We required rapid access to hundreds of grams of a key building block to support early scale-up campaigns during one of our Oncology programs. Accordingly, we report herein the exploration of two synthetic approaches to this compound by our Discovery Process team. This work culminated in the development and optimization of a phase-appropriate synthetic route that was successfully utilized by one of our contract development and manufacturing organizations (CDMOs) to quickly deliver 300 g of intermediate 1 center dot TsOH.

Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges.

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure-activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

ROS1 rearrangements account for 1-2% of non-small cell lung cancer patients, yet there are no specifically designed, selective ROS1 therapies in the clinic. Previous knowledge of potent ROS1 inhibitors with selectivity over TrkA, a selected antitarget, enabled virtual screening as a hit finding approach in this project. The ligand-based virtual screening was focused on identifying molecules with a similar 3D shape and pharmacophore to the known actives. To that end, we turned to the AstraZeneca virtual library, estimated to cover 1015 synthesizable make-on-demand molecules. We used cloud computing-enabled FastROCS technology to search the enumerated 1010 subset of the full virtual space. A small number of specific libraries were prioritized based on the compound properties and a medicinal chemistry assessment and further enumerated with available building blocks. Following the docking evaluation to the ROS1 structure, the most promising hits were synthesized and tested, resulting in the identification of several potent and selective series. The best among them gave a nanomolar ROS1 inhibitor with over 1000-fold selectivity over TrkA and, from the preliminary established SAR, these have the potential to be further optimized. Our prospective study describes how conceptually simple shape-matching approaches can identify potent and selective compounds by searching ultralarge virtual libraries, demonstrating the applicability of such workflows and their importance in early drug discovery.

For most oral small-molecule projects within drug discovery, the extent and duration of the effect are influenced by the total clearance of the compound; hence, designing compounds with low clearance remains a key focus to help enable sufficient protein target engagement. Comprehensive understanding and accurate prediction of animal clearance and pharmacokinetics provides confidence that the same can be observed for human. During a MERTK inhibitor lead optimization project, a series containing a biphenyl ring system with benzylamine meta-substitution on one phenyl and nitrogen inclusion as the meta atom on the other ring demonstrated multiple routes of compound elimination in rats. Here, we describe the identification of a structural pharmacophore involving two key interactions observed for both the MERTK program and an additional internal project. Four strategies to mitigate these clearance liabilities were identified and systematically investigated. We provide evidence that disruption of at least one of the interactions led to a significant reduction in CL that was subsequently predicted from rat hepatocytes using in vitro/in vivo extrapolation and the well-stirred scaling method. These tactics will likely be of general utility to the medicinal chemistry and DMPK community during compound optimization when similar issues are encountered for biphenyl benzylamines.

Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, in vivo efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.

Hybridisation of amino-pyrimidine based SYK inhibitors (e.g. 1a) with previously reported diamine-based SYK inhibitors (e.g. TAK-659) led to the identification and optimisation of a novel pyrimidine-based series of potent and selective SYK inhibitors, where the original aminomethylene group was replaced by a 3,4-diaminotetrahydropyran group. The initial compound 5 achieved excellent SYK potency. However, it suffered from poor permeability and modest kinase selectivity. Further modifications of the 3,4-diaminotetrahydropyran group were identified and the interactions of those groups with Asp512 were characterised by protein X-ray crystallography. Further optimisation of this series saw mixed results where permeability and kinase selectivity were increased and oral bioavailability was achieved in the series, but at the expense of potent hERG inhibition.

Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers by blocking the tumor cell's ability to produce glutamine-derived nutrients. Starting from the known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, we describe the medicinal chemistry evolution of a series from lipophilic inhibitors with suboptimal physicochemical and pharmacokinetic properties to cell potent examples with reduced molecular weight and lipophilicity, leading to compounds with greatly improved oral exposure that demonstrate in vivo target engagement accompanied by activity in relevant disease models.

Background Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between -2.5 and -4.0 if no previous radiographic vertebral fracture, or between -1.5 and -4.0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than -4.0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36.5 months (IQR 34.43-40.15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47.6 months, IQR 35.45-60.06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3.7% (251/6770) versus 7.8% (542/6910), hazard ratio (HR) 0.46, 95% CI 0.40-0.53; hip fractures 0.8% (65/8043) versus 1.6% (125/8028), 0.53, 0.39-0.71; non-vertebral fractures 5.1% (412/8043) versus 6.7% (541/8028), 0.77, 0.68-0.87; all p<0.0001. Combined results from LOFT plus LOFT Extension for cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 4.9% (341/6909) versus 9.6% (675/7011), HR 0.48, 95% CI 0.42-0.55; hip fractures 1.1% (86/8043) versus 2.0% (162/8028), 0.52, 0.40-0.67; non-vertebral fractures 6.4% (512/8043) versus 8.4% (675/8028), 0.74, 0.66-0.83; all p<0.0001. In LOFT, the composite cardiovascular endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 273 (3.4%) of 8043 patients in the odanacatib group versus 245 (3.1%) of 8028 in the placebo group (HR 1.12, 95% CI 0.95-1.34; p=0.18). New-onset atrial fibrillation or flutter occurred in 112 (1.4%) of 8043 patients in the odanacatib group versus 96 (1.2%) of 8028 in the placebo group (HR 1.18, 0.90-1.55; p=0.24). Odanacatib was associated with an increased risk of stroke (1.7% [136/8043] vs 1.3% [104/8028], HR 1.32, 1.02-1.70; p=0.034), but not myocardial infarction (0.7% [60/8043] vs 0.9% [74/8028], HR 0.82, 0.58-1.15; p=0.26). The HR for all-cause mortality was 1.13 (5.0% [401/8043] vs 4.4% [356/8028], 0.98-1.30; p=0.10). When data from LOFT Extension were included, the composite of cardiovascular death, myocardial infarction, or stroke occurred in significantly more patients in the odanacatib group than in the placebo group (401 [5.0%] of 8043 vs 343 [4.3%] of 8028, HR 1.17, 1.02-1.36; p=0.029, as did stroke (2.3% [187/8043] vs 1.7% [137/8028], HR 1.37, 1.10-1.71; p=0.0051). Interpretation Odanacatib reduced the risk of fracture, but was associated with an increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis. Based on the overall balance between benefit and risk, the study's sponsor decided that they would no longer pursue development of odanacatib for treatment of osteoporosis. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

While the treatment of gastrointestinal stromal tumors (GISTs) has been revolutionized by the application of targeted tyrosine kinase inhibitors capable of inhibiting KIT-driven proliferation, diverse mutations to this kinase drive resistance to established therapies. Here we describe the identification of potent pan-KIT mutant kinase inhibitors that can be dosed without being limited by the tolerability issues seen with multitargeted agents. This effort focused on identification and optimization of an existing kinase scaffold through the use of structure-based design. Starting from a series of previously reported phenoxyquinazoline and quinoline based inhibitors of the tyrosine kinase PDGFRα, potency against a diverse panel of mutant KIT driven Ba/F3 cell lines was optimized, with a particular focus on reducing activity against a KDR driven cell model in order to limit the potential for hypertension commonly seen in second and third line GIST therapies. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalized predominantly by the interaction of water molecules with the protein and ligand in the active site, and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST.

A metal-free aminoarylation of internal alkynes is described, yielding tetrasubstituted enaminoates. The transformation proceeds in good to excellent yields through a tandem conjugate addition/Smiles rearrangement involving aryl and heteroaryl sulfonamides. Substrate scope is very broad under simple, user-friendly conditions, and the reaction can be used to easily access biologically active phenethylamine derivatives.

GPR120 agonists have therapeutic potential for the treatment of diabetes, but few selective agonists have been reported. We identified an indazole-6-phenylcyclopropylcarboxylic acid series of GPR120 agonists and conducted SAR studies to optimize GPR120 potency. Furthermore, we identified a (S,S)-cyclopropylcarboxylic acid structural motif which gave selectivity against GPR40. Good oral exposure was obtained with some compounds displaying unexpected high CNS penetration. Increased MDCK efflux was utilized to identify compounds such as 33 with lower CNS penetration, and activity in oral glucose tolerance studies was demonstrated. Differential activity was observed in GPR120 null and wild-type mice indicating that this effect operates through a mechanism involving GPR120 agonism.

AbstractA wide range of substrates bearing various functional groups and having a primary, secondary, or tertiary benzylic position are utilized in azidation reactions for the C—N bond formation at benzylic C—H positions.

Herein we describe the synthesis of a series of novel, functionalised pyrrolothiazolo–pyrimidines, –pyridines and –pyrazines employing a short reaction sequence, utilising the under-reported interrupted Pummerer reaction to effect cyclisation in the final step.

S-1. Odanacatib Efficacy and Safety in Postmenopausal Women with Osteoporosis: 5-Year Data from the Extension of the Phase 3 Long-term Odanacatib Fracture Trial (LOFT) Michael R. McClung1, Bente Langdahl2, Socrates Papapoulos3, Kenneth G. Saag4, Henry Bone5,6, Douglas P. Kiel7, Kurt Lippuner8, Toshitaka Nakamura9, Ian Reid10, Norman Heyden11, Carolyn DaSilva11, Boyd B. Scott11, Rachid Massaad12, Keith D. Kaufman11, S. Aubrey Stoch11, Arthur Santora11, Deborah Gurner11, Antonio Lombardi11. 1Oregon Osteoporosis Center, Portland, OR; 2Aarhus University Hospital, Aarhus, Denmark; 3Leiden University Medical Center, Leiden, Netherlands; 4University of Alabama at Birmgham, Birmingham, AL; 5Michigan Bone & Mineral Clinic, Detroit, MI; 6The Osteoporosis Center at St. Luke’s Hospital, Chesterfield, MO; 7Institute for Aging Research, Hebrew Senior Life, Harvard Medical School, Boston, MA; 8Bern University Hospital, Bern, Switzerland; 9University of Occupational and Environmental Health, Fukuoka, Japan; 10University of Auckland, Auckland, New Zealand; 11Merck & Co., Inc., Kenilworth, NJ; 12MSD Europe, Inc., Brussels, Belgium Objective: Odanacatib (ODN) is a selective oral inhibitor of cathepsin K in development for the treatment of osteoporosis. The randomized, double-blind, placebo (PBO)controlled, event-driven, Phase 3 Fracture Trial (Long-Term Odanacatib Fracture Trial [LOFT]; NCT00529373) evaluated efficacy and safety of ODN in postmenopausal women with osteoporosis. In a planned double-blind extension to LOFT, eligible patients continued on their originally assigned treatment for up to 5 years. We present efficacy and safety data for the entire 5-year double-blind period. Design: Women ≥65 years of age with BMD T-score ≤–2.5 at total hip (TH) or femoral neck (FN), or with radiographic vertebral fracture (VFx) and T-score ≤–1.5 at TH or FN, were randomized (1:1) to ODN 50 mg/week or PBO. All received vitamin D3 (5600 IU/week) and calcium as required. Endpoints included morphometric VFx, hip fracture, non-VFx, clinical VFx, and safety and tolerability. Specific adverse events (AEs) were adjudicated. Results: Of 16,071 patients (8043 ODN, 8028 PBO) in LOFT, 12,290 (6092 ODN, 6198 PBO) completed the study. Among these, 8,257 (4297 ODN, 3960 PBO) who were eligible and consented entered the extension and 6,047 (3432 ODN, 2615 PBO) completed it. Mean (SD) age at randomization was 72.8 (5.3) years, 46.5% had prior VFx, and mean BMD T-scores were lumbar spine (LS) –2.7, TH –2.4, and FN –2.7. Mean (SD) follow-up was approximately 44 (18) months. Compared with PBO, ODN treatment over 5 years resulted in relative risk reductions of 52% for morphometric VFx, 48% for hip fracture, 26% for non-VFx, and 67% for clinical VFx (all p<0.001). Compared with PBO, ODN treatment led to progressive mean percent increases (95% CI) in BMD of 10.9% (10.5, 11.2) at LS and 10.3% (10.0, 10.6) at TH (both p<0.001) at 5 years. Incidences of AEs and serious AEs overall were balanced for ODN vs PBO (88.3 vs 88.2% and 30.3 vs 30.4%, respectively). Deaths reported in patients being followed on study were 378 (4.7%) vs 327 (4.1%), ODN vs PBO, respectively (HR 1.12 [95% CI: 0.97, 1.30]); more complete ITT analysis of deaths among all patients, including those who discontinued from study, showed 682 (8.5%) vs 660 (8.2%), respectively (HR 1.04 [95% CI: 0.93, 1.16]). Delayed fracture union occurred in 18 patients in each group. Femoral shaft fractures occurred more often with ODN (26 patients [0.3%] vs 7 [0.1%]), of which 10 (0.1%) on ODN and none on PBO met criteria for atypical femoral shaft fractures (AFFs). No cases of osteonecrosis of the jaw (ONJ) were confirmed. Morphea-like skin lesions occurred more often with ODN (13 [0.2%] vs 3 [<0.1%]), most with onset within 2 years and all improved or fully recovered. Systemic sclerosis occurred in 2 (<0.1%) with ODN vs 1 (<0.1%) with PBO. Independent adjudication of CV events is ongoing and will be presented. Conclusion: Consistent with the results of LOFT, treatment with ODN for up to 5 years reduced the risk of hip, vertebral and non-vertebral fractures. Overall incidence of AEs, including serious AEs, was generally balanced between ODN and PBO. Femoral shaft fractures, including AFFs, and morphea-like skin lesions were uncommon but more frequent with ODN. Sources of Funding: This study was sponsored by Merck & Co., Inc., Kenilworth, NJ, USA S-2. Women’s Health Initiative Clinical Trials: The Interactive Effect of Calcium and Vitamin D Supplementation with Hormonal Therapy on Cardiovascular Events and Venous Thromboembolism Xuezhi Jiang, MD1,2, John Robbins4, Matthew Nudy3, Kayler Gabbett1, David O’Sullivan, PhD1, Anita M. Kelsey, MD, FACC, FASE8, Aaron Aragaki6, Erin S LeBlanc7, Lisa S. Martin9, JoAnn E. Manson5, James Shikany10, Karen Johnson11, Marcia Stefanick12, Martha Payne13, Jane Cauley14, Barbara Howard15, Peter F. Schnatz, DO1,2. 1ObGyn, The Reading Hospital, West Reading, PA; 2OBGYN, Sidney Kimmel Medical School of Thomas Jefferson University, Philadelphia, PA; 3Internal Medicine, Hershey Medical Center, Hershey, PA; 4Internal Medicine, UC Davis Medical Center, Sacramento, CA; 5Preventive medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA; 6Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; 7Center for Health Research NW, Kaiser Permanente, Portland, OR; 8Cardiology, Saint Francis Medical Group, Inc., Hartford, CT; 9Internal Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC; 10Preventive medicine, University of Alabama at Birmingham, School of Medicine, Birmingham, AL; 11Preventive medicine, University of Tennessee Health Science Center, Memphis, TN; 12Medicine, Stanford University School of Medicine, Stanford, CA; 13the Office of Research, Duke University Medical Center, Durham, NC; 14Epidemiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA; 15MedStar Health Research Institute, Washington, DC Objective: Evidence from limited data suggests that calcium and vitamin D (CaD) at moderate to high doses may reduce cardiovascular disease (CVD) risk. Using randomized trial data we analyzed if the effect of menopausal hormone therapy (HT) on various cardiovascular disease events is enhanced by calcium and vitamin D (CaD) supplementation. Design: A prospective, randomized, double-blind, placebo controlled trial was implemented among Women’s Health Initiative (WHI) postmenopausal women. A total of 27,347 women were randomized to the HT trials (0.625 mg/d of conjugated equine estrogens [CEE] alone for women without a uterus or 0.625 mg of CEE in addition to 2.5 mg of medroxyprogesterone acetate daily [CEE+MPA] for women with a uterus versus placebo). After 1 year, 16, 089 women in the HT trial were randomized to the CaD trial to receive either 1,000 mg of elemental calcium carbonate plus 400 IU of vitamin D3 daily or placebo. The mean (SD) duration of follow-up after CaD randomization were 6.2(1.3) and 4.6(1.1) years, respectively. CVD events analyzed in this subgroup analysis include coronary heart disease (CHD), stroke, pulmonary embolism, all-cause mortality, plus select secondary endpoints (total myocardial infarction, coronary revascularization, deep venous thrombosis, cardiovascular death, and all CVD events). The time-to-event methods were used and models were fit with a Cox proportional hazards regression model. Results: In the CEE trial, CaD did not significantly modify the effect of CEE on most CVD outcomes but did modify its effect on cardiovascular death (p-interaction = 0.03). In the CaD-placebo group, the effect of CEE on cardiovascular death was somewhat harmful (HR [95%CI] = 1.47[0.86, 2.53]); in the CaD-supplement group, the effect of CEE was somewhat beneficial (HR [95%CI] = 0.57[0.29, 1.10]), see figure 1. Similar results were found for CHD deaths, which account for the majority of the cardiovascular deaths (52 of 92; p-interaction=0.04). We did not observe significant CEE x CaD interactions for CHD, total CVD events, or any of the remaining endpoints. Contrary to the CEE trial, there was no evidence that the effect of CEE+MPA on cardiovascular death or other CVD endpoints was modified by the CaD-supplementation (p-interaction = 0.24), see figure 2. Moreover, hazard ratios were in the opposite direction of those observed in the CEE trial. Conclusion: Calcium and vitamin D supplementation did not consistently modify the effect of CEE therapy on CVD events, but did appear to modify its effect on CVD death. The effect of CEE (active vs. placebo) on CVD death was favorable among women randomized to CaD supplement use but unfavorable among those randomized to CaD-Placebo. While CaD significantly modified the effect of CEE on cardiovascular death (p-interaction = 0.03), these differences were not individually significant. CaD did not significantly modify the effect of CEE+MPA on CVD death or any CVD events. Additional research on potential interactions between CaD and HT is warranted. Sources of Funding: None

Optimization of cellular lipophilic ligand efficiency (LLE) in a series of 2-anilino-pyrimidine IGF-1R kinase inhibitors led to the identification of novel 2-(pyrazol-4-ylamino)-pyrimidines with improved physicochemical properties. Replacement of the imidazo[1,2-a]pyridine group of the previously reported inhibitor 3 with the related pyrazolo[1,5-a]pyridine improved IGF-1R cellular potency. Substitution of the amino-pyrazole group was key to obtaining excellent kinase selectivity and pharmacokinetic parameters suitable for oral dosing, which led to the discovery of (2R)-1-[4-(4-{[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone (AZD9362, 28), a novel, efficacious inhibitor of IGF-1R.