, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give a further 30g of a white solid. The solids were combined to give the title compound in 98% yield, 152g.

¹H NMR(400MHz，CDCl₃)δ：6.63(dd，1H)，7.43(dd，1H)，8.96(s，1H)，9.07(s，1H)，11.65(br.s.，1H)。

Preparation 203: n- (5- {7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl ] -7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl } -pyridin-3-yl) -2- (4-chloro-phenyl) acetamide:

(5-amino-pyridin-3-yl) - {7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } -methanone (preparation 216, 30mg, 0.068mmol) was dissolved in dry pyridine (2mL) under a nitrogen atmosphere, to which was added (4-chloro-phenyl) -acetic acid (17mg, 0.102mmol), followed by HATU (39mg, 0.102 mmol). The reaction was heated to 50 ℃ 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 × 5 mL). The combined organic layers were concentrated to dryness to give N- (5- {7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl ] -7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl } -pyridin-3-yl) -2- (4-chloro-phenyl) -acetamide as a light yellow solid, 35mg, 87% yield.

¹H NMR(400MHz，CDCl₃)δ-0.23(s，6H)0.65(s，9H)3.77(s，2H)4.26(s，2H)4.89(d，J=7.6Hz，2H)5.27(d，J=7.8Hz，2H)7.30(d，J=8.6Hz，2H)7.37-7.44(m，2H)7.72(s，1H)8.49(s，1H)8.70(d，J=2.3Hz，1H)8.78(s，1H)8.94(s，1H)9.64(s，1H)。

Preparation 204: n- (5- {7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl ] -7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl } -pyridin-3-yl) -2- (4-trifluoromethyl-phenyl) -acetamide:

(5-amino-pyridin-3-yl) - {7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } -methanone (preparation 216, 30mg, 0.068mmol) was dissolved in dry pyridine (2mL) under a nitrogen atmosphere, to which was added (4-trifluoromethyl-phenyl) -acetic acid (21mg, 0.102mmol), followed by HATU (39mg, 0.102 mmol). The reaction was heated to 50 ℃ and stirred overnight. The reaction was then cooled to room temperature, diluted with dichloromethane (5mL) and saturated aqueous sodium bicarbonate (5mL) was added. The phases were separated and the aqueous layer was extracted with dichloromethane (3 × 5 mL). The combined organic layers were concentrated to dryness to give N- (5- {7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl ] -7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl } -pyridin-3-yl) -2- (4-trifluoromethyl-phenyl) -acetamide as a light yellow solid, 39mg, 92% yield.

¹H NMR(400MHz，DMSO-d₆)　-0.29(s，6H)0.58(s，9H)3.84(s，2H)4.16(s，2H)4.77(d，J=7.4Hz，2H)5.21(d，J=7.4Hz，2H)7.56(d，J=7.8Hz，2H)7.68(d，J=7.8Hz，2H)8.28(s，1H)8.46(t，J=2.1Hz，1H)8.69(d，J=2.0Hz，1H)8.91-8.95(m，2H)9.46(s，1H)10.71(s，1H)。

Preparation 205: 2-allyl-malonic acid diethyl ester

Diethyl malonate (100g, 0.625mol) was added dropwise to a mixture of sodium ethoxide (46.8g, 0.688mol) in ethanol (1L) at 0 ℃. The reaction mixture may be stirred for 4 hours. 3-bromo-propene (83.2g, 0.688moles) was added dropwise to the mixture at 0 ℃. 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 give the title compound in 86% yield, 100g, which was used in the next step without further purification.

Preparation 206: 5-allyl-6-hydroxy-3H-pyrimidin-4-one

Diethyl 2-allyl-malonate (preparation 205, 100g, 0.5mol) was added dropwise at 0-5 ℃ to a mixture of sodium methoxide (27g, 0.5mol) in ethanol (1L), and the mixture was stirred at that temperature for 10 min. Formamidine acetate (51.9g, 0.5mol) was added and the mixture was stirred at 0-20 ℃ overnight at room temperature. The solvent was removed in vacuo and aqueous hydrochloric acid (36.5%) and water were added to adjust the pH to about 3. The resulting mixture was filtered to give the title compound as a colorless solid in 57% yield, 87.12g.

¹H NMR(400MHz，DMSO-d₆)δ：2.96(d，1H)，4.89(m，2H)，5.76(m，1H)，7.89(s，1H)。

Preparation 207: 5-Allyl-4, 6-dichloro-pyrimidine

5-allyl-6-hydroxy-3H-pyrimidin-4-one (preparation 206, 40g, 0.263mol) was added to POCl at room temperature₃(100 mL). The solution was stirred and warmed to reflux for 8 hours. The mixture was evaporated in vacuo to remove most of the POCl₃. The residue was poured slowly onto ice-water, extracted with ethyl acetate (500mL x4), washed with brine (300mL), dried over sodium sulfate and evaporated in vacuo to give the title compound as a yellow oil, 59% yield, 31g.

¹H NMR(400MHz,CDCl₃)δ：3.59(m，2H)，5.09(m，2H)，5.79(m，1H)，8.59(s，1H)。

Preparation 208: (4, 6-dichloro-pyrimidin-5-yl) -acetaldehyde

To a stirred solution of 5-allyl-4, 6-dichloro-pyrimidine (preparation 207, 30g, 0.159mole) in dry dichloromethane (400mL) was added bubbled ozone for 30min at-70 ℃. After purging excess ozone with nitrogen, dimethyl sulfide (10mL) was added at-5 ℃ and the reaction was stirred for 2 hours. The mixture was washed with water, brine, dried over sodium sulfate and evaporated in vacuo. The crude material was purified by trituration from pentane-ether to give the title compound as a colourless solid, 84% yield, 10g.

¹H NMR(400MHz,CDCl₃)δ：4.15(s，2H)，8.74(s，1H)，9.80(s，1H)。

Preparation 209: 2- (4-chloro-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-hydroxymethyl-propane-1, 3-diol

Tris-amine (1.27g, 10.5mmol) was added to 4, 6-dichloro-pyrimidin-5-yl) -acetaldehyde (preparation 208, 1.0g, 5.2mmol) in ethanol (40mL) and stirred at reflux for 16 h. The reaction mixture was evaporated in vacuo and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The separated aqueous phase was extracted 2 more times with dichloromethane and the combined organic layers were washed with saturated brine and evaporated in vacuo to give the title compound as a yellow foam in 74% yield, 1.0 g.

¹H NMR(400MHz,CDCl₃) δ ppm2.97(br.s, 1H), 3.09-3.27(m, 2H), 3.51(d, J =9.18Hz, 1H), 3.83-4.00(m, 4H), 4.06(d, J =11.13Hz, 1H), 5.43(dd, J =6.44, 1.76Hz, 1H), 6.16(dd, J =10.74, 4.69Hz, 1H), 8.40(s, 1H); LCMS (system 2): r_t=1.04min；m/z258[M+H]⁺.

Preparation 210: toluene-4-sulfonic acid 2- (4-chloro-pyrrolo [2,3-d ] pyrimidin-7-yl) -3-hydroxy-2-hydroxymethyl-propyl ester

Triethylamine (0.879mL, 6.31mmol) and trimethylamine hydrochloride (253mg, 2.65mmol) were added to a solution of 2- (4-chloro-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-hydroxymethyl-propane-1, 3-diol (preparation 209, 650mg, 2.52mmol) in dichloromethane (20mL) at 0 ℃. The mixture was treated stepwise with tosyl chloride (505mg, 2.65mmol) and stirred at 0 ℃ for 16 h. The reaction mixture was treated with water and stirred for 10 min. The resulting mixture was washed with citric acid, saturated aqueous sodium bicarbonate and saturated brine, then evaporated in vacuo. The crude product was purified by silica gel column chromatography (EtOAc: DCM0: 100-30: 70 gradient) to give the title compound as a colorless solid in 55% yield, 570 mg.

LCMS (system 2): r_t=1.28min；m/z412[M+H]⁺.

Preparation 211: [3- (4-chloro-pyrrolo [2,3-d ] pyrimidin-7-yl) -oxetan-3-yl ] -methanol

N-butyllithium (12.2mL, 30.6mmol, 2.5M in hexanes) was added to toluene-4-sulfonic acid 2- (4-chloro-pyrrolo [2,3-d ] in THF (100mL) at 0 deg.C]Pyrimidin-7-yl) -3-hydroxy-2-hydroxymethyl-propyl ester (preparation 210, 5.73g, 13.9mmol) was stirred for 5 min. The reaction mixture was then warmed to room temperature and stirred for 16 hours, at which time it was quenched with saturated aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (100mL x3) and the combined organic phases were dried (MgSO₄) And (4) concentrating in vacuum. The crude product was triturated with dichloromethane and filtered to give the title compound in 36% yield, 1.2g.

¹H NMR(400MHz，MeOH-d₄)δ：4.15(s，2H)，4.92(d，J=7.22Hz，2H)，5.22(d，J=7.03Hz，2H)，6.69(d，J=3.51Hz，1H)，7.51(d，J=3.71Hz，1H)，8.51(s，1H)。

Preparation 212: 7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl ] -4-chloro-7H-pyrrolo [2,3-d ] pyrimidine

Imidazole (277mg, 4.07mmol) was added to [3- (4-chloro-pyrrolo [2,3-d ] pyrimidin-7-yl) -oxetan-3-yl ] -methanol (preparation 211, 650mg, 2.71mmol) in dichloromethane (10mL) and the mixture was treated with a solution of tert-butyldimethylsilyl chloride (495mg, 3.25mmol) 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 × 50mL), the combined organic phases were washed with water and saturated brine and evaporated in vacuo to give the title compound as a light brown oil in 91% yield 875 mg.

¹H NMR(400MHz，CDCl₃) δ: -0.21(s, 6H), 0.77(s, 9H), 4.22(s, 2H), 4.88(d, J =7.22Hz, 2H), 5.19(d, J =7.03Hz, 2H), 6.61(d, J =3.71Hz, 1H), 7.11(d, J =3.71Hz, 1H), 8.55(s, 1H); LCMS (system 2): r_t=1.82min；m/z354[M+H]⁺.

Preparation 213: 7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl ] -7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared according to the procedure described for preparation 8 using 7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl ] -4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (preparation 212) to afford the title compound as a brown oil in 82% yield of 650 mg.

¹H NMR(400MHz，CDCl₃) δ: -0.24(s, 6H), 0.76(s, 9H), 4.24(s, 2H), 4.91(d, J =7.03Hz, 2H), 5.22(d, J =7.03Hz, 2H), 6.55(d, J =3.51Hz, 1H), 7.08(d, J =3.71Hz, 1H), 8.78(s, 1H), 8.97(s, 1H); LCMS (system 2): r_t=0.90min；m/z320[M+H]⁺.

Preparation 214: 7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl ] -5-iodo-7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared according to the procedure described for preparation 14 using 7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl ] -7H-pyrrolo [2,3-d ] pyrimidine (preparation 213) and DMF to give the title compound as a brown solid in 75% yield, 675 mg.

¹H NMR(400MHz，CDCl₃) δ: -0.24(s, 6H), 0.77(s, 9H), 4.20(s, 2H), 4.88(d, J =7.22Hz, 2H), 5.21(d, J =7.03Hz, 2H), 7.17(s, 1H), 8.77(s, 1H), 8.81(s, 1H); LCMS (system 2): r_t=1.55min；m/z446[M+H]⁺.

Preparation 215: (7- (3- (((tert-butyldimethylsilyl) oxy) methyl) oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (5- ((diphenylmethylene) amino) pyridin-3-yl) methanone

The title compound was prepared according to the procedure described for preparation 24 using 7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl ] -5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (preparation 214) and 5- [ (diphenylmethylene) amino ] -N-methoxy-N-methylnicotinamide (preparation 23) to give the title compound as a purple solid in 51% yield 240 mg.

¹H NMR(400MHz，CDCl₃)δ：0.20(s，6H)，0.70(s，9H)，4.28(s，2H)，4.89(d，J=7.22Hz，2H)，5.20(d，J=7.22Hz，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=7.42Hz，2H)，8.18(d，J=2.54Hz，1H)，8.60(d，J=1.95Hz，1H)，8.93(s，1H)，9.60(s，1H)。

Preparation 216: (5-amino-pyridin-3-yl) - {7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } -methanone

The title compound was prepared according to the procedure described for preparation 37 using (7- (3- (((tert-butyldimethylsilyl) oxy) methyl) oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (5- ((diphenylmethylene) amino) pyridin-3-yl) methanone (preparation 215) to give the title compound as a colorless individual in 76% yield, 132 mg.

¹H NMR(400MHz，CDCl₃)δ：0.01(s，6H)，0.88(s，9H)，4.11(br.s，2H)，4.45(s，2H)，5.17(m，2H)，5.40(m，2H)，7.58(s，1H)，7.80(s，1H)，8.45(s，1H)，8.61(s，1H)，9.15(s，1H)，9.83(s，1H)。

Preparation 217: 2- (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-methylpropan-1, 3-diol

The title compound was prepared according to the procedure described for preparation 1 using (4, 6-dichloropyrimidin-5-yl) acetaldehyde (preparation 208) and 2-amino-2-methylpropane-1, 3-diol to give the title compound as a yellow liquid in 79% yield, 3.88g.

¹H NMR(400MHz，DMSO-d₆)δ：1.66(s，3H)，3.86(dd，2H)，4.13(dd，2H)，4.92(t，2H)，6.58(d，1H)，7.73(d，1H)，8.59(s，1H)。

Preparation 218: 4-chloro-7- (3-methyloxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine

n-BuLi (6.6mL of a 2.5M solution in hexane, 16.5mmol) was added to 2- (4-chloro-7H-pyrrolo [2,3-d ] at-78 deg.C]Pyrimidin-7-yl) -2-methylpropan-1, 3-diol (preparation 217, 3.63g, 15.0mmol) in THF (80 mL). The reaction mixture was warmed to-50 ℃ over 2 hours and a solution of TsCl (3.15mg, 16.5mmol) in THF (20mL) was added to the reaction. The reaction system was warmed to 0 ℃ over 3 hours, and n-BuLi (6.6mL of a 2.5M solution in hexane, 16.5mmol) was added slowly to the reaction mixture. The mixture was stirred at 0 ℃ for 1 hour and at 60 ℃ for 16 hours. After cooling to room temperature, 50mL of saturated NH were used₄The reaction was stopped with aqueous Cl and 100mL water and the mixture was extracted with EtOAc (3 × 100 mL). With MgSO₄The combined organic layers were dried and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EtOAc: heptane 20: 80-70: 30 gradient) to give a solid, 55% yield, 1.87 mg.

¹H NMR(400MHz，DMSO-d₆)δ：1.79(s，3H)4.72(d，2H)5.15(d，2H)6.69(d，1H)7.78(d，1H)8.59(s，1H)。

Preparation 219: 7- (3-Methyloxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared according to the procedure described for preparation 8 using 4-chloro-7- (3-methyloxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine (preparation 218) to give the title compound as a yellow liquid in 22% yield, 0.341g.

¹H NMR(400MHz，DMSO-d₆)δ：1.81(s，3H)，4.72-4.77(m，2H)，5.16-5.21(m，2H)，6.69(d，1H)，7.66(d，1H)，8.76(s，1H)，9.02(s，1H)。

The title compound can also be prepared according to the following method:

LiHMDS (14.5mL of a 1M solution in THF, 14.5mmol) was added slowly over a 2 hour period to 2-methyl-2-pyrrolo [2,3-d ] at 0 ℃ under a nitrogen atmosphere]Solution of pyrimidin-7-yl-propane-1, 3-diol (preparation 278, 3g, 14.5mmol) in anhydrous THF (200mL) (using syringe pump). After the addition was complete, the reaction mixture was stirred for a further 40min, then TsCl (2.76g, 14.5mmol) was added slowly as a solution in THF (50 mL). The mixture was stirred at 0 ℃ for a further 1 hour. TLC showed the starting material was consumed and another equivalent of LiHMDS (14.5mL, 14.5mmol) was added to the mixture, which was heated at 60 ° for 16 hours. Then heating saturated NH₄Aqueous Cl (200mL), then the mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (Na)₂SO₄) And (4) evaporating in vacuum. The crude material was purified by silica gel column chromatography (EtOAc: hexanes 3: 7-2: 3 gradient) to give the title compound as a colorless gum in 37% yield, 1g.

Preparation 220: 5-iodo-7- (3-methyloxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared according to the procedure described for preparation 14 using 7- (3-methyloxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine (preparation 219) to give the title compound as a yellow solid in 78% yield, 0.44g.

¹H NMR(400MHz，DMSO-D6)δ：1.80(s，3H)，4.71(d，2H)，5.18(d，2H)，7.94(s，1H)，8.76(s，1H)，8.82(s，1H)。

Preparation 221: (5- ((diphenylmethylene) amino) pyridin-3-yl) (7- (3-methyloxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone

The title compound was prepared according to the procedure described for preparation 24 using 5-iodo-7- (3-methyloxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine (preparation 220) to afford the title compound.

LCMS (system 2): r_t=1.24min；m/z474[M+H]⁺.

Preparation 222: (5-Aminopyridin-3-yl) [7- (3-methyloxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] methanone

The procedure described for preparation 37 was followed using (5- ((diphenylmethylene) amino) pyridin-3-yl) (7- (3-methyloxetan-3-yl) -7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) methanone (preparation 221) the title compound was prepared as a white solid in 14% yield in 2 steps, 64 mg.¹H NMR(400MHz，DMSO-d₆) δ: 1.89(s, 3H), 4.75(d, 2H), 5.23(d, 2H), 5.64(br s, 2H), 7.29-7.36(m, 1H), 8.17(d, 1H), 8.24(d, 1H), 8.41(s, 1H), 8.95(s, 1H), 9.46(s, 1H); LCMS (system 4): r _t=2.30min；m/z310[M+H]⁺.

Preparation 223: n- [5- ({7- [3- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) oxetan-3-yl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } carbonyl) pyridin-3-yl ] -2- (5-chloropyridin-2-yl) acetamide

(5-amino-pyridin-3-yl) - {7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl]-7H-pyrrolo [2,3-d]Pyrimidin-5-yl } -methanone (preparation 216, 30mg, 0.068mmol) was added to a stirred mixture of (5-chloropyridin-2-yl) acetic acid (17.5mg, 0.102mmol) and HATU (38.8mg, 0.102mmol) in pyridine (2 ml). The reaction mixture was warmed to 50 ℃ and stirred at this temperature for 14 hours. The reaction was then cooled and a further portion of HATU (38.8mg, 0.102mmol) was added. The reaction was warmed to 50 ℃, stirred at that temperature for 8 hours, then cooled to room temperature and stirred for an additional 60 hours. The reaction was then diluted with DCM (20ml) and saturated NaHCO₃(20ml) the resulting solution was quenched. The layers were separated and the aqueous layer was extracted with DCM (3 × 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 (35mg), which was used to prepare example 238.

Preparation 224: n- [5- ({7- [3- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) oxetan-3-yl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } carbonyl) pyridin-3-yl ] -2- [3- (trifluoromethyl) -1H-pyrazol-1-yl ] acetamide

(5-amino-pyridin-3-yl) - {7- [3- (tert-butyl-dimethyl-silanyloxymethyl) -oxetan-3-yl]-7H-pyrrolo [2,3-d]Pyrimidin-5-yl } -methanone (preparation 216, 3)0mg, 0.068mmol) was added to a stirred [3- (trifluoromethyl) -1H-pyrazol-1-yl group]Acetic acid (19.8mg, 0.102mmol) and HATU (38.8mg, 0.102mmol) in pyridine (2 ml). The reaction mixture was warmed to 50 ℃ and stirred at this temperature for 14 hours. The reaction mixture was then cooled to room temperature, diluted with DCM (20ml) and saturated NaHCO₃(20ml) the resulting solution was quenched. The layers were separated and the aqueous layer was extracted with DCM (3 × 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 (44mg), which was used to prepare example 239.

Preparation 225: 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine

To 4-chloro-7H-pyrrolo [2,3-d]A suspension of pyrimidine (70.5g, 0.45mol) in DCM (1.8L) was added N-iodosuccinimide (120g, 0.54mol) in portions. After addition, the mixture was stirred at room temperature overnight. The solid was filtered, washed with water (250mL), MeOH (280mL), and CH₂Cl₂(280mL) were washed sequentially. Vacuum drying the solid to obtain 4-chloro-5-iodo-7H-pyrrolo [2,3-d ]Pyrimidine was a brown solid, 79% yield, 107g.

Preparation 226: 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine

To 4-chloro-5-iodo-7H-pyrrolo [2,3-d at 0 deg.C]Pyrimidine (preparation 225, 30g, 0.1mol), Cs₂CO₃(50g, 0.15mol) to a mixture in DMF (150mL) MeI (28.4g, 0.2mol) was added dropwise. After the addition, the mixture was stirred at room temperature for 10 hours. The reaction mixture was cooled to 0 ℃ and quenched by addition of water (500mL), then the solid was collected by filtration and Et₂O (100mL) to give 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d]Pyrimidine was a brown solid, 61% yield, 20 g.

Preparation 227: 5-bromo-N-methoxy-N-methyl-nicotinamide

To a solution of 5-bromo-nicotinic acid (100g, 0.5mol) in THF (2L) at 0 deg.C was added (COCl)₂(95g, 0.74 mol). After stirring for 0.5h Et was added₃N (152g, 1.5mol) and O, N-dimethylhydroxylamine HCl (140g, 1.5 mol). The reaction mixture was stirred at room temperature for 2.5 h, then water (200mL) and EtOAc (500mL) were added. The organic layer was separated and dried (MgSO)₄) Concentration in vacuo afforded the 5-title compound as a brown oil in 82% yield, 100%.

Preparation 228: (4-chloro-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (5- ((diphenylmethylene) amino) pyridin-3-yl) methanol

At-75 ℃ in N₂Stirring 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d in an atmosphere]To a solution of pyrimidine (preparation 226, 6.6g, 22.7mmol) in THF (130mL) was added n-BuLi (18.2mL of a 2.5M solution in hexane, 45mmol) and the mixture was stirred for 50 min. A solution of 5- ((diphenylmethylene) amino) nicotinaldehyde (preparation 106, 6.5g, 22.7mmol) in dry THF (50mL) was added and the mixture was stirred at-70 ℃ for 80 min. With saturated NH₄The mixture was quenched with aqueous Cl and extracted with EtOAc (300 mL). Drying the organic layer (Na)₂SO₄) Concentration in vacuo gave the title compound as a brown solid in 48% yield, 5.2 g.

Preparation 229: (4-chloro-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) (5- ((diphenylmethylene) amino) pyridin-3-yl) methanone

To (4-chloro-7-methyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) (5- ((diphenylmethylene) amino) pyridin-3-yl) methanol (preparation 228, 11.4g, 25mmol) in CH₂Cl₂(150mL) was added portionwise to a solution of dess-Martin periodinane (15.9g, 37 mmol). The reaction mixture was stirred at room temperature for 10 hours, then aqueous NaOH (30mL) was added. The mixture was stirred for a further 0.5 h. Then separating the mixture with CH₂Cl₂The aqueous layer was extracted (100 mL. times.2). The combined organic layers were concentrated and washed with diethyl ether to give the title compound as a brown solid in 99% yield, 11g.

¹H NMR(400MHz，CDCl₃)　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-pyridin-3-yl) - (4-chloro-7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -methanone

To [5- (benzhydrylidene-amino) pyridin-3-yl]- (4-chloro-7-methyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) -methanone (preparation 229, 30g, 0.066mol) in THF (200mL) was added aqueous citric acid solution (200mL) and the mixture was stirred at room temperature for 30 min. Diethyl ether was added and the layers were separated. With Na₂CO₃The aqueous layer was adjusted to pH 7. The mixture was then filtered. The filter cake was evaporated with toluene and the residue was washed with EtOAc (200mL) to give the title compound as a brown solid in 95% yield, 18 g.

Preparation 231: (5-amino-pyridin-3-yl) - (7-methyl-4-methylsufanyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -methanone

To (5-amino-pyridin-3-yl) - (4-chloro-7-methyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) -methanone (preparation 230, 21g, 0.073mol) in MeOH (300mL) was added CH₃SNa (15.5g, 0.22 mol). The resulting mixture was stirred at room temperature for 7 hours. The mixture was poured into ice-water (200mL), the precipitate was filtered, and the filter cake was washed with water (100mL) and then acetone (20mL) to give (5-amino-pyridin-3-yl) - (7-methyl-4-methylsulfanyl-7H-pyrrolo [2, 3-d) ]Pyrimidin-5-yl) -methanone was a brown solid in 69% yield, 15 g.

Preparation 232: (5-amino-pyridin-3-yl) - (7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -methanone

Reacting (5-amino-pyridin-3-yl) - (7-methyl-4-methylsulfanyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) -methanone (preparation 231, 1.5g, 5mmol), Raney Ni (10g) and NH₃H₂O (150mL) in twoThe mixture in alkane (150mL) was refluxed for 6 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to give (5-amino-pyridin-3-yl) - (7-methyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) -methanone was a brown solid in 15% yield, 0.19g.¹H NMR(400MHz DMSO-d₆)3.88(s，3H)，5.63(s，2H)，7.27-7.28(m，1H)，8.15-8.18(m，2H)，8.40(s，1H)，8.97(s，1H)，9.42(s，1H)。

Preparation 233: 5,6,7, 8-tetrahydro- [1,7] naphthyridine hydrochloride

Argon gas is used to supply 7-benzyl-5, 6,7, 8-tetrahydro- [1,7]]Methanol solution of naphthyridine (25mL) (J.het.chem.2001, 38, 535) (1.5g, 6.69mmol) was degassed for 20min, then 4N HCl bis (HCl) was addedThe alkane solution (2mL) and Pd/C (300mg, 20wt%) were stirred at room temperature for 24h under a 50psi hydrogen atmosphere. After completion of the reaction, the mixture was filtered through a short pad of celite and washed with methanol (4 × 25 mL). The filtrate was evaporated to dryness in vacuo and crystallized from methanol to give the title compound as a pale yellow solid in 65% yield (calculated as 2HCl salt), 900 mg.

¹H NMR (400MHz, DMSO-D6) delta: 3.10(t, 2H), 3.40(q, 2H), 4.36(s, 2H), 7.50(dd, 1H), 7.91(d, 1H), 8.55(d, 1H), 9.96(brs, 2H); LCMS (system 10): r_t=1.56min；m/z135.2[M+H]⁺.

234 preparation: (5, 8-dihydro-6H- [1,7] naphthyridin-7-yl) -acetic acid tert-butyl ester

Mixing 5,6,7, 8-tetrahydro- [1,7]]A solution of naphthyridine hydrochloride (preparation 233, 400mg, 1.93mmol), bromo-tert-butyl acetate (414.1mg, 2.12mmol) and triethylamine (1.64mL, 11.92mmol) in DMF (8mL) was heated at 80 ℃ for 16 h. The reaction mixture was diluted with EtOAc (40mL), washed with water (3X25mL), brine (20mL), and Na₂SO₄Drying and evaporation to dryness in vacuo gave the title compound as a colourless viscous solid in 100% yield, 480mg.

¹H NMR (400MHz, DMSO-D6) delta: 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_t=3.02min；m/z249.4[M+H]⁺.

Preparation 235: (5, 8-dihydro-6H- [1,7] naphthyridin-7-yl) -acetic acid hydrochloride

Di (4N HCl) at room temperatureAlkane solution (25ml) 5, 8-dihydro-6H- [1,7]Naphthyridin-7-yl) -acetic acid tert-butyl ester (preparation 234, 1.25g, 5.03mmol) was treated for 2 hours. The mixture was evaporated to dryness in vacuo and the solid residue triturated with ether to give the title compound as a white solid in 78% yield (calculated as the HCl salt), 900mg.

¹H NMR(400MHz，MeOD)δ：3.38(t，2H)，3.79(t，2H)，4.38(s，2H)，4.84(s，2H)，7.79(dd，1H)，8.25(d，1H)，8.70(d，1H)。

Preparation 236: phenyl- [ (tetrahydro-pyran-2-yloxy) ] -acetic acid

To a stirred solution of hydroxy-phenyl-acetic acid (2g, 13.4mmol) in DCM (30mL) was added PTSA (51.2mg, 0.27mmol) at 0 deg.C, followed by 3, 4-dihydro-2H-pyran (1.55g, 18.4 mmol). The mixture was stirred at 0 ℃ for a further 15min, then gradually warmed to room temperature and stirred for a further 1.5 h. The reaction mixture was diluted with DCM (100 mL). With Na₂CO₃Saturated aqueous solution (2X20mL), water (20mL), brine (20 m)L) washing the organic phase and drying (Na)₂SO₄) And (4) evaporating in vacuum. The crude material was purified by silica gel column chromatography (EtOAc: petroleum ether 2:5) to give the title compound as a yellow viscous solid, 48% yield, 1.5g.lcms (system 10): r_t=1.82min；m/z237[M+H]⁺.

Preparation 237: n- [5- (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl) -pyridin-3-yl ] -2-phenyl-2- (tetrahydro-pyran-2-yloxy) -acetamide

The title compound was prepared according to the procedure described for example 1 using phenyl- [ (tetrahydro-pyran-2-yloxy) ] -acetic acid (preparation 236) and (5-amino-pyridin-3-yl) - (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -methanone (preparation 95) to give the title compound as a yellow solid in 68% yield, 60mg.

LCMS (system 10): r_t=3.56min；m/z500.2[M+H]⁺.

Preparation 238: 5-bromo-6-hydroxy-nicotinic acid

Bromine (3.6mL, 70.5mmol) was added dropwise to a suspension of 6-hydroxy-nicotinic acid (7g, 50.32mmol) in water (70mL) at 0 deg.C, and the mixture was stirred at room temperature for 4 hours. The precipitated solid was filtered, washed with cold water and dried to give the title compound as an off-white solid in 82% yield, 9g.

¹H NMR(400MHz，DMSO-D6)δ：8.03(d，1H)，8.14(d，1H)，12.57(br s，1H)。

Preparation 239: 5-bromo-6-hydroxy-N-methoxy-N-methyl-nicotinamide

5-bromo-6-hydroxy-nicotinic acid (preparation 238, 4g, 18.4mmol), HATU (13.95g, 36.71mmol), O, N-dimethyl-hydroxylamine hydrochloride (2.15g, 22.02mmol) and DIPEA (15.82mL, 91.75mmol) were dissolved in anhydrous DMF (30 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (150mL) and saturated Na₂CO₃Washed with aqueous solution (2 × 50mL), water (4 × 30mL), brine (30mL), dried (Na)₂SO₄) And (4) evaporating in vacuum. The crude mixture was purified by column chromatography (EtOAc: Hex4: 6-6: 4 gradient) to give the title compound as a bright yellow viscous solid, 38%, 1.8g.

¹H NMR (400MHz, DMSO-D6) delta: 3.22(s, 3H), 3.61(s, 3H), 7.95(d, 1H), 8.14(d, 1H), 12.45(br s, 1H); LCMS (system 10): r_t=1.67min；m/z261，263[M+H]⁺.

Preparation 240: 5-bromo-6-ethoxy-N-methoxy-N-methyl-nicotinamide

A mixture of 5-bromo-6-hydroxy-N-methoxy-N-methyl-nicotinamide (preparation 239, 1.80g, 6.90mmol), iodoethane (2.8mL, 34.5mmol), and silver carbonate (3.8g, 13.8mmol) in DCM (10mL) was stirred at room temperature for 40 h. The reaction mixture was diluted with DCM (50mL), washed with water (2 × 30mL), brine (20mL), dried (Na) ₂SO₄) And (4) evaporating in vacuum. The crude material was purified by silica gel column chromatography (EtOAc: petroleum ether 2:5) to give the title compound as a yellow viscous solid in 30% yield, 600mg.

¹H NMR(400MHz，CDCl3)δ：1.44(t，3H)，3.35(s，3H)，3.57(s，3H)，4.47(q，2H)，8.23(d，1H)，8.54(d，1H)。

Preparation 241: (5-bromo-6-ethoxy-pyridin-3-yl) - (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -methanone

Reacting 5-iodo-7-isopropyl-7H-pyrrolo [2,3-d ] in a nitrogen atmosphere]A solution of pyrimidine (preparation 93, 530mg, 1.85mmol) in dry ether (8mL) was cooled to-78 deg.C and n-BuLi (1mL of a 2.03M solution in hexane, 2.03mmol) was added dropwise over a 10min period. Just after the N-BuLi addition was complete, a solution of 5-bromo-6-ethoxy-N-methoxy-N-methyl-nicotinamide (preparation 240) in dry diethyl ether (7mL) was slowly added to the mixture, which was stirred at the same temperature for an additional 1 hour. The reaction mixture was warmed to room temperature and stirred for an additional 1 hour with saturated NH₄Aqueous Cl (15mL) was quenched. The mixture was extracted with EtOAc (3X15mL), washed with water (20mL), brine (15mL), dried (Na)₂SO₄) And (4) evaporating in vacuum. The crude material was purified by silica gel column chromatography (EtOAc: petroleum ether 2:10) to give the title compound as a yellow gum in 49% yield, 350mg.

¹H NMR(400MHz，CDCl3)δ：1.50(t，3H)，1.60(d，6H)，4.55(q，2H)，5.15-5.20(m，1H)，7.82(s，1H)，8.32(d，1H)，8.57(d，1H)，9.00(s，1H)，9.53(s，1H)。

Preparation 242: (5-amino-6-ethoxy-pyridin-3-yl) - (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -methanone

Copper (I) oxide (38.6mg, 0.27mmol) was added to (5-bromo-6-ethoxy-pyridine) in concentrated ammonia solution (6mL) and NMP (1mL)3-yl) - (7-isopropyl-7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) -methanone (preparation 241, 350mg, 0.89 mmol). The mixture was heated at 130 ℃ for 17 hours in a sealed container. The reaction mixture was cooled to room temperature and diluted with water (10 ml). Extracted with 20% i-PrOH in DCM (6X50mL) and dried (Na)₂SO₄) And (4) evaporating in vacuum. The crude material was purified by silica gel column chromatography (MeOH: DCM5:95) to give the title compound as a yellow solid in 24% yield, 70 mg. LCMS (system 10): r_t=2.99min；m/z326[M+H]⁺.

Preparation 243: 2- (4-chloro-phenyl) -3-hydroxy-propionic acid methyl ester

To a stirred solution of (4-chloro-phenyl) -acetic acid methyl ester (2g, 10.8mmol) in DMSO (22mL) was added sodium methoxide (29.2mg, 0.54mmol) at 0 ℃. Paraformaldehyde (342mg, 11.4mmol) was then added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (100mL), washed with water (3X20mL), brine (20mL), dried (Na)₂SO₄) And (4) evaporating in vacuum. The crude material was purified by silica gel column chromatography (hexanes: EtOAc100: 0-84: 16 gradient) to give the title compound as a colorless gum in 52% yield, 1.2 g.

¹H NMR (400MHz, CDCl3) delta: 2.23(t, 1H), 3.70(s, 3H), 3.79-3.83(m, 2H), 4.05-4.12(m, 1H), 7.20(d, 2H), 7.30(d, 2H); LCMS (system 10): r_t=3.03min；m/z215[M+H]⁺.

Preparation 244: 2- (4-chloro-phenyl) -3-hydroxy-propionic acid

2- (4) stirred at 0 deg.C-chloro-phenyl) -3-hydroxy-propionic acid methyl ester (preparation 243, 500mg, 2.33mmol) in THF (7mL) was added dropwise a solution of lithium hydroxide monohydrate (244mg, 5.82mmol) in water (2mL) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was acidified (pH 3) with 2N hydrochloric acid and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (10mL) and dried (Na)₂SO₄) And evaporated in vacuo to give the title compound as a white solid in 90% yield, 420mg.

¹H NMR(400MHz，DMSO-D6)δ：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 ] pyrimidin-7-yl) -cyclopropanecarboxylic acid methyl ester

To a stirred solution of (4, 6-dichloro-pyrimidin-5-yl) acetaldehyde (preparation 208, 2g, 10.5mmol) and 1-amino-cyclopropane-carboxylic acid methyl ester hydrochloride (1.33g, 11.6mmol) in ethanol (30mL) was added triethylamine (4.4mL, 31.6mmol), and the mixture was heated in a sealed tube at 100 ℃ for 10 hours. Acetic acid (1.21mL, 21.1mmol) was then added and the mixture heated at 100 ℃ for an 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 × 50mL), brine (50mL) and dried (Na) ₂SO₄) And (4) evaporating in vacuum. The crude material was purified by silica gel column chromatography (hexanes: EtOAc100: 0-90: 10 gradient) to give the title compound as a solid in 35% yield, 900 mg.

¹H NMR (400MHz, CDCl3) delta: 1.63-1.66(m, 2H), 1.96-1.99(m, 2H), 3.63(s, 3H), 6.60(d, 1H), 7.23(d, 1H), 8.65(s, 1H); LCMS (system 10): r_t=2.89min；m/z252.1[M+H]⁺.

Preparation 246: 1-pyrrolo [2,3-d ] pyrimidin-7-yl-cyclopropanecarboxylic acid methyl ester

A solution of methyl 1- (4-chloro-pyrrolo [2,3-d ] pyrimidin-7-yl) -cyclopropanecarboxylate (preparation 245, 920mg, 3.65mmol) in ethanol (20mL) was degassed with argon for 15 min. Ammonium hydroxide (4mL) and 10% palladium on carbon were added and the reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 5 hours. The reaction mixture was filtered through a pad of celite, washed with ethanol (2 × 10mL), the filtrate was concentrated in vacuo and the crude material was purified by silica gel column chromatography (DCM: methanol gradient 100: 0-98: 2) to give the title compound as a gum in 59% yield, 470 mg.

¹H NMR (400MHz, CDCl3) delta: 1.63-1.66(m, 2H), 1.95-1.99(m, 2H), 3.63(s, 3H), 6.55(d, 1H), 7.20(d, 1H), 8.90(s, 1H), 8.94(s, 1H); LCMS (system 10): r_t=2.22min；m/z218.2[M+H]⁺.

Preparation 247: (1-pyrrolo [2,3-d ] pyrimidin-7-yl-cyclopropyl) -methanol

To the stirred 1-pyrrolo [2,3-d]To a solution of pyrimidin-7-yl-cyclopropanecarboxylic acid methyl ester (preparation 246, 610mg, 2.80mmol) in ethanol (15mL) was added sodium borohydride (318.7mg, 8.42mmol) and the mixture was heated to reflux for 16 h. The reaction mixture was quenched with water (5mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (5mL), brine (5mL) and dried (Na)₂SO₄) And (4) evaporating in vacuum. The crude material was purified by silica gel column chromatography (DCM: methanol gradient 100: 0-98: 2) to give the title compound as a pale yellow solid in 47% yield, 250 mg.

Preparation 248: 7- [1- (tetrahydro-pyran-2-yloxymethyl) -cyclopropyl ] -7H-pyrrolo [2,3-d ] pyrimidine

To a stirred solution of (1-pyrrolo [2,3-d ] pyrimidin-7-yl-cyclopropyl) -methanol (preparation 247, 240mg, 1.27mmol) in THF (12mL) was added 3, 4-dihydro-2H-pyran (0.46mL, 5.07mmol), followed by PTSA (24mg, 0.13 mmol). The reaction mixture was stirred at 60 ℃ for 4 hours. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate (15mL), and extracted with dichloromethane (3 × 25 mL). The combined organic layers were washed with brine (10mL), dried over sodium sulfate and evaporated in vacuo. The crude material was purified by silica gel column chromatography (dichloromethane: methanol gradient 100: 0-98: 2) to give the title compound as a pale brown gum in 90% yield, 320 mg.

¹H NMR (400MHz, CDCl3) delta: 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_t=2.82min；m/z274.6[M+H]⁺.

Preparation 249: 5-iodo-7- [1- (tetrahydro-pyran-2-yloxymethyl) -cyclopropyl ] -7H-pyrrolo [2,3-d ] pyrimidine

To a stirred solution of 7- [1- (tetrahydro-pyran-2-yloxymethyl) -cyclopropyl ] -7H-pyrrolo [2,3-d ] pyrimidine (preparation 248, 390mg, 1.43mmol) in DMF (8mL) was added N-iodosuccinimide (481.5mg, 2.14mmol) and stirred at room temperature for 4 hours. The reaction mixture was quenched with water (8mL), extracted with ethyl acetate (3 × 20mL), and the combined organic layers were washed with water (5 × 15mL), brine (10mL), dried over sodium sulfate, and evaporated in vacuo. The crude material was purified by silica gel column chromatography (dichloromethane: methanol gradient 100: 0-99: 1) to give the title compound as a solid in 79% yield, 450 mg.

¹H NMR (400MHz, CDCl3) delta: 1.18-1.70(m, 10H), 3.28-3.32(m, 1H), 3.42(t, 1H), 3.65(d, 1H), 3.87(d, 1H), 4.47(s, 1H), 7.44(s, 1H), 8.70(s, 1H), 8.90(s, 1H); LCMS (system 10): r _t=3.28min；m/z400.2[M+H]⁺.

Preparation of 250: (5-bromo-pyridin-3-yl) - {7- [1- (tetrahydro-pyran-2-yloxymethyl) -cyclopropyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } -methanone

To a stirred solution of 5-iodo-7- [1- (tetrahydro-pyran-2-yloxymethyl) -cyclopropyl ] -7H-pyrrolo [2,3-d ] pyrimidine (preparation 249, 450mg, 1.13mmol) in diethyl ether (6mL) was added dropwise n-butyllithium (2M in hexane, 0.62mL, 1.24mmol) at-70 ℃. A solution of 5-bromo-N-methoxy-N-methyl-nicotinamide (304mg, 1.24mmol) in diethyl ether (2.5mL) was then added dropwise at-70 deg.C and stirred at the same temperature for an additional 30 minutes. The reaction was slowly warmed to room temperature. The reaction was quenched with saturated aqueous ammonium chloride (10mL), extracted with ethyl acetate (3 × 20mL), the combined organic layers were washed with water (20mL), brine (20mL), dried over sodium sulfate, and evaporated in vacuo. The crude material was purified by silica gel column chromatography (dichloromethane: methanol gradient 100: 0-98: 2) to give the title compound as a light brown viscous solid in 35% yield, 250 mg.

¹H NMR (400MHz, DMSO-D6) delta: 1.25-1.57(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 _t=3.17min；m/z456.8，459[M+H]⁺.

Preparation 251: (5-amino-pyridin-3-yl) - {7- [1- (tetrahydro-pyran-2-yloxymethyl) -cyclopropyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } -methanone

To a stirred solution of (5-bromo-pyridin-3-yl) - {7- [1- (tetrahydro-pyran-2-yloxymethyl) -cyclopropyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } -methanone (preparation 250, 200mg, 0.45mmol) in 1-methyl-pyrrolidin-2-one (1.5mL) was added ammonium hydroxide (15mL), followed by copper (I) oxide (3mg, 0.02mmol), and the reaction mixture was heated in a sealed tube at 130 ℃ for 16 hours. The reaction mixture was cooled to room temperature and extracted with 10% methanol in dichloromethane (5 × 25 mL). The combined organic layers were dried over sodium sulfate and evaporated in vacuo. The crude material was purified by silica gel column chromatography (dichloromethane: methanol gradient 100: 0-96: 4) to give the title compound as a white viscous solid in 45% yield, 80 mg.

¹H NMR (400MHz, DMSO-D6) delta: 1.17-1.53(m, 10H), 3.17-3.28(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_t=2.59min；m/z394.1[M+H]⁺.

Preparation 252: (S) -2-pyrrolo [2,3-d ] pyrimidin-7-yl-propan-1-ol

The title compound was prepared according to the procedure described for preparation 8 using (2S) -2- (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) propan-1-ol (preparation 4) to give the title compound as a white solid in 100% yield, 2.8g.

¹H NMR(400MHz，DMSO-d6)δ：1.43(d，3H)，3.68-3.79(m，2H)，4.89-4.94(m，1H)，4.97(t，1H)，6.61(d，1H)，7.71(d，1H)，8.75(s，1H)，8.97(s，1H)。

Preparation 253: (2-hydroxy-1, 1-dimethyl-ethyl) -carbamic acid tert-butyl ester

To a mixture of 2-amino-2-methyl-propan-1-ol (2g, 22.43mmol) and triethylamine (3.12mL, 22.43mmol) in THF was slowly added boc-anhydride (4.89g, 22.43mmol) at 0 deg.C and stirred at the same temperature for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and evaporated in vacuo to give the title compound as a colorless oil in 92% yield, 3.9g.

¹H NMR(400MHz，CDCl₃)δ：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

KOH (3.47g, 61.82mmol) was added to (2-hydroxy-1, 1-dimethyl-ethyl) -carbamic acid tert-butyl ester (preparation 253, 3.9g, 20.6mmol) in 1, 4-bisTo a solution in alkane (30mL), then slowly add dimethyl sulfate at room temperature. The mixture was stirred at room temperature for a further 48 hours. The reaction was filtered through a short pad of celite, washing with DCM (3 × 50 mL). The combined filtrates were washed with water (2 × 50mL), brine (30mL), dried over sodium sulfate and evaporated in vacuo to give the title compound as a yellow oil in 88% yield, 3.7g.

¹H NMR(400MHz，CDCl₃)δ：1.27(s，6H)，1.41(s，9H)，3.29(s，2H)，3.35(s，3H)，4.73(brs，1H)。

Preparation 255: 2-methoxy-1, 1-dimethyl-ethylamine

TFA (5.8mL, 78.7mmol) was added slowly to a solution of (2-methoxy-1, 1-dimethyl-ethyl) -carbamic acid tert-butyl ester (preparation 254, 3.2g, 15.74mmol) in DCM (25mL) at 0 ℃. The mixture was stirred at room temperature for a further 3 hours, and the volatiles were removed in vacuo. With saturated NaHCO₃The residue was treated with aqueous solution (50mL) and extracted with IPA/DCM mixture (1:4) (4X50 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness in vacuo to give the title compound as a light brown oil in 100% yield, 1.6 g.

1H NMR(400MHz，CDCl3)δ：1.32(s，6H)，3.30(s，2H)，3.35(s，3H)，7.80(brs，2H)。

Preparation of 256: (5-bromo-2-chloro-pyrimidin-4-yl) - (2-methoxy-1, 1-dimethyl-ethyl) -amine

Triethylamine (73.1mL, 526.6mmol) was added slowly to a solution of 5-bromo-2, 4-dichloro-pyrimidine (40g, 175.5mmol) in acetonitrile (400mL) at 0 deg.C, and then 2-methoxy-1, 1-dimethyl-ethylamine (preparation 255, 23.4g, 263.3mmol) was added stepwise to the mixture. The reaction mixture was stirred at room temperature for a further 16 hours. TLC showed the presence of untreated starting pyrimidine, but the reaction did not proceed any more. All volatiles were removed in vacuo and the residue was dissolved in ethyl acetate, washed with water, brine, dried over sodium sulfate and evaporated to dryness in vacuo. The crude material was purified by silica gel column chromatography (100-200 mesh, gradient ethyl acetate: hexanes 1: 9-2: 4) to give the title compound as a white solid in 23% yield (10 g of starting pyrimidine recovered), 12 g.

¹H NMR (400MHz, DMSO-D6) delta: 1.40(s, 6H), 3.32(s, 3H), 3.48(s, 2H), 6.19(s, 1H), 8.29(s, 1H); LCMS (system 10): r_t=3.56min；m/z294，296[M+H]⁺.

Preparation 257: [ 2-chloro-5- ((E) -2-ethoxy-vinyl) -pyrimidin-4-yl ] - (2-methoxy-1, 1-dimethyl-ethyl) -amine

The title compound was prepared according to the procedure described for preparation 61 using (5-bromo-2-chloro-pyrimidin-4-yl) - (2-methoxy-1, 1-dimethyl-ethyl) -amine (preparation 256), catecholborane and ethoxyacetylene (40% in hexane) to give the title compound as a light brown gum in 44% yield, 2.6g.

1H NMR (400MHz, DMSO-D6) delta: 1.25(t, 3H), 1.37(s, 6H), 3.26(s, 3H), 3.56(s, 2H), 3.92(q, 2H), 5.74(d, 1H), 6.12(s, 1H), 6.94(d, 1H), 7.88(s, 1H); LCMS (system 10): r_t=3.65min；m/z286.3[M+H]⁺.

Preparation 258: 2-chloro-7- (2-methoxy-1, 1-dimethyl-ethyl) -7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared according to the procedure described for preparation 62 using [ 2-chloro-5- ((E) -2-ethoxy-vinyl) -pyrimidin-4-yl ] - (2-methoxy-1, 1-dimethyl-ethyl) -amine (preparation 257) to afford the title compound as an off-white solid in 91% yield, 2g.

¹H NMR (400MHz, DMSO-D6) Δ 1.68(s, 6H), 3.17(s, 3H), 3.85(s, 2H), 6.62(D, 1H), 7.63(D, 1H), 8.90(s, 1H); LCMS (system 10): r _t=3.29min；m/z240[M+H]⁺.

Preparation 259: 2-chloro-5-iodo-7- (2-methoxy-1, 1-dimethyl-ethyl) -7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared according to the procedure described for preparation 63 using 2-chloro-7- (2-methoxy-1, 1-dimethyl-ethyl) -7H-pyrrolo [2,3-d ] pyrimidine (preparation 258) to give the title compound as a light yellow solid in 75% yield, 2.3g.

¹H NMR (400MHz, DMSO-D6) delta: 1.67(s, 6H), 3.17(s, 3H), 3.83(s, 2H), 7.81(s, 1H), 8.64(s, 1H); LCMS (system 10): r_t=3.65min；m/z365.8[M+H]⁺.

Preparation 260: (5-bromo-pyridin-3-yl) - [ 2-chloro-7- (2-methoxy-1, 1-dimethyl-ethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -methanone

The title compound was prepared according to the procedure described for preparation 64 using 2-chloro-5-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 give the title compound as a yellow gum in 34% yield, 900mg.

¹H NMR(400MHz，DMSO-D6)δ：1.73(s，6H)，3.21(s，3H)，3.90(s，2H)，8.22(s，1H)，8.42(t，1H)，8.98(t，2H)，9.35(s，1H)。

Preparation 261: [ 2-amino-7- (2-methoxy-1, 1-dimethyl-ethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] - (5-amino-pyridin-3-yl) -methanone

The title compound was prepared according to the procedure described for preparation 65 using (5-bromo-pyridin-3-yl) - [ 2-chloro-7- (2-methoxy-1, 1-dimethyl-ethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -methanone (preparation 260) to give the title compound as a yellow solid in 41% yield, 300mg.

¹H NMR (400MHz, DMSO-D6) delta: 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_t=2.40min；m/z341.2[M+H]⁺.

Preparation 262: 5-iodo-7- (2-methoxy-1, 1-dimethyl-ethyl) -7H-pyrrolo [2,3-d ] pyrimidine

A solution of 2- (5-iodo-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-methyl-propan-1-ol (preparation 22) (32g, 100.91mmol) in anhydrous THF (100mL) was slowly added to a suspension of NaH (60% solution in paraffin oil, 2.98g, 121.13mmol) in anhydrous THF (200mL) at 0 deg.C under a nitrogen atmosphere. The mixture was warmed to room temperature, stirred for an additional 30 minutes, cooled to 0 ℃ and iodomethane (19mL, 302.82mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness in vacuo. The crude material was purified by silica gel column chromatography (100-200 mesh, hexanes: EtOAc100: 0-70: 30 gradient) to afford the title compound as a yellow viscous solid in 22% yield, 7.5g.

¹H NMR (400MHz, DMSO-D6) delta: 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 _t=3.42min；m/z331.6[M+H]⁺.

Preparation 263: (5-bromo-pyridin-3-yl) - [7- (2-methoxy-1, 1-dimethyl-ethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -methanone

The title compound was prepared according to the procedure described for preparation 64 using 5-iodo-7- (2-methoxy-1, 1-dimethyl-ethyl) -7H-pyrrolo [2,3-d ] pyrimidine (preparation 262) and 5-bromo-N-methoxy-N-methyl-nicotinamide to give the title compound as a light brown gum in 51% yield, 3g.

¹H NMR(400MHz，DMSO-d₆) δ: 1.76(s, 6H), 3.19(s, 3H), 3.96(s, 2H), 8.17(s, 1H), 8.42(t, 1H), 8.98(brs, 2H), 9.00(s, 1H), 9.47(s, 1H); LCMS (system 10): r_t=3.13min；m/z388.6，390.6[M+H]⁺.

Preparation 264: 2- (3, 5-difluoro-pyridin-2-yl) -malonic acid diethyl ester

To a stirred solution of 2,3, 5-trifluoro-pyridine (2g, 15.02mmol) in dimethylsulfoxide (20mL) was added diethyl malonate (4.60g, 28.72mmol) followed by cesium carbonate (9.35g, 28.72mmol) and the reaction mixture was heated to 110 ℃ 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 × 25mL), brine (25mL), dried over sodium sulfate and evaporated in vacuo to give the title compound as an oil in 85% yield, 3.5 g.

¹H NMR(400MHz，CDCl₃)δ：1.25-1.30(m，6H)，4.20-4.29(m，4H)，4.88(s，1H)，7.77-7.81(m，1H)，8.01(s，1H)。

Preparation 265: (3, 5-difluoro-pyridin-2-yl) -acetic acid

To a stirred solution of diethyl 2- (3, 5-difluoro-pyridin-2-yl) -malonate (1g, 3.56mmol) (preparation 264) in THF (15mL) was added dropwise a solution of lithium hydroxide monohydrate (462mg, 10.4mmol) in water (4mL) at 0 deg.C and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, acidified (pH-3) with 2N hydrochloric acid and extracted with 20% isopropanol-dichloromethane (5 × 20 mL). The combined organic layers were dried (Na)₂SO₄) And (4) evaporating in vacuum. The crude material was purified by silica gel column chromatography (DCM: MeOH100: 0-95: 5 gradient) to give the title compound as a solid in 53% yield, 336mg.

¹H NMR (400MHz, DMSO-D6) delta 3.32(s, 2H), 7.74-7.79(m, 1H), 7.99(t, 1H); LCMS (system 10): r_t=0.65min；m/z174[M+H]⁺.

Preparation 266: (4-Nitro-phenyl) -acetic acid ethyl ester

To a stirred solution of (4-nitro-phenyl) -acetic acid (3g, 16.4mmol) in ethanol (30mL) was added sulfuric acid (1mL) and the reaction mixture was heated to reflux for 16 h. The reaction mixture was neutralized with 2N aqueous NaOH and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (Na)₂SO₄) Evaporation in vacuo gave the title compound as a pale yellow oil in 98% yield, 3.4 g.

¹H NMR(400MHz，CDCl₃)δ：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

A solution of (4-nitro-phenyl) -acetic acid ethyl ester (preparation 266, 3.4g, 16.1mmol) in methanol (100mL) was degassed with argon for 15min, treated with 10% palladium on carbon (700mg), and stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 16 h. The reaction mixture was filtered through celite, washed with methanol (2 × 20mL) and the filtrate was concentrated in vacuo to give the title compound as an oil in 96% yield, 2.8 g.

¹H NMR(400MHz，CDCl₃)δ：1.23(t，3H)，3.47(s，2H)，3.60(brs，2H)，4.11(q，2H)，6.63(d，2H)，7.05(d，2H)。

Preparation 268: (4-Formylamino-phenyl) -acetic acid ethyl ester

A mixture of acetic anhydride (0.33mL, 3.57mmol) and formic acid (0.17mL, 4.46mmol) was heated at 60 deg.C for 2 hours. The reaction mixture was cooled to 0 ℃, a solution of (4-amino-phenyl) -acetic acid ethyl ester (preparation 267, 500mg, 2.79mmol) in THF (10mL) was slowly added to the reaction mixture, and the reaction was stirred at room temperature for 16 hours. With saturated Na₂CO₃The reaction mixture was neutralized with aqueous solution and extracted with diethyl ether (2 × 25 mL). The combined organic layers were dried (Na)₂SO₄) And (4) evaporating in vacuum. The crude material was purified by silica gel column chromatography (DCM: MeOH100: 0-98: 2 gradient) to give the title compound as an oil in 93% yield, 500mg.

¹H NMR(400MHz，DMSO-d₆)δ：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

To a stirred solution of (4-formylamino-phenyl) -acetic acid ethyl ester (preparation 268, 500mg, 2.41mmol) in THF (10mL) at 0 deg.C was added borane-dimethyl sulfide complex (0.3mL, 3.13mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with MeOH (5mL) and evaporated in vacuo. The crude material was purified by silica gel column chromatography (hexanes: EtOAc100: 0-75: 25 gradient) to give the title compound as an oil in 91% yield, 460 mg.

¹H NMR(400MHz，CDCl₃)δ：1.23(t，3H)，2.81(s，3H)，3.48(s，2H)，3.66(br s，1H)，4.11(q，2H)，6.56(d，2H)，7.09(d，2H)。

Preparation 270: [4- (methylsulfonyl-methyl-amino) -phenyl ] -acetic acid ethyl ester

To a stirred solution of (4-methylamino-phenyl) -acetic acid ethyl ester (preparation 269, 418mg, 2.16mmol) in pyridine (4mL) was added methanesulfonyl chloride (0.25mL, 3.24mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (10mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with water (10mL), brine (10mL), and dried (Na)₂SO₄) Evaporation in vacuo gave the title compound as a gum in 78% yield, 460 mg.

¹H NMR(400MHz，CDCl₃)δ：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- (methylsulfonyl-methyl-amino) -phenyl ] -acetic acid

The title compound was prepared according to the procedure described for preparation 265 using [4- (methanesulfonyl-methyl-amino) -phenyl ] -acetic acid ethyl ester (preparation 270) to give the title compound as a solid in 85% yield, 350mg.

¹H NMR (400MHz, DMSO-D6) delta: 2.92(s, 3H), 3.21(s, 3H), 3.55(s, 2H), 7.28(d, 2H), 7.33(d, 2H); LCMS (system 10): r_t=1.05min；m/z244[M+H]⁺.

Preparation 272: 2-iodo-5-methyl-pyridines

To a stirred solution of 2-bromo-5-methyl-pyridine (2g, 11.6mmol) in acetonitrile (25mL) was added sodium iodide (6.97g, 46.5mmol) and the mixture was heated to reflux. Acetyl chloride (1.24mL, 17.44mmol) was added dropwise under reflux and the reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to room temperature and saturated Na was added ₂CO₃The aqueous solution was quenched (15mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (10mL) and dried (Na)₂SO₄) Evaporation in vacuo gave the title compound as an oil in 55% yield, 1.4 g.

LCMS (system 10): r_t=3.10min；m/z220[M+H]⁺.

Preparation 273: 2- (5-methyl-pyridin-2-yl) -malonic acid diethyl ester

To a stirred mixture of 2-iodo-5-methyl-pyridine (preparation 272, 1g, 4.57mmol) and diethyl malonate (2.08mL, 13.70mmol) in anhydrous dioxaneTo a solution in an alkane (12mL) was added cesium carbonate (4.46gm, 13.7mmol) and the solution was degassed with argon for 30 min. CuI (174mg, 0.91mmol) and picolinic acid (225mg, 1.83mmol) were added and the resulting mixture was heated in a sealed tube at 100 ℃ for 16 hours. The reaction mixture was cooled to room temperature, quenched with water (25mL), and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with water (2 × 10mL) and brine (10mL) and dried (Na)₂SO₄) And (4) evaporating in vacuum. The crude material was purified by silica gel column chromatography (hexanes: EtOAc100: 0-90: 10 gradient) to give the title compound as an oil in 23% yield, 300 mg.

¹H NMR(400MHz，DMSO-D6)δ：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-pyridin-2-yl) -acetic acid

The title compound was prepared according to the procedure described for preparation 265 using 2- (5-methyl-pyridin-2-yl) -malonic acid diethyl ester (preparation 273) to give the title compound as a solid in 83% yield, 100mg.

¹H NMR (400MHz, DMSO-D6) delta: 2.26(s, 3H), 3.64(s, 2H), 7.21(d, 1H), 7.53(d, 1H), 8.29(s, 1H); LCMS (system 10): r_t=0.73min；m/z152[M+H]⁺.

Preparation 275: [1,2,4] triazolo [1,5-a ] pyridine-7-carboxylic acid

To a solution of methyl 2-aminoisonicotinate (28.8g, 191mmol) in DMF (97.5mL) was added DMF-DMA (70.6mL, 496mmol) and the mixture was heated to 130 ℃ for 12 h. The mixture was then concentrated to give a residue. MeOH (381mL) was added to the residue, followed by NH₂OHSO₄(31.9g, 248mmol) and the resulting mixture was stirred at room temperature overnight. Concentrating the reaction mixture to obtain [1,2,4]]Triazolo [1,5-a]Pyridine-7-carboxylic acid methyl ester, 18% yield, 6 g. To stirring [1,2,4]]Triazolo [1,5-a]To a solution of pyridine-7-carboxylic acid methyl ester (3g, 16mmol) in methanol was added 1M aqueous LiOH (70mL), and the resulting mixture was stirred at room temperature for 10 hours. The pH was adjusted to 5-6 using aqueous HCl and the entire mixture was extracted with EtOAc (30 mL. times.3). The combined organic layers were dried (Na)₂SO₄) True of trueConcentration in vacuo afforded the title compound as a white solid, 38% yield, 1.05g

1H NMR(400MHz，DMSO-d6)δ：7.56-7.58(m，1H)，8.32(m，1H)，8.66(m，1H)，9.04-9.06(m，1H)，13.5-14.0(s，1H)。

Preparation 276: 1-methyl-1H-pyrrolo [2,3-c ] pyridine-3-carboxylic acid

Reacting 1-methyl-1H-pyrrolo [2,3-c ] in a nitrogen atmosphere ]Pyridine-3-carbaldehyde (WO05066132) (6.5g, 40.6mmol) was dissolved in a mixture of THF (120mL) and tert-butanol (40 mL). 2-methyl-2-butene (120mL of a solution of 2M in THF, 46mmol) was added followed by NaClO₂(11.0g, 122mmol) and NaH₂PO₄(21.9g, 183mmol) in water (30 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction mixture was concentrated in vacuo to remove the organic solvent and the residue was filtered. The precipitate contained the title compound as a white solid in 57% yield, 4.1 g.

1H NMR(400MHz，DMSO-d6)δ：3.96(S，3H)，7.87-7.89(d，1H)，8.23(s，1H)，8.28(d，1H)，8.91(s，1H)，12.3(s，1H)。

Preparation 277: 2- (4-cyano-phenyl) -N- {5- [7- (2-trimethylsilyl-ethoxymethyl) -7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl ] -pyridin-3-yl } -acetamide

The title compound was prepared according to the method described for example 1 using (5-amino-pyridin-3-yl) - [7- (2-trimethylsilyl-ethoxymethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -methanone (preparation 103) and 4-cyanophenylacetic acid to give the title compound as an off-white solid in 71% yield, 235mg.

¹H NMR (400MHz, DMSO-D6) delta: -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 _t=3.25min；m/z513[M+H]⁺.

Preparation 278: 2-methyl-2-pyrrolo [2,3-d ] pyrimidin-7-yl-propane-1, 3-diol

The title compound was prepared according to the method described for preparation 246 using 2- (4-chloro-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-methyl-propane-1, 3-diol (preparation 217) to give the title compound as an off-white solid in 93% yield, 800mg.

¹H NMR(400MHz，DMSO-D6)δ：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 ] pyrimidine-5-carbonyl } -pyridin-3-yl) -2- (4-cyclopropyl-pyrazol-1-yl) -acetamide

The title compound was prepared according to the method described for example 1 using (5-amino-pyridin-3-yl) - {7- [2- (tert-butyl-dimethyl-silanyloxy) -1, 1-dimethyl-ethyl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } -methanone (preparation 38) and (4-cyclopropyl-1H-pyrazol-1-yl) acetic acid (preparation 88) to give the title compound as an off-white solid in 41% yield, 55mg.

¹H NMR (400MHz, DMSO-D6) delta: -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 _t=3.78min；m/z574[M+H]⁺.

Preparation 280: bicyclo [1.1.1] pent-1-yl- (5-bromo-2-chloro-pyrimidin-4-yl) -amine

To 5-bromo-2, 4-dichloro-pyrimidine (6g, 26.3mmol) and bicyclo [1.1.1]To a solution of pentan-1-ylamine (4.7g, 39.5mmol) in acetonitrile (60mL) was added TEA (16.5mL, 118mmol) and the mixture was stirred at 25 ℃ for 18 h. The volatiles were removed in vacuo and the residue partitioned between water and EtOAc. The organic phase was dried (Na)₂SO₄) And (4) evaporating in vacuum. Purification by silica gel column chromatography (EtOAc: hexane 1:99) afforded the title compound as a white solid, 82% yield, 4.8 g.

¹H NMR (400MHz, DMSO-D6) delta: 2.10(d, 6H), 2.48-2.50(m, 1H), 8.26(d, 2H); LCMS (system 10): r_t=3.64min；m/z276[M+H]⁺.

Preparation 281: bicyclo [1.1.1] pent-1-yl- [ 2-chloro-5- ((Z) -2-ethoxy-vinyl) -pyrimidin-4-yl ] -amine

To a stirred bicyclo [1.1.1]Pent-1-yl- (5-bromo-2-chloro-pyrimidin-4-yl) -amine (preparation 280, 2g, 7.29mmol) inTo a solution in dry toluene (70mL) was added (Z) -1-ethoxy-2- (tributylstannyl) ethylene (2.7mL, 8.03 mmol). With N₂The reaction mixture was purged for 20min, then Pd (PPh) was added₃)₄(421mg, 0.36mmol) and then degassed for a further 20min under N₂Heat to 110 ℃ overnight under an atmosphere. The reaction was cooled to room temperature, quenched with 2M KF solution, and filtered through celite. The filtrate was partitioned between water (50mL) and EtOAc (200mL), the organic phase was washed with brine (2 × 25mL), dried (Na) ₂SO₄) And (4) evaporating in vacuum. The crude residue was purified by silica gel column chromatography (EtOAc: hexane 18: 82) to give the title compound as a pale green solid in 77% yield, 1.5 g.

¹H NMR (400MHz, DMSO-D6) delta: 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_t=3.54min；m/z266[M+H]⁺.

Preparation 282: 7-bicyclo [1.1.1] pent-1-yl-2-chloro-7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared according to the procedure described for preparation 62 using bicyclo [1.1.1] pent-1-yl- [ 2-chloro-5- ((Z) -2-ethoxy-vinyl) -pyrimidin-4-yl ] -amine (preparation 281) to give the title compound as an off-white solid in 89% yield, 1.4g.

¹H NMR (400MHz, DMSO-D6) delta: 2.41(d, 6H), 2.69(m, 1H), 6.67(d, 1H), 7.61(d, 1H), 8.92(s, 1H); LCMS (system 10): r_t=3.45min；m/z220[M+H]⁺.

Preparation 283: 7-bicyclo [1.1.1] pent-1-yl-2-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine

The title compound was prepared according to the procedure described for preparation 63 using 7-bicyclo [1.1.1] pent-1-yl-2-chloro-7H-pyrrolo [2,3-d ] pyrimidine (preparation 282) to give the title compound as a brown solid in 72% yield, 1.3g.

¹H NMR (400MHz, DMSO-D6) delta: 2.40(d, 6H), 2.68(m, 1H), 7.90(s, 1H), 8.67(s, 1H); LCMS (system 10): r _t=3.89min；m/z346[M+H]⁺.

Preparation 284: (7-bicyclo [1.1.1] pent-1-yl-2-chloro-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) - (5-bromo-pyridin-3-yl) -methanone

The title compound was prepared according to the procedure described for preparation 64 using 7-bicyclo [1.1.1] pent-1-yl-2-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (preparation 283) to afford the title compound as an off-white solid in 58% yield, 1.1g.

¹H NMR (400MHz, DMSO-D6) delta: 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_t=3.73min；m/z405[M+H]⁺.

Preparation 285: [ 7-bicyclo [1.1.1] pent-1-yl-2- (4-methoxy-benzylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] - (5-bromo-pyridin-3-yl) -methanone

To (7-bicyclo [ 1.1.1)]pent-1-yl-2-chloro-7H-pyrrolo [2,3-d]Pyrimidin-5-yl) - (5-bromo-pyridin-3-yl) -methanonePreparation of 284, 1.1g, 2.72mmol) and 4-methoxybenzylamine (1.06mL, 8.16mmol) in bisDIPEA (1.7mL, 10.8mmol) was added to a solution in an alkane (40mL) and the mixture was heated at 110 ℃ for 6 hours under microwave irradiation. Volatiles were removed in vacuo and the residue was partitioned between water (50mL) and ethyl acetate (150mL), the organic phase was dried over sodium sulfate, evaporated in vacuo and purified by silica gel column chromatography (EA: hexanes 25: 75 gradient) to give the title compound as an off-white solid in 84% yield, 1.15 g.

¹H NMR (400MHz, DMSO-D6) delta: 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_t=3.81min；m/z504.2[M+H]⁺.

Preparing 286: [5- (Benzylidene-amino) -pyridin-3-yl ] - [ 7-bicyclo [1.1.1] pent-1-yl-2- (4-methoxy-benzylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -methanone

To stirred [ 7-bicyclo [1.1.1]]Pent-1-yl-2- (4-methoxy-benzylamino) -7H-pyrrolo [2,3-d]Pyrimidin-5-yl]- (5-bromo-pyridin-3-yl) -methanone (preparation 285, 1.18g, 2mmol) and benzophenone imine (0.50mL, 3mmol) in dry toluene (50mL) was added cesium carbonate (3.2g, 10mmol) in N₂The reaction mixture was purged under atmosphere for 20min, then Pd (OAc) was added₂(45mg, 0.2mmol) and BINAP (125mg, 0.2mmol), followed by additional degassing for 10min and refluxing overnight. The reaction mass was cooled to room temperature and filtered through a pad of celite. The filtrate was partitioned between water (25mL) and EtOAc (100mL), the organic phase was washed with brine (10mL), dried (Na)₂SO₄) And (4) evaporating in vacuum. Purified by silica gel column chromatography (EtOAc: hexane 25:75),the title compound was obtained as a yellow solid in 85% yield, 1.1 g.

¹H NMR (400MHz, DMSO-D6) delta: 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 _t=4.02min；m/z605[M+H]⁺.

Preparation 287: (5-amino-pyridin-3-yl) - [ 7-bicyclo [1.1.1] pent-1-yl-2- (4-methoxy-benzylamino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl ] -methanone

To [5- (benzhydrylidene-amino) -pyridin-3-yl at room temperature]- [ 7-bicyclo [1.1.1]]Pent-1-yl-2- (4-methoxy-benzylamino) -7H-pyrrolo [2,3-d]Pyrimidin-5-yl]To a solution of methanone (preparation 286, 475mg, 0.78mmol) in THF (15mL) was added citric acid (15mL of a 1N solution in water), and the reaction mixture was stirred for 2 hours. Then saturated Na is used₂CO₃The reaction was quenched with aqueous solution and extracted with EtOAc (2 × 25 mL). The combined organic phases were dried (Na)₂SO₄) And (4) evaporating in vacuum. Purification by neutral alumina column chromatography (methanol: DCM 3: 97) gave the title compound as a light yellow solid in 92% yield, 320 mg.

¹H NMR (400MHz, DMSO-D6) delta: 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_t=3.10min；m/z441[M+H]⁺.

Preparation 288: 1-cyclobutyl-1H-imidazole-4-carboxylic acid hydrochloride

Ethyl 3- (dimethylamino) -2-isocyanoacrylate (WO2007042545) (45g, 0.27mol) was added to cyclobutyl amine (50g, 0.70mol) and heated to reflux for 2 hours. The solution was then cooled and concentrated. The residue was purified by silica gel column chromatography (3:1EtOAc: heptane). The oily residue was triturated with TBME: heptane (1:1) and the resulting solid collected and dried to give ethyl 1-cyclobutyl-1H-imidazole-4-carboxylate (35g, 67%, second crop not collected). 1-cyclobutyl-1H-imidazole-4-carboxylic acid ethyl ester (35g, 0.21mol) was dissolved in 6N HCl (300mL) and refluxed for 1 day. The solution was concentrated to dryness in vacuo. The solid was azeotroped with toluene, triturated with toluene and dried under vacuum to give the title compound in 88% yield, 37.2g, M/z167[ M + H ] ]⁺.

Preparation 289: (2-methylimidazo [2,1-b ] [1,3] thiazol-6-yl) acetate hydrochloride

Ethyl 4-bromo-3-oxobutanoate (92g, 0.35mol) was added to a solution of 5-methylthiazol-2-amine (40g, 0.35mol) in acetone (400 mL). The mixture was left to stand overnight and then evaporated to give 2-amino-3- (4-ethoxy-2, 4-dioxobutyl) -5-methylthiazol-3-ium bromide, 82% yield, 101 g. 2-amino-3- (4-ethoxy-2, 4-dioxobutyl) -5-methylthiazol-3-ium (101g, 0.28mol) was then refluxed in ethanol (250mL) for 2 hours. Then evaporating the solvent to obtain 2- (2-methylimidazo [2, 1-b)]Thiazol-6-yl) acetic acid ethyl ester hydrobromide as yellow crystals in 97% yield, 85 g. Mixing the solid K₂CO₃To 2- (2-methylimidazo [2,1-b ]]Thiazol-6-yl) acetic acid ethyl ester hydrobromide (85g, 0.28mol) in water (300mL) to pH 8. The product was extracted with chloroform (3X 100mL) and Na₂SO₄Drying the combined extracts and evaporating to obtainTo 2- (2-methylimidazo [2,1-b ]]Thiazol-6-yl) acetic acid ethyl ester, 84% yield, 52 g. 2- (2-methylimidazo [2,1-b ]]Thiazol-6-yl) acetic acid ethyl ester (52g, 0.23mol) was refluxed in 10% aqueous HCl (150mL) for 2 hours. The solution was evaporated to dryness to give the title compound as brown crystals in 59% yield 32.3 g; m/z197[ M + H ]⁺.

Preparation 290: 3-methyl-5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid

To a solution of benzyl acetoacetate (57.6g, 300mmol) in MeOH (50mL) in a 350mL pressure vessel was added H₂NMe (150mL of a 2M solution in MeOH, 300mmol) and acetic acid (2 mL). The capped vessel was put into an oil bath at 70 ℃ and the reaction mixture was stirred for 16 hours. After cooling the mixture to room temperature, the solvent was evaporated in vacuo to give a yellow emulsion, which was dissolved in EtOAc (500mL) and MgSO was added₄To remove water. The drying agent was filtered off and the solvent was evaporated in vacuo to give benzyl 3- (methylamino) but-2-enoate as a viscous yellow oil in quantitative yield of 60g, which was used without further purification.

To a solution of benzyl 3- (methylamino) but-2-enoate (60g, 300mmol) and pyridine (27mL, 330mmol) in THF (500mL) cooled to-20 ℃ was added triflic anhydride (45mL, 315mmol) over a 30min period. During the addition, the temperature was maintained below-10 ℃. The reaction mixture was allowed to warm to room temperature overnight to give a yellow clear reaction mixture. The solvent was evaporated in vacuo and the orange residue dissolved in water (1L) and Et₂O (1L). Upon shaking the mixture in the 3-L separatory funnel thoroughly, all solid material dissolved. The organic layer was separated, washed with water (3X 500mL), brine (500mL), and MgSO ₄And (5) drying. Filtration and evaporation of the solvent in vacuo afforded benzyl 3- (methylamino) -2- (trifluoroacetyl) but-2-enoate as an off-white solid in 97% yield, 90g, which was used without further purification.

To a solution of benzyl 3- (methylamino) -2- (trifluoroacetyl) but-2-enoate (90g, 300mmol) in a mixture of THF (900mL) and acetic acid (100mL) was added hydrazine monohydrate (14.6mL, 300mmol) over a 5min period. The reaction mixture was heated to reflux for 3 hours, cooled to room temperature and the solvent evaporated in vacuo to give a bright yellow mass. The mass was dissolved in EtOAc (1L) and water (1L) under moderate heating, cooled to room temperature and quenched with NaHCO₃The aqueous layer was neutralized to pH 7-8. The mixture was transferred to a 3-L separatory funnel, the layers were mixed vigorously, separated, the organic layer washed with water (3X 500mL), dried (MgSO)₄) Filtration and evaporation in vacuo gave 3-methyl-5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid benzyl ester as an off-white solid in 89% yield, 74g, which was used without further purification.

In Parr apparatus at room temperature with H₂(15psi) A mixture of benzyl 3-methyl-5- (trifluoromethyl) -1H-pyrazole-4-carboxylate (74g, 285mmol), Pd/C (45g, 10% on C), and EtOAc (1L) was treated for 5H. The catalyst was filtered off with celite and the solvent was removed in vacuo. Et was added ₂O (1L) and water (200mL), over Na₂CO₃The aqueous layer was made moderately alkaline (pH 8-9). Separate the layers with Et₂The aqueous layer was O (5X 200 mL). Concentrated HCl was added dropwise to the aqueous layer until pH4-5, then Et₂O (3X 500 mL). The combined organic layers were dried (MgSO)₄) Filtered and evaporated in vacuo to give the title compound in 74% yield, 7.4 g; m.p.308-310 deg.C (decomposition) M/z195[ M + H ]]⁺

Preparation 291: [4- (3-hydroxyphenyl) -1H-1,2, 3-triazol-1-yl ] acetic acid ethyl ester

Ethyl azidoate (14.9g, 115mmol) was dissolved in t-butanol (200mL) and 95% 3-hydroxybenzonitrile (13.7g, 110mmol) was added. A solution of sodium ascorbate (2.18g, 11mmol) in water (100mL) was added followed by a 0.3M copper sulfate solution under an argon atmosphere. Mixing the above materialsThe mixture was stirred at room temperature for 12 hours. The solution was evaporated to dryness in vacuo, the residue dissolved in EtOAc (100mL) and dried (MgSO)₄) Filtered and evaporated in vacuo to give the title compound as brown crystals in 100% (27.7g) yield.

MS m/z246[M-H]^-

Preparation 292: [4- (3-hydroxyphenyl) -1H-1,2, 3-triazol-1-yl ] acetic acid hydrate

Reacting [4- (3-hydroxyphenyl) -1H-1,2, 3-triazol-1-yl]Ethyl acetate (preparation 291, 27.2g, 0.110mol) was dissolved in methanol (200mL), and a solution of NaOH (4.84g, 121mmol) in water (40mL) was added. The solution was kept at room temperature for 24 hours. Methanol was evaporated in vacuo, water (120mL) was added and the solution was refluxed with charcoal. The mixture was filtered and 11M HCl was added to the filtrate. The mixture was dissolved by adding water (120mL) and cooled to effect crystallization. The crystals were filtered, washed with water (2X25mL) and evaporated to dryness to give the title compound as brown crystals (mp186.3-188.7 ℃ C.), 99.0% yield, 23.9g. MS M/z218[ M-H ] ]^-

Preparation 293: [4- (1-Hydroxycyclopentyl) -1H-1,2, 3-triazol-1-yl ] acetic acid ethyl ester

Ethyl azidoacetate (2.58g, 20mmol) was dissolved in tert-butanol (15mL) and 1-hydroxycyclopentanenitrile (2.20g, 20mmol) was added. A solution of ascorbic acid (0.792g, 4mmol) in water (10mL) was added to the mixture followed by a 0.3M copper sulfate solution (0.67mL) and stirring continued at room temperature for an additional 48 hours. The solution was evaporated to dryness in vacuo, the residue dissolved in EtOAc (50mL) and dried (MgSO)₄) Filtered and evaporated in vacuo to give the titled compoundCompound, green-yellow crystals, 98% yield, 4.69g.

MS m/z238[M-H]^-

Preparation 294: [4- (1-Hydroxycyclopentyl) -1H-1,2, 3-triazol-1-yl ] acetic acid

To [4- (1-hydroxycyclopentyl) -1H-1,2, 3-triazol-1-yl group]To a solution of ethyl acetate (preparation 293, 36.4g, 151mmol) in water (50mL) was added a solution of NaOH (7.60g, 190mmol) in water (25 mL). Refluxing the solution with activated charcoal, filtering through celite, adding NaHSO₄(25.8g, 190 mmol). EtOAc (50mL) was added to the filtrate. The precipitate formed was isolated by filtration, dissolved in EtOAc (100mL), and the solution was filtered. The aqueous layer was extracted with EtOAc (10X 50mL) and the combined extracts were evaporated to a volume of 100 mL. The precipitate was filtered, washed with ethyl acetate (2 × 50mL) and concentrated under reduced pressure to give the title compound as a colorless crystalline material in 87% yield, 27.8g.mp124.0-126.0 ℃; MS M/z212[ M + H ] ]⁺

Preparation 295: 1- (1-methyl-1H-pyrazol-4-yl) hydrazine-1, 2-dicarboxylic acid di-tert-butyl ester

To a solution of 4-iodo-1-methyl-1H-pyrazole (21g, 0.12mol) in dry ether (200mL) was added n-BuLi (84.5mL of a 2.5M solution in hexane, 0.18mol) at-78 deg.C over 30min, and the mixture was stirred for an additional 30 min. A solution of di-tert-butyl (Z) -diazene-1, 2-dicarboxylate (30.4g, 0.12mol) in diethyl ether (100ml) was added to the reaction mixture over a 10min period and the resulting mixture was stirred at-78 ℃ for 1 h. The reaction was warmed to 0 ℃, quenched with ice water and extracted with ether (3 × 100 mL). The organic phase was separated and dried (Na)₂SO₄) And (4) evaporating in vacuum. The crude material was washed with hexane and then dried under vacuum to give the title compound in 30% yield, 11.2g.

¹H NMR(400MHz，DMSO-d6)：d9.60(s，1H)，7.62(s，1H)，7.25(s，1H)，3.76(s，3H)，1.44(m，18H)。LCMS：313(M+H)+

Preparation 296: 3-tert-butyl-1 ' -methyl-1 ' H-1,4' -bipyrazol-5-amine

A mixture of di-tert-butyl 1- (1-methyl-1H-pyrazol-4-yl) hydrazine-1, 2-dicarboxylate (preparation 295,12.3g, 0.039mol) and 4, 4-dimethyl-3-oxovaleronitrile (5.4g, 0.043mol) was dissolved in MeOH (36mL) and HCl (12mL) was added slowly. The reaction mixture was stirred at 65 ℃ for 16 hours. The reaction was distilled to remove MeOH, saturated NaHCO₃Basification of the aqueous solution to pH 8, followed by extraction with DCM, separation of the organic layer and drying (Na) ₂SO₄) And then concentrated in vacuo. The crude mixture was purified by silica gel column chromatography (hexane: EtOAc50:50) to give the title compound in 41% yield, 7.2g.

¹H NMR(400MHz，DMSO-d6)d7.91(s，1H)，7.58(s，1H)，5.28(s，1H)，5.04(s，2H)，3.81(s，3H)，1.21(s，9H)；LCMS：m/z220[M+H]⁺.

Preparation 297: 3-cyclopropyl-1 ' -methyl-1 ' H-1,4' -bipyrazol-5-amine

The title compound was prepared according to the procedure described for preparation 296: using di-tert-butyl 1- (1-methyl-1H-pyrazol-4-yl) hydrazine-1, 2-dicarboxylate (preparation 295) and 3-cyclopropyl-3-oxopropanenitrile, the title compound was obtained in 48% yield, 1.7g.

¹HNMR(400MHZ，DMSO-d6)：0.55-0.57(m，2H)，0.75-0.80(m，2H)，1.68-1.72(m，1H)，3.83(s，3H)，5.08-5.09(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) oxetan-3-yl ] -7H-pyrrolo [2,3-d ] pyrimidin-5-yl } carbonyl) pyridin-3-yl ] -2- (4-chlorophenyl) acetamide

The title compound was prepared according to the procedure described for preparation 223 using (5-aminopyridin-3-yl) (7- (3-methyloxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (preparation 222) to give the title compound as a white solid in 87% yield, 35 mg.

LCMS (system 2): r_t=1.49min；m/z592[M+H]⁺.

Preparation 299: 5- (methoxymethyl) -1-methyl-1H-pyrazole-3-carboxylic acid

To a solution of ethyl 5- (methoxymethyl) -1-methyl-1H-pyrazole-3-carboxylate (WO9743277) (177mg, 0.893mmol) in MeOH was added a 0.5M LiOH solution (5.3mL, 2.68mmol) and the reaction was stirred at room temperature overnight. The solution was evaporated to dryness and the residue was adjusted to pH5 with 2n hcl solution. The aqueous solution was extracted with EtOAc and Na ₂SO₄The organic layer was dried and evaporated in vacuo to give the title compound as a white solid, 95%, 145mg.

¹H NMR (400MHz, methanol-d 4)6.68(s, 1H), 4.44(s, 2H), 3.84(s, 3H), 3.29(s, 3H). MS M/z171[ M + H [)]⁺

Preparation 300: imidazo [1,2-a ] pyrimidine-6-carboxylic acid

Reacting 6-bromoimidazo [1,2-a ] in an atmosphere of CO (50psi)]A mixture of pyrimidine (1.17g, 6mmol, BINAP (18mg, 0.06mmol), PdCl2(6mg) in MeOH (30mL) and triethylamine (1.8mL) was heated to 80 deg.C in DMF (97.5mL) for 12 h DMF-DMA (70.6mL, 495.8mmol) was added, the mixture was heated to 130 deg.C for 12 h the mixture was filtered and concentrated to give imidazo [1,2-a ] 1]Pyrimidine-6-carboxylic acid methyl ester (365mg, 35%) as a yellow solid, which was used in the next step without further purification. To imidazo [1,2-a ]]To a solution of pyrimidine-6-carboxylic acid methyl ester (365mg, 2.1mmol) in methanol was added 1M aqueous LiOH (9.0mL) and the resulting mixture was stirred at room temperature for 10 hours. The pH was adjusted to 5-6 using aqueous HCl and the entire mixture was extracted with EtOAc (3 × 30 mL). With Na₂SO₄The combined organic layers were dried and evaporated in vacuo to give the title compound as a white solid in 39% yield, 133mg

¹H NMR(400MHz，DMSO-d6)：δ9.15(m，1H)，8.8(m，1H)，7.9(m，1H)，7.65(m，1H)，

Preparation 301: [1,2,4] triazolo [1,5-a ] pyridine-7-carboxylic acid

To a solution of methyl 2-aminoisonicotinate (28.8g, 191mmol) in DMF (97.5mL) was added DMF-DMA (70.6mL, 496mmol) and the mixture was heated to 130 ℃ for 12 h. Then concentrating the mixtureTo obtain a residue. Methanol (381mL) was added to the residue followed by NH2OHSO4(31.9g, 248mmol) and the resulting mixture was stirred at room temperature overnight. Concentrating the reaction mixture to obtain [1,2,4 ]]Triazolo [1,5-a]Pyridine-7-carboxylic acid methyl ester, 18% yield, 6 g. To [1,2,4 ]]Triazolo [1,5-a]To a solution of pyridine-7-carboxylic acid methyl ester (3g, 16mmol) in methanol was added 1M aqueous LiOH (70mL), and the resulting mixture was stirred at room temperature for 10 hours. The pH was adjusted to 5-6 using aqueous HCl and the entire mixture was extracted with EtOAc (30 mL. times.3). With Na₂SO₄The combined organic layers were dried and concentrated in vacuo to give the title compound as a white solid in 38% yield, 1.05g

1H NMR(400MHz，DMSO-d6)：δ13.5-14.0(s，1H)，9.04-9.06(m，1H)，8.66(m，1H)，8.32(m，1H)，δ7.56-7.58(m，1H)。

Preparation 302: 1-methyl-1H-pyrrolo [2,3-c ] pyridine-3-carboxylic acid

Reacting 1-methyl-1H-pyrrolo [2,3-c ] in a nitrogen atmosphere]Pyridine-3-carbaldehyde WO05066132) (6.5g, 40.6mmol) was dissolved in a mixed solvent of THF (120mL) and t-butanol (40 mL). A solution of 2M 2-methyl-2-butene in THF (120mL, 46mmol) was added followed by NaClO ₂(11.02g, 122mmol) and NaH₂PO₄(21.9g, 183mmol) in water (30 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction mixture was concentrated in vacuo to remove the organic solvent and the residue was filtered. The precipitate contained the title compound as a white solid in 57% yield, 4.1 g.

1H NMR：DMSO-d6400MHz：δ3.96(S，3H)，7.87-7.89(d，1H)，8.23(s，1H)，8.28(d，1H)，8.91(s，1H)，12.3(s，1H)。

Preparation 303: 2- ((tert-Butoxycarbonyl) amino) -2- (4-chlorophenyl) acetic acid

To a solution of 4-chlorophenylglycine (1.50g, 8.08mmol) and sodium hydroxide (0.65g, 16.2mmol) in water (20mL) was added di-tert-butyl dicarbonate (1.76g, 8.08mmol) in acetonitrile (15mL) and the mixture was stirred at room temperature for 18 h. The mixture was then washed with DCM (20mL) and acidified with 2N HCl. The resulting aqueous layer was extracted with DCM (2 × 25mL), the combined organic layers were washed with brine and then MgSO₄Drying, filtration and evaporation in vacuo gave the title compound as a colourless oil in 87% yield, 2.00 g.

Preparation of 304: (1- (4-chlorophenyl) -2- ((5- (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine-5-carbonyl) pyridin-3-yl) amino) -2-oxoethyl) carbamic acid tert-butyl ester

To pyridine (4mL) in a sealed vessel was added 2- ((tert-butoxycarbonyl) amino) -2- (4-chlorophenyl) acetic acid (67mg, 0.24mmol) (see preparation 303), (5-aminopyridin-3-yl) (7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (52mg, 0.18mmol) (see preparation 95) and N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (105mg, 0.28 mmol). The reaction was heated at 50 ℃ for 18 hours and then evaporated in vacuo,

Purification by column chromatography (100: 0-88: 12DCM: MeOH gradient) gave the title compound in 49% yield, 64 mg. Lcms (basic): r_t=0.81min；m/z549[M+H]⁺。

Biological activity

Isolated TRK enzyme assayUsing HTRF KinEASE-TK kit (Cisbio Cat # 62T)K0PEJ) with a recombinant His-tagged cytoplasmic domain from each TRK receptor from Invitrogen (see table below). This activity assay measures phosphorylation of tyrosine residues within substrates from HTRF kits that have been validated by Cisbio against a variety of tyrosine kinases, including the TRK receptor.

Detailed contents of the test:

a 0.5mM stock solution of test compound was prepared and serially diluted with 100% DMSO. A standard curve was also prepared for each test panel using 150uM of the compound of example 135 disclosed in WO 2005/116035. High Percentage Effect (HPE) was defined with 150uM PF-00593157-00 and 0% effect (ZPE) with 100% DMSO. Greiner small volume black plaques containing 0.2ul of serial dilutions of compound, standard and HPE/ZPE were generated using a Bravo nanoliter (nanoliter) dispenser.

The 1 Xenzyme buffer was prepared from 5 Xenzyme buffer from the Cisbio KinEASE TK kit using MilliQ water. The buffer was then supplemented with 10mM MgCl and 2mM DTT (both from Sigma). For TRKB, the buffer was also supplemented with 125nM Supplemental Enzyme Buffer (SEB) from the Cisbio kit.

The enzyme of 2X FAC and 2X FAC ATP diluted in 1X complete enzyme buffer were incubated for 20 minutes at room temperature to pre-activate the enzyme. After this pre-activation step, 5 ul/well of enzyme + ATP mixture was added to the assay plate using multidropicro, and the plate was spotted with 0.2ul of 100% DMSO compound. This was left to stand at room temperature for 20mins, then 5ul2uM TK-substrate-biotin (from Cisbio kit) diluted with 1 Xenzyme buffer (1uM FAC) was added using a Multidrop Micro. The reaction was incubated at room temperature for the optimized assay reaction time (see table). The reaction was stopped by adding 10 ul/well of HTRF detection buffer containing 0.25uM streptavidin-XL 665(0.125uM FAC) and 1:200TK antibody-cryptate using Multidrop.

After addition of the detection reagents, the plates were covered and incubated for 60 minutes at room temperature. The HTRF signal was read using an Envision reader and determined as the emission ratio at two different wavelengths 620nm and 665 nm. Any compound that inhibits the effect of TRK kinase will have a fluorescence ratio of 665/620nM lower than a compound that does not inhibit TRK kinase. Test compound data are expressed as percent inhibition defined by HPE and ZPE values for each test panel. IC was determined from the sigmoidal curve obtained by plotting the percent inhibition in the presence of test compound on a logarithmic scale versus compound concentration ₅₀。

Cell lines from Discovexx, PathHunter technology and reagents for their use in antagonist assaysCell-based assays：

Target	DiscovexX cell line Cat #	Related neurotrophic factors
			TRKA	93-0462C3	NGF
TRKA coexpressed with p75	93-0529C3	NGF
			TRKB	93-0463C3	BDNF
Is shown together with p75TRKB of Dada	93-0530C3	BDNF
			TRKC	93-0464C3	NT3
TRKC co-expressed with p75	93-0531C3	NT3

The assay is based on the DiscovexX proprietary Enzyme Fragment Complementation (EFC) technique. In the case of the TRK cell line, an Enzyme Acceptor (EA) protein was fused with the SH2 protein, and a Prolink label was used to label the TRK receptor of interest.

Upon neurotrophic factor binding, the TRK receptor is phosphorylated and the labeled SH2 protein binds. This results in functional complementation and recovered β -galactosidase activity that can be measured using the luminescent Galacton Star substrate in the PathHunter reagent kit.

In general, small molecule inhibitors bind to the kinase domain and therefore do not compete with neurotrophic factors (agonists) binding to extracellular sites. This means that the IC is₅₀Is a good measure of affinity and should not be affected by concentrated neurotrophic factor stimulators.

Cryopreserved PathHunter cells from batches generated by this unit or large batches purchased directly from DiscoveRx were used. The cryopreserved cells were thawed, spun at 1000rpm for 4min to remove the freezing medium, and resuspended in MEM +0.5% horse serum (both from Invitrogen) to 5e ⁵Cells/ml. The cells were then plated at 20 ul/well into Greiner white tissue culture treated plates using Multidrop, 5% CO at 37 ℃₂And incubated at high humidity for 24 h. On the day of the test,the cell culture plate was allowed to cool to room temperature for 30min before the assay was performed.

Stock solutions of test compounds at 4mM were prepared and serially diluted with 100% DMSO. A standard curve was also prepared for each test plate using the highest concentration of 150uM of the compound of WO2005/116035 example 135. A High Percentage Effect (HPE) was defined with 150uM WO2005/116035, example 135 compound, and a 0% effect (ZPE) with 100% DMSO. With assay buffer (PBS-Ca)²⁺、-Mg²⁺With 0.05% pluronic F127), using Wellmate, platmate + was applied, the plate containing 1ul of serially diluted compound, standard and HPE/ZPE was diluted 1/66, then 5ul of 1/66 diluted test compound was transferred to the cell culture plate, equilibrated by incubation at room temperature for 30min, then agonist stimuli were added: 2nM (0.571 nCMAC) associated neurotrophic factor (Peprotech) diluted in agonist buffer (HBSS containing 0.25% BSA) at 10 ul/well. The final assay concentration of the test compound was 8.66. mu.M (compound of example 135, 0.325uM for WO2005/116035 FAC). The plates were allowed to stand at room temperature for an additional 2 hours, then 10ul DiscoverRx PathHunter detection reagent (prepared by adding 1 part of Galacton Star, 5 parts of Emerald II and 19 parts of cell assay buffer, according to the manufacturer's instructions) was added.

After reagent addition, the plates were covered and incubated for 60 minutes at room temperature. The luminescence signal was read using Envision. Test compound data are expressed as percent inhibition defined by HPE and ZPE values for each plate. IC was determined from the sigmoidal curve obtained by plotting the percent inhibition in the presence of test compound on a logarithmic scale versus compound concentration₅₀。

Brain penetration test

In vitro

MDCK-BCRP: according To "A96-Well Efflux Assay To Identify ABCG2 substructures, using a Stable transferred MDCK II Cell Line"http://pubs.acs.org/doi/full/10.1021/mp050088t

MDCK-BCRP data was collected as described in Yongling Xiao, Ralph Davidson, Arthur Smith, Dennis Pereira, Sabrina Zoao, John Soglia, David Gebhard, Sonia de Morais and DavidB.Duignan, mol.pharm., 2006, 3(1), pp 45-54.

MDCK-MDR 1: according to "Are MDCK Cells transformed with the Human MDR1Gene a Good Model of the Human interest Mucosa? "http://www.springerlink.com/content/qfhqlqbr4fnp3khf/fullt ext.pdf

MDCK-MDR1 data were collected as described in Fuxing Tang, Kazutoshi Horie and Ronald T.Borchardt, Pharmaceutical Research, Vol.19, No.2002, 6.6.6.

In vivo

According to "Assessing bridge free from free in early dry discovery". Read, K; brain penetration was determined as described in Bragg io, S., Expert Opinion Drug Metab Toxicol (2010)6(3) 337-344.

All publications cited in this application are herein incorporated by reference in their entirety. Although the present invention has been described with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the detailed description is only illustrative of the present invention. It will be understood that various modifications may be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

Claims

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein

R¹Is that

H, or

R²Is H or methyl;

R¹⁰¹h, OH, methyl, cyclopropyl, methoxy, ethyl, ethoxy or CN;

x is a bond, O, (CH-R)⁴)_n、NR¹⁰⁴、OCH₂Or CH₂O；

n is 1 or 2;

R¹⁰²is a ring system which is a 3-to 7-membered monocyclic carbocyclic or heterocyclic ring system or an 8-to 14-membered bicyclic ring system, which ring system may be saturated or partially or fully unsaturated, whereinThe heterocyclic ring system may have up to 5 ring heteroatoms selected from N, S and O, where the bicyclic ring system may be 2 rings (carbocycle-carbocycle, carbocycle-heterocycle, heterocycle-carbocycle or heterocycle-heterocycle) fused or connected by a single bond, optionally substituted, if possible, with up to 3 substituents independently selected from halogen, CN, NR ⁵R⁶、SO₂R⁷、SR⁷Optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_1-4Alkyl, optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_3-6Cycloalkyl, C substituted by up to 3 halogens_1-3Alkyl, OH, O (C)_1-3Alkyl), O (optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_3-6Cycloalkyl), O (C optionally substituted with up to 3 halogens_1-3Alkyl), O (optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_1-3Alkyl), NR)⁵SO₂R⁷、=O、R⁸、C(O)R⁸、NO₂、NR⁵CO₂R⁷、NR⁵COR⁷、OR⁸、S(O)R⁷And CH₂R⁸；

R⁵And R⁶Each independently is

H, or

A ring system selected from C_3-5Cycloalkyl, spiroalkyl or a 4-to 6-membered saturated heterocyclic ring, which ring system is optionally substituted with up to 3 substituents independently selected from OH, CON (R)⁷R⁷)、SO₂R⁷、CO₂R⁷、SONR⁷R⁷、NR⁷SO₂R⁷、CN、NO₂Halogen, NR⁷R⁷、SR⁷Optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_1-4Alkyl, optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_3-6Cycloalkyl, C substituted by 1-3 halogens_1-3Alkyl, O (optionally substituted by up to 3 OH and/or C)_1-3Alkoxy-substituted C_3-6Cycloalkyl), O (C substituted by up to 3 halogens)_1-3Alkyl), O (optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_1-3Alkyl), NR) ⁷SO₂R⁷、=O、NO₂、NR⁷CO₂R⁷And S (O) R⁷，

Or R⁵And R⁶Together with the N to which they are attached may be a 4-7 membered ring optionally including up to 2 additional heteroatoms independently selected from N, O, S, optionally substituted with C_1-3Alkoxy and/or C_1-3Alkyl substitution;

R⁷is H, C_1-5Alkyl or C_1-5Alkoxy radical, C_1-5Alkyl or C_1-5Alkoxy is optionally substituted with up to 3 substituents independently selected from halogen;

R⁸is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic ring system or an 8-14 membered bicyclic ring system which may be saturated or partially or fully unsaturated, wherein the heterocyclic ring system may have up to 5 ring heteroatoms selected from N, S and O, wherein the bicyclic ring system may be 2 rings (carbocyclic-carbocyclic, carbocyclic-heterocyclic, heterocyclic-carbocyclic or heterocyclic-heterocyclic) fused or connected by single bonds, which ring system is optionally substituted, if possible, with up to 3 substituents independently selected from halogen, CN, NR⁵R⁶、SO₂R⁷、SR⁷Optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_1-4Alkyl, optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_3-6Cycloalkyl, C substituted by up to 1-3 halogens_1-3Alkyl, OH, O (C)_1-3Alkyl), O (optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_3-6Cycloalkyl), O (optionally substituted by Multiple 3 halogen substituted C_1-3Alkyl), O (optionally substituted by up to 3 OH and/or C_1-3Alkoxy-substituted C_1-3Alkyl), NR)⁵SO₂R⁷、=O、NO₂、NR⁷COR⁷、NR⁵CO₂R⁷And S (O) R⁷；

Wherein each CH moiety may be replaced by a CF moiety.

2. A compound or salt of claim 1, wherein R¹Is H, C optionally substituted by up to 2 OH _1-5An alkyl group; or R¹Is C_1-5Alkyl radical, by CONH₂、CONHCH₃、CON(CH₃)₂、CO₂H、CO₂CH₃、OCH₃、SCH₃、SO₂CH₃Substitution; or R¹Is a ring system selected from C_3-5Cycloalkyl, spiroalkyl or oxetanyl, the ring system being optionally substituted by methyl, OH or CH₂And (4) OH substitution.

3. A compound or salt of any one of claims 1 or 2, wherein R¹Is tert-butyl, hydroxy-tert-butyl, dihydroxy-tert-butyl, 1-hydroxypropan-2-yl or 1, 3-dihydroxypropan-2-yl.

4. A compound or salt as claimed in any one of claims 1 to 3, wherein R²Is H.

5. A compound or salt as claimed in any one of claims 1 to 4, wherein R³Is H or NH₂。

6. A compound or salt as claimed in any one of claims 1 to 5, wherein R³Is NH₂。

7. A compound or salt as claimed in any one of claims 1 to 5, wherein R³Is H.

8. A compound or salt of any one of claims 1 to 7 wherein R¹⁰¹Is H.

9. A compound or salt of any one of claims 1 to 7 wherein R¹⁰¹Is OH.

10. A compound or salt of any one of claims 1 to 9 wherein X is a bond, O, CH₂、C₂H₄、CH(CH₃)CH₂、CH(CH₃)、CH(CH₂OH)、CH₂O、CH(NH₂) CH (OH) or NH.

11. A compound or salt as claimed in any one of claims 1 to 10 wherein X is CH₂。

12. A compound or salt as claimed in any one of claims 1 to 11 wherein R¹⁰²Is an optionally substituted nitrogen-containing ring system attached to the X moiety through a nitrogen ring atom.

13. A compound or salt as claimed in any one of claims 1 to 11 wherein R ¹⁰²Is an optionally substituted ring system, wherein the ring system is selected from benzimidazolyl, benzisoxazoleAzolyl, benzofuranyl, benzoAzolyl, benzotriazolyl, biphenyl, bipyrazolyl, cinnolinyl, cyclobutylimidazolyl, cyclobutylpyrazolyl, cyclobutylthiazolyl, cyclopentyltriazolyl, cyclopropylisopropylAzolyl, cyclopropylAzolyl, cyclopropylpyrazolyl, cyclopropyltriazolyl, diazacyclopropenylphenyl, dihydronaphthyridinyl, dihydropyrrolopyrazolyl, dioxanaphthyridinyl, furazanyl, furopyridinyl, furopyrrolyl, imidazolyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyridylOxazolopyrimidinyl, imidazothiadiazolyl, imidazothiazolyl, indanyl, indazolyl, indolyl, isoindolylAzolopyridinyl, isoAzolyl, isoquinolyl, naphthyridinyl,Oxazolyl, phenyl, phenylcyclopropyl, phenylimidazolyl, phenylpyrazolyl, phenylpyrrolyl, phenyltetrazolyl, phthalazinyl, purinyl, pyrazinyl, pyrazolyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyridyl, pyridazinyl, pyridyltriazolyl, pyrimidinyl, pyrroloimidazolyl, pyrrolopyrazinyl, pyrrolopyrimidyl, pyrrolopyridyl, pyrrolyl, quinolinyl, quinazolinyl, quinoxalinyl, tetrahydrobenzisoxazolyl Oxazolyl, tetrahydrocyclopentapyrazolyl, tetrahydrotriazolopyridyl, tetrazolopyridazinyl, tetrazolopyridyl, thiazolyl, thiazolopyridyl, thiazolopyrimidinyl, thienylpyrazolyl, thienopyridinyl, triazolopyridyl and triazolyl.

14. The compound or salt of claim 13, wherein the optional substituents are independently selected from halogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, CF, if possible₃、CHF₂、CH₂F、CH₂OCH₃、CN、CH₂OH、OCH₃、=O、NH₂、SCH₃、SO₂CH₃Phenoxy, fluorophenoxy, benzyl, SCF₃、OCF₃、SO₂CF₃、NHSO₂CH₃、NHSO₂CF₃、C(O)CF₃、C(O)CH₃Benzoyl, azetidinylmethyl, fluoroazetidiylmethyl and morpholinomethyl.

15. A compound or salt as claimed in any one of claims 1 to 11, 13 or 14 wherein R¹⁰²Selected from phenyl, pyrazol-1-yl, 1,2, 3-triazol-1-yl, benzotriazol-2-yl, pyridin-3-yl and pyridin-4-yl, each optionally substituted with halogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, CF₃、CHF₂、CH₂F、CH₂OCH₃、CN、CH₂OH、OCH₃、=O、NH₂、SCH₃、SO₂CH₃Phenoxy, fluorophenoxy, benzyl, SCF₃、OCF₃、SO₂CF₃、NHSO₂CH₃、NHSO₂CF₃、C(O)CF₃、C(O)CH₃Benzoyl, azetidinylmethyl, fluoroazetidiylmethyl and/or morpholinomethyl.

16. A compound or salt as claimed in any one of claims 1 to 15 wherein R is present⁵And R⁶Group, wherein R ⁵And R⁶Each independently is H, optionally substituted by C_1-3Alkoxy-substituted C_1-3Alkyl radical, C_3-5Cycloalkyl, spiroalkyl, oxetanyl, tetrahydrofuryl or pyranyl, or R⁵And R⁶Together with the N to which they are attached may be an azetidine, pyrrolidine, piperidine, piperazine or morpholine ring, optionally substituted with C_1-3Alkoxy and/or C_1-3Alkyl substitution.

17. The compound of claim 1 having the structure of formula IA:

or a pharmaceutically acceptable salt thereof, wherein

R³Is H or NH₂；

R¹Is C optionally substituted by 1 or 2 OH groups_2-4An alkyl group;

R¹⁰¹is H or OH;

18. A compound or salt of claim 17, R¹⁰¹Is H.

19. The compound or salt of claim 18, wherein

R¹Is tert-butyl, hydroxy-tert-butyl or 1-hydroxypropan-2-yl;

and R is¹⁰²Is 4-trifluoromethylphenyl, 4-chlorophenyl, 2, 4-difluorophenyl, 5-chloropyridin-2-yl, 5-fluoropyridin-2-yl, 3-trifluoromethylpyrazolyl-1-yl, 4-trifluoromethylpyrazol-1-yl, 3-trifluoromethyl-5-methylpyrazol-1-yl, 3-cyclopropylpyrazol-1-yl, 4-trifluoromethyl (1,2, 3-triazol-1-yl), 4-cyclopropyl (1,2, 3-triazol-1-yl) or benzotriazol-2-yl.

20. The compound of claim 1 selected from:

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

or a pharmaceutically acceptable salt thereof.

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

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

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

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

25. Use of a compound of formula (I) or a pharmaceutically acceptable salt or composition thereof as defined in any one of claims 1 to 20 in the manufacture of a medicament for the treatment of a disease for which a Trk receptor antagonist is indicated.

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

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

28. A method of treating pain in a mammal, which comprises treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 20.

29. A compound or salt according to any one of claims 1 to 20 for use in medical therapy in combination with another drug substance.