WO2008154241A1 - Indazoles à substitution 5-hétéroaryle servant d'inhibiteurs de kinases - Google Patents

Indazoles à substitution 5-hétéroaryle servant d'inhibiteurs de kinases Download PDF

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WO2008154241A1
WO2008154241A1 PCT/US2008/065727 US2008065727W WO2008154241A1 WO 2008154241 A1 WO2008154241 A1 WO 2008154241A1 US 2008065727 W US2008065727 W US 2008065727W WO 2008154241 A1 WO2008154241 A1 WO 2008154241A1
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Prior art keywords
indazol
triazol
benzyl
carboxamide
indazole
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PCT/US2008/065727
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English (en)
Inventor
Irini Akritopoulou-Zanze
Brian D Wakefield
Helmut Mack
Sean C Turner
Alan F Gasiecki
Vijaya J Gracias
Kathy Sarris
Douglas M Kalvin
Melissa J Michmerhuizen
Qi Shuai
Jyoti R Patel
Margaretha Bakker
Nicole Teusch
Eric T Johnson
Peter J Kovar
Stevan W Djuric
Andrew J Long
Anil Vasudevan
Adrian Hobson
Nigel St. John Moore
Lu Wang
Dawn George
Biqin Li
Kristine Frank
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Abbott Laboratories
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Priority to CN200880102038A priority Critical patent/CN101790526A/zh
Priority to AU2008262038A priority patent/AU2008262038A1/en
Priority to EP08770094A priority patent/EP2167491A1/fr
Priority to BRPI0811065-4A2A priority patent/BRPI0811065A2/pt
Priority to MX2009013213A priority patent/MX2009013213A/es
Priority to CA002689117A priority patent/CA2689117A1/fr
Priority to JP2010511293A priority patent/JP5451602B2/ja
Priority to RU2009149696/04A priority patent/RU2487873C2/ru
Publication of WO2008154241A1 publication Critical patent/WO2008154241A1/fr
Priority to IL202318A priority patent/IL202318A0/en
Priority to ZA2009/08624A priority patent/ZA200908624B/en

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Definitions

  • the present invention relates to 5-substituted indazole containing compounds, methods of making the compounds, compositions containing the compounds which are useful for inhibiting kinases such as Glycogen Synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus Kinases (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNKl, aurora, pirn 1 and nek 2.
  • kinases such as Glycogen Synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus Kinases (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNKl, aurora, pirn 1 and nek 2.
  • Protein kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine, serine, threonine, or histidine residue located on a protein substrate. Protein kinases clearly play a role in normal cell growth. Many of the growth factor receptor proteins have intracellular domains that function as protein kinases and it is through this function that they effect signaling. The interaction of growth factors with their receptors is a necessary event in the normal regulation of cell growth, and the phosphorylation state of substrate proteins often is related to the modulation of cell growth.
  • protein kinases have become the targets of new pharmaceutical research (Cohen, P. Nature Reviews Drug Discovery, 1 :309-315, 2002).
  • Various protein kinase inhibitors have been used clinically in the treatment of a wide variety of diseases, such as cancer, chronic inflammatory diseases, diabetes and stroke.
  • the protein kinases are a large and diverse family of enzymes that catalyze protein phosphorylation and play a key role in cellular signaling. Protein kinases may exert positive or negative regulatory effects, depending upon their target protein. Protein kinases are involved in specific signaling pathways which regulate cell functions such as, but not limited to, metabolism, cell cycle progression, cell adhesion, vascular function, apoptosis, and angiogenesis. As a result, malfunctions of cellular signaling have been associated with many diseases, the most characterized of which include cancer and diabetes. The regulation of signal transduction by cytokines and the association of signal molecules with proto- oncogenes and tumor suppressor genes have been well documented. Similarly, the connection between diabetes, viral infections and the conditions related thereto has also been associated with the regulation of protein kinases.
  • protein kinases regulate nearly every cellular process, including metabolism, cell proliferation, cell differentiation, and cell survival, they are attractive targets for therapeutic intervention for various disease states.
  • cell-cycle control and angiogenesis in which protein kinases play a pivotal role are cellular processes associated with numerous disease conditions such as, but not limited to, cancer, inflammatory diseases, abnormal angiogenesis and diseases related thereto, atherosclerosis, macular degeneration, diabetes, obesity, and pain.
  • Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase encoded by two isoforms, GSK-3 ⁇ and GSK-3 ⁇ with molecular weights of 51 and 47 kDa, respectively. These share 97% sequence similarity in their kinase catalytic domains.
  • the GSK-3 ⁇ isoform has an extended glycine-rich N-terminal tail.
  • a minor splice variant of GSK-3 ⁇ has been identified (expressed at ⁇ 15% of total) with a 13 amino acid insert within the kinase domain. This variant had a reduced activity towards tau.
  • GSK-3 is highly conserved throughout evolution, and found in all mammals thus far with high homology in the kinase domain. Both isoforms are ubiquitously expressed in mammalian tissues, including the brain.
  • GSK-3 inhibitors are not able to selectively inhibit one of the isoforms.
  • GSK-3 ⁇ plays an important role in the control of metabolism, differentiation and survival. It was initially identified as an enzyme able to phosphorylate and hence inhibit glycogen synthase. Subsequently, it was recognized that GSK-3 ⁇ was identical to tau protein kinase 1 (TPKl), an enzyme that phosphorylates tau protein in epitopes that are also found to be hyperphosphorylated in Alzheimer's disease and in several taupathies.
  • TPKl tau protein kinase 1
  • protein kinase B (AKT) phosphorylation of GSK-3 ⁇ results in a loss of kinase activity, and it has been proposed that this inhibition may mediate some of the effects of neurotrophic factors.
  • phosphorylation of ⁇ -catenin (a protein involved in cell survival) by GSK-3 ⁇ results in its degradation by an ubiquitinilation dependent proteasome pathway.
  • GSK-3 ⁇ activity may result in neurotrophic activity.
  • lithium an uncompetitive inhibitor of GSK-3 ⁇ , enhances neuritogenesis in some models and can also increase neuronal survival, through the induction of survival factors such as Bcl-2 and the inhibition of the expression of proapoptotic factors such as P53 and Bax.
  • GSK-3 ⁇ may be the link between the two major pathological processes in Alzheimer's disease: abnormal APP (Amyloid Precursor Protein) processing and tau protein hyperphosphorylation.
  • APP Amyloid Precursor Protein
  • frontotemporoparietal dementia corticobasal degeneration, Pick's disease, progressive supranuclear palsy
  • dementia including vascular dementia; acute stroke and other traumatic injuries; cerebrovascular accidents (e.g. age related macular degeneration); brain and spinal cord trauma; peripheral neuropathies; retinopathies and glaucoma.
  • GSK-3 ⁇ may also have utility in the treatment of other diseases such as: non-insulin dependent diabetes and obesity; manic depressive illness; schizophrenia; alopecia; inflammation; cancers such as breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and several virus-induced tumors.
  • diseases such as: non-insulin dependent diabetes and obesity; manic depressive illness; schizophrenia; alopecia; inflammation; cancers such as breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and several virus-induced tumors.
  • Rho kinases the first Rho effectors to be described, are serine/threonine kinases that are important in fundamental processes of cell migration, cell proliferation and cell survival. Abnormal activation of the Rho/ROCK pathway has been observed in various disorders. Examples of disease states in which compounds of the present invention have potentially beneficial therapeutic effects due to their anti vasospasm activity includes cardiovascular diseases such as hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, cerebral vasospasm after subarachnoid bleeding, pulmonary hypertension and atherosclerosis. The muscle relaxing property is also beneficial for treating asthma, male erectile dysfunctions, female sexual dysfunction, and over-active bladder syndrome.
  • cardiovascular diseases such as hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, cerebral vasospasm after subarachnoid bleeding, pulmonary hypertension and atherosclerosis.
  • the muscle relaxing property is also beneficial for treating asthma, male erectile dysfunctions, female sexual dysfunction
  • ROCKs ROCKs-induced neurite growth and sprouting. Inhibition of ROCKs results in induction of new axonal growth, axonal rewiring across lesions within the CNS, accelerated regeneration and enhanced functional recovery after acute neuronal injury in mammals (spinal-cord injury, traumatic brain injury). Inhibition of the Rho/ROCK pathway has also proved to be efficacious in other animal models of neurodegeneration like stroke, inflammatory and demyelinating diseases, Alzheimer's disease as well as the treatment of pain.
  • Rho/ROCK pathway inhibitors therefore have potential for preventing neurodegeneration and stimulating neuroregeneration in various neurological disorders, including spinal-cord injury, Alzheimer's disease, stroke, multiple sclerosis, amyotrophic lateral sclerosis, as well as the treatment of pain.
  • ROCK inhibitors have been shown to possess anti-inflammatory properties.
  • compounds of the invention can be used as treatment for neuroinflammatory diseases such as stroke, multiple sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and inflammatory pain, as well as other inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, irritable bowel syndrome, Crohn's disease, psoriasis, ulcerative colitis, Lupus, and inflammatory bowel disease.
  • ROCK inhibitors reduce cell proliferation and cell migration, they could be useful in treating cancer and tumor metastasis. Further more, there is evidence suggesting that ROCK inhibitors suppress cytoskeletal rearrangement upon virus invasion, thus they also have potential therapeutic value in anti-viral and anti-bacterial applications.
  • ROCK inhibitors are also useful for the treatment of insulin resistance and diabetes. Further, ROCK inhibitors have been shown to ameliorate progression of cystic fibrosis (Abstract S02.3, 8th World Congress on Inflammation, Copenhagen, Denmark, June 16-20, 2007).
  • Rho-associated coiled-coil forming protein kinases (ROCK)-I and -2, have been shown to enhance myosin light chain (MLC) phosphorylation by inhibiting MLC phosphatase as well as phosphorylating MLC. This results in the regulation of actin-myosin contraction.
  • ROCK myosin light chain
  • Recent reports have demonstrated that inhibition of ROCK results in disruption of inflammatory cell chemotaxis as well as inhibition of smooth muscle contraction in models of pulmonary inflammation associated with asthma. Therefore, the inhibitors of the Rho/ROCK pathway should be useful for the treatment of asthma.
  • JAKs The Janus kinases
  • PTKs protein tyrosine kinases
  • JAKl protein tyrosine kinases
  • JAK3 The Janus kinases
  • TYK2 The Janus kinases
  • the JAKs play critical roles in several important intracellular signaling pathways, including the eponymous JAK/STAT pathway, central to the mediation of cytokine signaling. It is this pivotal role in cytokine signaling that underpins the notion that specific JAK inhibitors may be therapeutically deployed in situations where cytokine activity results in disease.
  • JAK2 a member of the Janus kinase (JAK) family of protein tyrosine kinases (PTKs), is an important intracellular mediator of cytokine signaling. Mutations of the JAK2 gene are associated with hematologic cancers, and aberrant JAK activity is also associated with a number of immune diseases, including rheumatoid arthritis.
  • Aurora kinases are a family of multigene mitotic serine -threonine kinases that functions as a class of novel oncogenes. These kinases comprise aurora- A, aurora-B, and aurora-B members. These are hyperactivated and/or over-expressed in several solid tumors including but not limited to breast, ovary, prostate, pancreas, and colorectal cancers.
  • aurora-A is a centrosome kinase, and its localization depends on the cell cycle and plays an important role cell cycle progression and cell proliferation.
  • Aurora-A is located in the 20ql3 chromosome region that is frequently amplified in several different types of malignant tumors such as colorectal, breast and bladder cancers. Inhibition of aurora kinase activity could help to reduce cell proliferation, tumor growth and potentially tumorigenesis.
  • Ri is hydrogen, alkyl, aryl, heterocycle, heteroaryl, R a R b N-, R 0 R d N-C(O)- or R 0 RdN-S(O) 2 -;
  • R 2 is hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, heterocyclecarbonyl or ReR f N-alkyl-C(O)-;
  • R 3 is alkyl, alkoxy, aryl, cyano, cycloalkyl, halogen, haloalkyl, heteroaryl, nitro, or RgR h N-;
  • R 4 is alkyl, alkoxyalkyl, aryl, cycloalkyl, heteroaryl, heterocycle, heterocyclealkyl,
  • R 5 is alkyl, aryl, or heteroaryl;
  • R 6 is alkyl, alkoxyalkyl, R j R k N-alkyl-, aryl, cycloalkyl or heteroaryl;
  • R 7 is alkyl, aryl or heteroaryl
  • R a and R b are each independently hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, R 4 -C(O)-, or R 5 -S(O) 2 -;
  • Rc and Ra are each independently hydrogen, alkyl or heteroaryl
  • R. and R f are each independently hydrogen, alkyl, arylalkyl, heteroarylalkyl, R 6 -C(O)-, or R 7 -S(O) 2 -;
  • R g and Rj 1 are each independently hydrogen, alkyl, or alkylcarbonyl;
  • R, and R k are each independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heterocycle;
  • R xx , R ⁇ x i, R xx ii, and R xxm are each independently alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, aryl(hydroxy)alkyl, aryloxyalkyl, arylcarbonyl, arylthioalkyl, carboxy, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, trialkylsilylalkyl, H 2 NC(O)-alkyl, Z a Z b N-, Z a Z b Nalkyl, Z 0 ZdNC(O)- or ZcZdNS(O) 2 - wherein R X1V
  • Z c and Z d are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl(hydroxy)alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, H 2 NC(O)-alkyl-, dialkylNC(O)-alkyl-, dialkylN-alkyl-, or CHZ e Z f ;
  • Z f is heteroarylalkyl, heterocyclealkyl, or ZiZ 2 N-alkyl-; m is 0, 1 or 2; a is O or l; b is O, I, or 2; c is 0, 1, 2 or 3; and d is O, 1, 2, 3 or 4.
  • compositions comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically suitable carrier.
  • the object of the present invention is to provide compounds that are useful for the preventive of or treatment of diseases caused by abnormal protein kinase activity.
  • the invention also provides pharmaceutically effective compositions of the compounds of the present invention that are useful for the prevention of or treatment of said diseases.
  • the present invention also relates to a pharmaceutical composition which comprises at least one 5-substituted indazole compound of the formula (I) which may exist as a pharmaceutically acceptable salt or prodrug thereof, in the presence or absence of pharmaceutically acceptable carriers, dragees, adjuvants or other auxiliary substances.
  • the compounds of the present invention have inhibitory activity against GSK-3, ROCK-I, ROCK-2, JAK2 as well as other kinases and are useful for the inhibition of such kinases. Certain compounds of the present invention are selective toward one or more kinases and may be useful for the selective inhibition of such kinases. Accordingly, the compounds of the present invention are useful as an active ingredient for the preparation of a composition, which enables preventive and/or therapeutic treatment of a disease caused by abnormal GSK-3 activity and more particularly, of neurodegenerative diseases such as Alzheimer's disease. In addition, the compounds of the present invention are also useful as an active ingredient for the preparation of a composition for preventive and/or therapeutic treatment of neurodegenerative diseases such as Parkinson's disease, tauopathies (e.g.
  • frontotemporoparietal dementia corticobasal degeneration, Pick's disease, progressive supranuclear palsy
  • dementia including vascular dementia; acute stroke and other traumatic injuries; cerebrovascular accidents (e.g. age related macular degeneration); brain and spinal cord trauma; peripheral neuropathies; retinopathies and glaucoma; and other diseases such as non-insulin dependent diabetes (such as diabetes type II) and obesity; manic depressive illness; schizophrenia; alopecia; cancers such as breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and several virus-induced tumors.
  • compounds of the present invention have the formula (I) as described above. More particularly, compounds of formula (I) can include, but are not limited to, compounds wherein A is (ii), (iii), (iv), (vii), (x), (xiv), (xv), (xvi), (xvii), (xviii), (xix), (xx), (xxi), (xx ⁇ ), or (xxiii).
  • A is (ii), (iii), (iv), (vii), (x), (xiv), (xv), (xvi), (xvii), (xviii), (xix), (xx), (xxi), (xx ⁇ ), or (xxiii).
  • A is (ii)
  • Ri is hydrogen, aryl, heteroaryl, heterocycle, R 1 RbN- or R 0 RdN-C(O)-
  • R 2 is hydrogen, alkoxycarbonyl, heterocyclecarbonyl, alkylcarbonyl, or ReR f N-alkyl-C(O)-
  • R 4 is alkyl, alkoxyalkyl, aryl, cycloalkyl, heterocycle, heterocyclealkyl, R j R k N-, or R,R k N-alkyl-
  • R 5 is alkyl, aryl, or heteroaryl
  • R 3 and R b are each independently hydrogen, arylalkyl, cycloalkylalkyl, R4-C(0)-, or Rs-S(O) 2 -
  • R c and Rd are each independently hydrogen or heteroaryl
  • R 6 and R f are each independently hydrogen or alkyl
  • R, and R k are each independently hydrogen, alkyl, aryl, cyclo
  • Ri is hydrogen or R a R b N-;
  • R 2 is hydrogen;
  • R 4 is R,R k N-alkyl-;
  • R a and R b are each independently hydrogen or R 4 -C(O)-;
  • R 1 and R k are each alkyl;
  • R 111 is alkoxycarbonylalkyl, alkyl, arylalkyl, cyanoalkyl, heterocyclealkyl, or H 2 NC(O)-alkyl-;
  • c is 0, 1, or 2; and
  • m is 0.
  • Ri is hydrogen or R 3 R b N-;
  • R 2 is hydrogen;
  • R 3 and R b are each hydrogen;
  • R 1V is aryl, arylalkyl, heterocycle, heterocyclealkyl, Z a ZbNalkyl or Z c ZdNS(O) 2 -;
  • Z a and Zb are each independently hydrogen or alkyl;
  • Z c and Zd are each alkyl;
  • c is 0, 1, or 2; and
  • m is 0.
  • Ri is hydrogen, alkyl, or R a RbN;
  • R 2 is hydrogen;
  • R a and Rb are each hydrogen;
  • R V11 is alkyl, alkoxycarbonyl, aryl, arylalkyl, cycloalkyl, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, or Z c Z d NC(O)-;
  • Z c and Z d are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl(hydroxy)alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, or CHZ e Z f j Z e is aryl or heteroaryl, Z f is heteroarylalkyl, heterocyclealkyl, or ZiZ 2 N-alkyl-;
  • X l Ri is hydrogen; R 2 is hydrogen; R x is alkyl, aryl, or Z a Z b N-; Z a and Z b are each independently hydrogen, alkyl, aryl, or arylalkyl; b is 1 or 2; and m is 0.
  • A is (xiv)
  • Ri is hydrogen;
  • R 2 is hydrogen;
  • R X1V is Z a ZbN-;
  • Z a and Zb are each independently hydrogen or cycloalkyl;
  • c is 1 ; and
  • m is 0.
  • Ri is hydrogen or R 3 RbN-;
  • R 2 is hydrogen;
  • R 3 and Rb are each hydrogen;
  • R xv is ZaZbN-;
  • Z a and Zb are each independently hydrogen, alkoxycarbonylalkyl, aryl, arylalkyl, or cycloalkyl;
  • d is 0 or 1; and
  • m is 0.
  • A is (xvi)
  • Ri is hydrogen; R 2 is hydrogen; R XV1 is Z a Z b N-; Z a and Z b are each independently hydrogen or cycloalkyl; d is 1; and m is 0.
  • Ri is hydrogen;
  • R 2 is hydrogen;
  • R XV11 is aryl or Z a Z b N-;
  • Z a and Z b are each independently hydrogen, alkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, or H 2 NC(O)-alkyl-;
  • d is 0 or 1; and
  • m is 0.
  • Ri is RaRbN-; R 2 is hydrogen; Ra and Rb are each hydrogen; c is 0; and m is 0.
  • Ri is RaRbN-; R 2 is hydrogen; Ra and Rb are each hydrogen; c is 0; and m is 0.
  • Ri is RaRbN-; R 2 is hydrogen; Ra and Rb are each independently hydrogen; c is 0; and m is 0.
  • Ri is RaRbN-;
  • R 2 is hydrogen;
  • R 4 is R,R k N-alkyl-;
  • R a and Rb are each hydrogen or R 4 -C(O)-;
  • R, and R k are independently alkyl;
  • R xx is Z a Z b N- or heterocycle;
  • Z a and Z b are independently hydrogen or alkyl;
  • c is 0 or 1; and
  • m is 0.
  • A is (xxi)
  • Ri is R a R b N-;
  • R 2 is hydrogen;
  • R a and R b are each hydrogen;
  • R XX1 is alkoxy;
  • d is 1; and
  • m is O.
  • Ri is R a R b N-;
  • R 2 is hydrogen;
  • R 4 is R,R k N-alkyl-;
  • R a and R b are each independently hydrogen or R 4 -C(O)-;
  • R j and Rk are each alkyl;
  • c is 0 and m is 0.
  • Ri is RaRbN-;
  • R 2 is hydrogen;
  • R ⁇ and Rb are each hydrogen;
  • c is 0; and
  • m is 0.
  • Specific embodiments contemplated as part of the invention include, but are not limited to, compounds of formula (I), for example: 5-(l-benzyl-lH-l,2,3-triazol-5-yl)-lH-indazole compound with 5-(l-benzyl-lH- l,2,3-triazol-4-yl)-lH-indazole;
  • alkenyl as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
  • alkoxy means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkoxyalkoxy means an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein.
  • Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy.
  • alkoxyalkoxyalkyl as used herein, means an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
  • Representative examples of alkoxyalkoxyalkyl include, but are not limited to, tert-butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy)methyl, and 2-(2- methoxyethoxy)ethyl.
  • alkoxyalkyl as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
  • alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
  • alkoxycarbonyl as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
  • alkoxycarbonylalkyl as used herein, means an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
  • alkoxycarbonylalkyl include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and 2-tert-butoxycarbonylethyl.
  • alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkylcarbonyl as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl- 1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
  • alkylcarbonylalkyl means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
  • Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.
  • alkylcarbonyloxy as used herein, means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.
  • alkylene means a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 10 carbon atoms.
  • Representative examples of alkylene include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH(CH 3 )CH 2 -.
  • alkylene-NR g - means an alkylene group, as defined herein, appended to the parent molecular moiety through a -NRg- group, as defined herein.
  • alkylsulfmyl means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulf ⁇ nyl group, as defined herein.
  • Representative examples of alkylsulfmyl include, but are not limited to, methylsulfmyl and ethylsulfinyl.
  • alkylsulfmylalkyl as used herein, means an alkylsulfmyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
  • alkylsulfinylalkyl include, but are not limited to, methylsulfmylmethyl and ethylsulfinylmethyl.
  • alkylsulfonyl as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
  • alkylsulfonylalkyl as used herein, means an alkylsulfonyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
  • Representative examples of alkylsulfonylalkyl include, but are not limited to, methylsulfonylmethyl and ethylsulfonylmethyl.
  • alkylthio as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom.
  • Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.
  • alkylthioalkyl as used herein, means an alkylthio group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
  • Representative examples of alkylthioalkyl include, but are not limited to, methylthiomethyl and 2-(ethylthio)ethyl.
  • alkynyl as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
  • Representative examples of alkynyl include, but are not limited to, acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
  • aryl means phenyl, a bicyclic aryl or a tricyclic aryl.
  • the bicyclic aryl is naphthyl, or a phenyl fused to a cycloalkyl, or a phenyl fused to a cycloalkenyl, or a phenyl fused to a monocyclic heteroaryl ring as defined herein, or a phenyl fused to a monocyclic heterocycle as defined herein.
  • the bicyclic aryl of the present invention must be attached to the parent molecular moiety through any available carbon atom contained within the phenyl ring.
  • bicyclic aryl examples include, but are not limited to, 2,3-dihydro-l,4-benzodioxin-5-yl, 2,3-dihydro-l,4-benzodioxin-6-yl, 3,4- dihydro-2H-l,5-benzodioxepin-6-yl, dihydroindenyl, indenyl, indol-4-yl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl.
  • the tricyclic aryl is anthracene or phenanthrene, or a bicyclic aryl fused to a cycloalkyl, or a bicyclic aryl fused to a cycloalkenyl, or a bicyclic aryl fused to a phenyl.
  • the tricyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the tricyclic aryl.
  • Representative examples of tricyclic aryl ring include, but are not limited to, azulenyl, dihydroanthracenyl, fluorenyl, and tetrahydrophenanthrenyl.
  • aryl groups of this invention are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulflnyl, alkylsulf ⁇ nylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, aryl*NC(O)-, aryl*NHC(O)NH-, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, fo ⁇ nylalkyl, halogen, haloalkyl, heteroaryl, hydroxy, hydroxyalkyl, mer
  • aryloxy as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4- methylphenoxy, and 3,5-dimethoxyphenoxy.
  • aryloxyalkyl as used herein, means an aryloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of aryloxyalkyl include, but are not limited to, 2-phenoxyethyl, 3- naphth-2-yloxypropyl and 3-bromophenoxymethyl.
  • arylalkyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.
  • aryl(hydroxy)alkyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkylene group bearing one hydroxy group, as defined herein.
  • Representative examples of aryl(hydroxy)alkyl include, but are not limited to, 2-phenylethanol-2-yl and 2-hydroxy-2-phenylethanyl.
  • arylcarbonyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of arylcarbonyl include, but are not limited to, benzoyl and naphthoyl.
  • arylthio as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a sulfur atom.
  • Representative examples of arylthio include, but are not limited to, phenylthio and 2-naphthylthio.
  • arylthioalkyl as used herein, means an arylthio group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
  • Representative examples of arylthioalkyl include, but are not limited to, phenylthiomethyl, 2- naphth-2-ylthioethyl, and 5 -phenylthiomethyl.
  • azido as used herein, means a -N 3 group.
  • azidoalkyl as used herein, means an azido group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
  • carbonyl as used herein, means a -C(O)- group.
  • carboxy as used herein, means a -CO 2 H group.
  • carboxyalkyl as used herein, means a carboxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2- carboxyethyl, and 3-carboxypropyl.
  • cyano as used herein, means a -CN group.
  • cyanoalkyl as used herein, means a cyano group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2- cyanoethyl, and 3-cyanopropyl.
  • cycloalkenyl as used herein, means a monocyclic or bicyclic ring system containing from 3 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • monocyclic ring systems include, but are not limited to, 2-cyclohexen-l-yl, 3-cyclohexen-l-yl, 2,4- cyclohexadien- 1 -yl and 3-cyclopenten-l-yl.
  • Bicyclic ring systems are exemplified by a monocyclic cycloalkenyl ring system which is fused to another monocyclic cycloalkyl ring as defined herein, a monocyclic aryl ring as defined herein, a monocyclic heterocycle as defined herein or a monocyclic heteroaryl as defined herein.
  • the bicyclic ring systems of the present invention must be appended to the parent molecular moiety through an available carbon atom within the cycloalkenyl ring.
  • bicyclic ring systems include, but are not limited to, 4,5-dihydro-benzo[l,2,5]oxadiazole, 3a, 4, 5, 6, 7, 7a-hexahydro-lH- indenyl, 1, 2, 3, 4, 5, 6-hexahydro-pentalenyl, 1, 2, 3, 4, 4a, 5, 6, 8a-octahydro-pentalenyl.
  • cycloalkyl as used herein, means a monocyclic, bicyclic, or spirocyclic ring system.
  • Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Bicyclic cycloalkyl groups of the present invention are exemplified by a monocyclic cycloalkyl ring fused to another monocyclic cycloalkyl ring, or a monocyclic cycloalkyl ring fused cycloalkenyl, or a monocyclic cycloalkyl ring fused to a phenyl ring, or a monocyclic cycloalkyl ring fused to a monocyclic heteroaryl ring as defined herein, or a monocyclic cycloalkyl ring fused to a monocyclic heterocycle as defined herein.
  • the bicyclic cycloalkyl ring systems of the present invention must be appended to the parent molecular moiety through an available carbon atom within the monocycloalkyl ring.
  • the cycloalkyl groups of the present invention are optionally substituted with 1, 2, 3, or 4 substituents selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, oxo, ZiZ 2 N-, or (Z 3 Z 4 N)carbonyl.
  • substituents selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkyls
  • cycloalkylalkyl means a cycloalkyl group appended to the parent molecular moiety through an alkyl group, as defined herein.
  • cycloalkylcarbonyl means cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl, and cyclohexylcarbonyl.
  • formyl as used herein, means a -C(O)H group.
  • formylalkyl as used herein, means a formyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of formylalkyl include, but are not limited to, formylmethyl and 2- formylethyl.
  • halo or halogen as used herein, means -Cl, -Br, -I or -F.
  • haloalkoxy means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2- fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
  • haloalkyl as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2- fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • heteroaryl means a monocyclic heteroaryl or a bicyclic heteroaryl.
  • the monocyclic heteroaryl is a 5 or 6 membered ring containing at least one heteroatom independently selected from O, N, or S.
  • the 5 membered ring contains two double bonds may contain one, two, three or four heteroatoms.
  • the 6 membered ring contains three double bonds may contain one, two, three or four heteroatoms.
  • the 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl.
  • monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl.
  • the bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a monocyclic aryl ring as defined herein, a monocyclic cycloalkyl ring as defined herein, a monocyclic cycloalkenyl ring as defined herein, another monocyclic heteroaryl or a monocyclic heterocycle ring as defined herein.
  • the bicyclic heteroaryl ring systems of the present invention must be appended to the parent molecular moiety through an available carbon atom within the heteroaryl ring.
  • the bicyclic heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the bicyclic heteroaryl.
  • bicyclic heteroaryl include, but are not limited to, benzofuranyl, benzoxadiazolyl, 1,3- benzothiazolyl, benzimidazolyl, benzodioxolyl, benzothiophenyl, chromenyl, cinnolinyl, furopyridine, indolyl, indazolyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine, quinolinyl, thienopyridine and thienopyridinyl.
  • heteroaryl groups of the present invention are optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, benzyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, ZiZ 2 N-, or (Z 3 Z 4 N)carbonyl.
  • Heteroaryl groups of the present invention that are substituted may be present as tautomers.
  • the present invention encompasses all tautomers including non-aromatic tauto
  • heteroarylalkyl means a heteroaryl group appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heterocycle or “heterocyclic” as used herein, refers to a monocyclic, bicyclic, tricyclic or a spirocyclic ring system that contains at least one heteroatom.
  • the monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S.
  • the 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S.
  • the 5 membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle.
  • monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, isoindoline-l,3-dione, mo ⁇ holinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl
  • the bicyclic heterocycle of the present invention is defined as a monocyclic heterocycle fused to a phenyl group, a cycloalkylgroup as defined herein, a cycloalkenyl group as defined herein, another monocyclic heterocycle group as defined herein, or a spirocyclic ring wherein one carbon atom of the monocyclic heterocycle is bridged by two ends of an alkylene chain.
  • the bicyclic heterocycle of the present invention is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclic ring.
  • bicyclic heterocycle include, but are not limited to, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-l,4- benzodioxinyl, 2,3-dihydro-l-benzofuranyl, 2,3-dihydro-l-benzothienyl, 3,4-dihydro-lH- isochromen-4-yl, 2,3-dihydro-lH-indolyl, succinmimidyl, and 1,2,3,4-tetrahydroquinolinyl.
  • the tricyclic heterocycle is a bicyclic heterocycle fused to a phenyl, or a bicyclic heterocycle fused to a cycloalkyl, or a bicyclic heterocycle fused to a cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle.
  • the tricyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the tricyclic heterocycle.
  • tricyclic heterocycle include, but are not limited to, 2,3,4,4a,9,9a-hexahydro-lH-carbazolyl, 5a,6,7,8,9,9a- hexahydrodibenzo[b,d]furanyl, and 5a,6,7,8,9,9a-hexahydrodibenzo[b,d]thienyl.
  • heterocycles of this invention are optionally substituted with 1, 2,or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, aryl, benzyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, hydroxyalkylcarbonyl, hydroxyalkoxyalkyl, mercapto, oxo, ZiZ 2 N-, or (Z3Z 4 N)carbonyl.
  • substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alk
  • heterocyclealkyl means a heterocycle group appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heterocyclecarbonyl means a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • hydroxy means an -OH group.
  • hydroxyalkyl as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkylene group, as defined herein.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4- hydroxyheptyl.
  • hydroxyalkylcarbonyl as used herein, means a hydroxyalkyl group, as defined herein, as appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples include, but are not limited to, 2-hydroxyacetyl, and 4-hydroxybutanoyl.
  • hydroxyalkoxyalkyl as used herein, means a hydroxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
  • Representative examples of hydroxyalkoxyalkyl include, but are not limited to, (2-hydroxy-ethoxy)-ethyl, and (3-hydroxyl-propoxyl)-ethyl.
  • hydroxy-protecting group or "O-protecting group” means a substituent that protects hydroxyl groups against undesirable reactions during synthetic procedures.
  • hydroxy-protecting groups include, but are not limited to, substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl)-ethoxymethyl, benzyl, and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal, acetonide and benzylidene acetal; cyclic ortho esters, for example, methoxymethylene; cyclic carbonates; and cyclic boronates. Commonly used hydroxy-protecting groups are disclosed in T.W. Greene and P.G.
  • mercapto as used herein, means a -SH group.
  • nitrogen protecting group means those groups intended to protect an amino group against undesirable reactions during synthetic procedures.
  • Preferred nitrogen protecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, tert-butoxycarbonyl (Boc), tert-butylacetyl, trifluoroacetyl, and triphenylmethyl (trityl).
  • nitro as used herein, means a -NO 2 group.
  • trialkylsilyl as used herein, means three independently selected alkyl groups, as defined herein, appended to the parent molecular moiety through a silicon atom.
  • Representative examples of trialkylsilyl include, but are not limited to, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and triisopropylsilyl.
  • trialkylsilylalkyl as used herein, means a trialkylsilyl group, as defined herein, appended to the parent molecular through an alkylene group, as defined herein.
  • Representative examples of trialkylsilylalkyl include, but are not limited to, trimethylsilylmethyl, 2-trimethylsilylethyl, and 2-t-butyldimethylsilylethyl.
  • ZiZ 2 N means two groups, Zi and Z 2 , which are appended to the parent molecular moiety through a nitrogen atom.
  • Zi and Z 2 are each independently hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl. In certain instances within the present invention, Zi and Z 2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring.
  • Z 1 Z 2 N include, but are not limited to, amino, methylamino, acetylamino, acetylmethylamino, phenylamino, benzylamino, azetidinyl, pyrrolidinyl and piperidinyl.
  • Z3Z 4 N means two groups, Z3 and Z 4 , which are appended to the parent molecular moiety through a nitrogen atom.
  • Z3 and Z 4 are each independently hydrogen, alkyl, aryl and arylalkyl.
  • Representative examples of Z 3 Z 4 N include, but are not limited to, amino, methylamino, phenylamino and benzylamino.
  • ( Z3Z 4 N)carbonyl means a NZ3Z 4 group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of (Z 3 Z 4 N)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
  • sulfinyl as used herein, means a -S(O)- group.
  • sulfonyl as used herein, means a -SO 2 - group.
  • sulfonamide as used herein means a -SO 2 NH 2 group.
  • tautomer means a proton shift from one atom of a compound to another atom of the same compound wherein two or more structurally distinct compounds are in equilibrium with each other.
  • Stereoisomers may exist as stereoisomers wherein, asymmetric or chiral centers are present. These stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom.
  • R and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30.
  • Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers.
  • Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials that contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution which is well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary; or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
  • the compounds and processes of the present invention will be better understood by reference to the following Examples, which are intended as an illustration of and not a limitation upon the scope of the invention. Further, all citations herein are incorporated by reference.
  • Compound names are assigned by using Name Pro naming software, which is provided by ACD/Labs.
  • compound names are assigned using AUTONOM naming software, which is provided by MDL Information Systems GmbH (formerly known as Beilstein Informationssysteme) of Frankfurt, Germany, and is part of the CHEMDRA W® ULTRA v. 6.0.2 software suite and ISIS Draw v. 2.5.
  • Such reactions between compounds of formula 1 and compounds of formula A-Sn(R z ) 3 utilize a palladium catalyst such as, but not limited to, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylidmeacetone)dipalladium or palladium diacetate, in the presence or absence of a ligand such as tri(2-furyl)phosphine or triphenylarsine in a solvent such as toluene or DMF at a temperature from about 25 0 C to about 150 0 C.
  • a palladium catalyst such as, but not limited to, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylidmeacetone)dipalladium or palladium diacetate, in the presence or absence of
  • Li(I), Cu(I), or Mn(II) salts may be added to improve reactivity or specificity.
  • Reactions between compounds of formula 1 and compounds of formula A-B(OR y ) 2 commonly known as Suzuki couplings utilize palladium catalysts such as, but not limited to, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylidineacetone)dipalladium or palladium diacetate.
  • a palladium ligand may be added such as 2-
  • the reaction may also be achieved with heating in a microwave reactor oven.
  • organo stannanes are commercially available or described in the literature, it is also possible to prepare additional stannanes from A-halides or A-triflates by treatment with a hexa-alkyldistannane of formula ((R 2 ⁇ Sn) 2 in the presence of Pd(PtLsP) 4 .
  • A-B(OR y ) 2 may be prepared from the corresponding halides or triflates (A-halo or A-triflate) via metal exchange with an organo lithium followed by the addition of the alkyl borate.
  • compounds of formula (I) may be synthesized utilizing Stille couplings as described in Scheme 3.
  • Compounds of formula 3_, wherein R 11 is defined in formula (I) when treated with compounds of formula 4, wherein Ri is defined in formula (I) and Pi is a nitrogen protecting group such as, but not limited to, tert- butyloxycarbonyl or acetyl, in the presence of dichlorobis(triphenylphosphine)palladium(II) and (thiophene-2-carbonyloxy)copper in toluene under heated conditions will provide compounds of formula 5_.
  • compounds of formula J_3 when treated with TMS-acetylene in the presence of copper iodide, dichlorobis(triphenylphosphine)palladium(II) and triethylamine followed by treatment with tetrabutylammonium fluoride or potassium hydroxide will provide compounds of formula j_4.
  • the reaction may be done in a solvent such as, but not limited to, DMF at ambient temperature or under heated conditions.
  • Compounds of formula 14 when treated with compounds of formula 9 ⁇ wherein R 11 is defined in formula (I), or sodium azide, copper sulfate and metallic copper under heated conditions will provide compounds of formula j_5.
  • Standard carboxylic acid amine coupling conditions include adding a coupling reagent such as, but not limited to, l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), l,3dicyclohexylcarbodiimide (DCC), Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl), O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) with or without an auxiliary reagent such as, but
  • Standard carboxylic acid- amine coupling conditions include adding a coupling reagent such as, but not limited to, l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1,3- dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl), O- (7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or O- benzotriazol-l-yl-N,N,N',N'-tetramethylurom ' um tetrafluoroborate (TBTU) with or without an auxiliary reagent such as, but not limited to, 1 -hydroxy-7-azabenzotriazole (HOAT) or 1- hydroxybenzotriazole hydrate (HOBT) in a solvent such as
  • Compounds of formula 34 when treated with a Grignard reagent such as benzylmagnesium bromide in a solvent such as tetrahydrofuran below ambient temperature will provide compounds of formula 35_.
  • Compounds of formula 3_5 when treated with a protecting group reagent such as, but not limited to, di-terf-butyldicarbonate and a catalytic amount of DMAP in a solvent such as THF or acetonitrile will provide compounds of formula 36.
  • Compounds of formula 36 when treated with pyridinium tribromide in a solvent such as, but not limited to, THF with or without the use of heat will provide compounds of formula 36 A.
  • compounds of formula 47 which are representative of compounds of formula (I), wherein A is (x) may be prepared accordingly.
  • Compounds of formula 4J_, wherein Ri is defined in formula (I) when treated with di-tert-butyldicarbonate and a catalytic amount of DMAP in a solvent such as THF or acetonitrile will provide compounds of formula 42.
  • Treatment of compounds of formula 42 with tributyl( 1 - ethoxyvinyl)stannane and dichlorobis(triphenylphosphine)palladium(II) will provide compounds of formula 44.
  • Compounds of formula 44 when treated with pyridinium tribromide in THF will provide compounds of formula 45_.
  • Compounds of formula 45 when treated with compounds of formula 46 in a solvent such as, but not limited to, ethanol, wherein R x is defined in formula (I), will provide compounds of formula 47.
  • compounds of formula 5_5 which are representative of compounds of formula (I) wherein A is (xiv), (xv), (xvi) or (xvii), may be prepared accordingly.
  • Compounds of formula (52), wherein Ri is defined in formula (I) when treated with butyllithium followed by treatment with DMF followed by an acidic work up will provide compounds of formula 48.
  • Compounds of formula 48 . when treated with compounds of formula 5_1, wherein X is -CH-, -N- or -S-, Y is -CH-, -N- or a bond, and scandium tri(triflate) followed by treatment with compounds of formula 54, wherein Z a is define in formula (I) will provide compounds of formula 5_5.
  • compounds of formula 5J ⁇ 1 which are representative of compounds of formula (I) wherein A is (vii) may be prepared accordingly.
  • Compounds of formula (11), wherein Ri is defined in formula (I) when treated with a reagent such as, but not limited to, ethyl 2-chloro-2-(hydroxyimino)acetate with a base such as, but not limited to, triethylamine will provide compounds of formula 56.
  • the reaction may be performed in a solvent such as but limited to toluene and may require the use of heat.
  • compounds of formula 29 which are representative of compounds of formula (I) wherein A is (ii) may be prepared accordingly.
  • Compounds of formula (27), wherein Ri is defined in formula (I) when treated with a compound of formula 9, R 11 C(O)Cl or ICl, CuI, and triethylamine in a solvent such as, but not limited to, tetrahydrofuran will provide compounds of formula 29.
  • the reaction may be performed at ambient temperature or with the use of heat.
  • compounds of formula 60 which are representative of compounds of formula (I), wherein A is (vi), may be prepared accordingly.
  • Compounds of formula 48, wherein Ri is defined in formula (I) when treated with l-(isocyanomethyl sulfonyl)-4-methylbenzene, 59, and a suitable base such as, but not limited to, potassium carbonate in a solvent such as methanol or tetrahydrofuran and subsequently treated with a suitable acid such as hydrochloric acid will provide compounds of formula 60.
  • compounds of formula 66 which are representative of compounds of formula (I), wherein A is (ix), may be prepared accordingly.
  • Compounds of formula 61, wherein R 1 is defined in formula (I) when treated with hydrazine in a suitable solvent such as tetrahydrofuran will provide compounds of formula 64.
  • Compounds of formula 64, when treated with trimethylortho formate, 65 , in the presence of a catalytic amount of /7-toluene sulfonic acid in a solvent such as tetrahydrofuran will provide compounds of formula 66.
  • compounds of formula 74 which are representative of compounds of formula (I), wherein R 11 and R 4 are as defined for formula (I) are prepared starting with compounds of formula 70, wherein Xi is iodo, bromo, or chloro.
  • Compounds of formula 71 upon reaction with acid chlorides of formula _18 in the presence of a base such as potassium carbonate in tetrahydrofuran at ambient temperature over 2 to 8 hours provide compounds of formula 72.
  • compounds of formula 72 can be made from compounds of formula 1 ⁇ _ using the conditions described in Scheme 6.
  • compounds of formula 76 which are representative of compounds of formula (I), wherein A and R 4 are as defined for formula (I) are obtained from compounds of formula 75.
  • Compounds of formula 75 can be treated with A-B(OR y ) 2 wherein A is defined as for formula (I) and R y is hydrogen, alkyl, aryl or the two R y groups together with the boron atom to which they are attached form a 1,3-dioxoborolane, in the presence of a palladium catalyst using the Suzuki reaction conditions described in Scheme 1 to give compounds of formula 76.
  • compounds of formulas 82, 83 . , 84, an d 85_ which are representative of compounds of formula (I), wherein A, R 4 , R5, Ra and R 1 are as defined for formula (I), are prepared from compounds of formula $]_.
  • Compounds of formula £ can be treated with an acid chloride, 1_8, in solvent such as tetrahydrofuran in the presence of a base such as potassium carbonate or triethylamine to give compounds of formula 82.
  • An alternative solvent is dichloromethane and an alternative base is pyridine.
  • the acid chlorides can be prepared from the corresponding carboxylic acids by treatment with oxalyl chloride with a catalytic amount of N,N-dimethylformamide.
  • compounds of formula $1_ can be treated with R 1 NCO in heated pyridine.
  • Compounds of formula 84 are prepared from compounds of formula 8! by treatment with R 5 SO 2 CI in pyridine at or near room temperature.
  • Compounds of formula 85 are also prepared from compounds of formula $1_ in a reductive amination reaction with R a CHO in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride and acetic acid in a solvent such as 1 ,2-dichloroethane at or near room temperature and subsequent treatment with trifluoroacetic acid in dichloromethane to remove the t-butoxycarbonyl protecting group.
  • compounds of formula 87 wherein A, R, and Rk are defined for formula (I), can be prepared from compounds of formula 86.
  • Compounds of formula 86 are prepared as described for compounds of formula 82 in Scheme 26.
  • Compounds of formula 86 can then be heated in the presence of an amine, HNR,R k , and a base such as triethylamine in a solvent such as acetom ' trile to give compounds of formula 87.
  • heterocycles such as pyrrolidine, piperidine, piperazine, and morpholine can be substituted for the amine.
  • compounds of formula 89 wherein A, Ri, R 2 , R3, m, Z c and Z d are as defined for formula (I), can be prepared form compound of formula $$_.
  • Compounds of formula 88 can be prepared as described in Schemesl-4, 7-9, 22, 24, and 26. During the preparation of compounds of formula 88, the carboxylic acid moiety pendant on A can be protected as an ester and subsequently hydrolyzed to expose the carboxylic acid by methods known to one skilled in the art of organic synthesis.
  • Compounds of formula 8£ when treated with an amine (HNZ c Zd) using carboxylic acid-amine coupling conditions known to one skilled in the art will provide compounds of formula 89.
  • Standard carboxylic acid amine coupling conditions include adding a coupling reagent such as, but not limited to, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), l,3dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl), O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) optionally in the presence of a base such as triethylamine or diisopropylethylamine with or without an auxiliary reagent such as, but not limited to, 1 -hydroxy-7-azabenzo
  • the mixture was extracted with dichloromethane, and the organics were dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure.
  • the crude solid was washed with methanol, dissolved in tetrahydrofuran (200 mL) and treated with a warm solution of KOH (60 g) in water (200 mL). The mixture was stirred for 15 minutes and was treated with 6N HCl to pH 1. The layers were separated, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure.
  • Example IB tert-Butyl 5 -((trimethylsilyl)ethynyl)- 1 H-indazole- 1 -carboxylate
  • Example IA (10.81 g, 31.4 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.1 g, 1.57 mmol), and copper (I) iodide (365 mg, 1.92 mmol) were combined in triethylamine (70 mL) under an inert atmosphere.
  • Trimethylsilyl acetylene 5.0 mL, 36.0 mmol was added and the mixture was stirred at 60 0 C overnight.
  • Example IB (7.93 g, 25.2 mmol) was dissolved in methanol (150 mL). A solution of
  • Example 1C Into a microwave vial were added 100.0 mg (0.70 mmol) of Example 1C, 81 mg (0.7 mmol) of trimethylsilyl azide, CuI (4 mg), and dimethylformamide/methanol (ImL, 9: 1). The mixture was heated at 160 0 C for 20 minutes using microwave irradiation (CEM- Discover, 100 Watts, 1 minute ramp time). The mixture was dissolved in ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous MgSU 4 , filtered and concentrated under reduced pressure, and purified by silica gel chromatography eluting with 80% ethyl acetate in hexanes to afford the title compound.
  • CEM- Discover microwave irradiation
  • the mixture was extracted with dichloromethane, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • the crude solid was washed with methanol, dissolved in tetrahydrofuran (200 mL) and treated with a warm solution of KOH (60 g) in water (200 mL). The mixture was stirred for 15 minutes and was treated with 6N HCl to pH 1. The layers were separated, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure.
  • Example 3B tert-Butyl 5 -((trimethylsilyl)ethynyl)- 1 H-indazole- 1 -carboxylate
  • Example 3A (10.81 g, 31.4 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.1 g, 1.57 mmol), and copper (I) iodide (365 mg, 1.92 mmol) were combined in triethylamine (70 mL) under an inert atmosphere.
  • Trimethylsilyl acetylene (5.0 mL, 36.0 mmol) was added and the mixture was stirred at 60 0 C overnight.
  • Example 3B (7.93 g, 25.2 mmol) was dissolved in methanol (150 mL). A solution of 1 N potassium hydroxide (50 mL) was added and the mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting slurry was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to afford the title compound.
  • Example 3C (40 mg, 0.28 mmol), benzyl azide (37 mg, 0.28 mmol), CuSO 4 (14 mg, 0.056 mmol) and Cu wire (14 mg) were combined in tert-butanol (0.5 mL) and water (0.5 mL) and heated in a CEM-Discover microwave for 10 minutes at 125 0 C and 100 Watts. To the mixture was added IM HCl and water, the product was extracted with dichloromethane, and purified by silica gel chromatography (50% ethyl acetate in hexanes) to afford the title compound.
  • Example 3C Into a 5 mL CEM Microwave reaction tube which contained a Teflon-coated micro- flea stirring bar were added 17.6 mg (0.124 mmol) of Example 3C, 300 uL aqueous solution containing 7.80 mg (0.118 mmol) of sodium azide; followed by 15.79 ⁇ L (0. 118 mmol; 21.80 mg 0.95 equivalents) of 2-methyl-benzyl bromide (added neat). To the suspension were then added 300 ⁇ L of fer ⁇ -butanol; 25 mg of copper wire; and finally 50 ⁇ L of 1 N aqueous copper sulfate pentahydrate solution.
  • the microwave reaction vessel was then capped and heated with stirring for 10 minutes at 125 0 C at 100 Watts power on a CEM- Discover microwave. After cooling to ambient temperature, the mixture was diluted with 0.25 N aqueous HCl; and the aqueous suspension was extracted with dichloromethane. The organic layer was washed with distilled water; saturated aqueous NaCl; and then dried over anhydrous sodium sulfate and filtered. The dried solution was diluted with acetonitrile; and the soluble organic material was then filtered thru a glass wool plug which was overlaid with additional anhydrous sodium sulfate. An aliquot of the filtrate was then removed for subsequent LC/MS analysis.
  • Example 6 5 -[ 1 -(4-methylbenzyl)- 1 H- 1 ,2,3-triazol-4-yl]- 1 H-indazole
  • Example 10 5_[ l -(4-fluorobenzyl)-lH- 1 ,2,3-triazol-4-yl]- lH-indazole
  • the title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 4-fluorobenzylbromide.
  • Example 27 methyl 3 - ⁇ [4-( 1 H-indazol-5 -yl)- 1 H- 1 ,2,3 -triazol- 1 -yl]methyl ⁇ benzoate
  • the title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 3-carbomethoxybenzylbromide.
  • Example 28 methyl 4- ⁇ [4-(lH-indazol-5-yl)-lH-l,2,3-triazol-l-yl]methyl ⁇ benzoate
  • the title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 4-carbomethoxybenzylbromide.
  • Example 35 5- ⁇ l-[2,4-bis(trifluoromethyl)benzyl]-lH-l,2,3-triazol-4-yl ⁇ -lH-indazole
  • the title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 2,4-bis(trifluoromethyl)bromide.
  • Example 36A 50 mg, 0.34 mmol and 2-aminothiazole (28 mg, 0.34 mmol) were combined with scandium triflate (8 mg, 0.017 mmol) in anhydrous methanol (1 mL) in a 4 mL vial. The vial was sealed and shaken at ambient temperature for 30 minutes. Cyclohexyl isocyanide (42 mL, 0.34 mmol) was added, and the mixture was shaken for 2 days at room temperature.
  • Example 36A Into a 20 mL scintillation vial was added 50.0 mg (0.34 mmol) of Example 36A. To the solid was added a 2.0 mL dimethylformamide solution containing 0.46 mmol (49 mg) of benzylamine and 50 mg of powdered activated 4A molecular sieves. The vial was then capped and heated at 60 0 C for 4 hours on an orbital shaker. The vial was allowed to cool to ambient temperature; and was uncapped. To the suspension was added 32 mg (0.23 mmol) of anhydrous potassium carbonate followed by 66 mg (0.23 mmol) ⁇ -(p-toluenesulfonyl)-4- fluorobenzylisonitrile.
  • the vial was then capped and heated overnight at 60 0 C on a shaker.
  • the vial was removed from the shaker; allowed to cool to ambient temperature; and the resulting suspension was filtered.
  • the filtrate was evaporated under reduced pressure at medium heat on a Savant Speed Vac.
  • the crude residues were redissolved in 1 : 1
  • Example 40 N- ⁇ 3-[4-(4-fluorophenyl)-5 -( 1 H-indazol-5 -yl)- 1 H-imidazol- 1 -yl]propyl ⁇ -N,N-dimethylamine
  • the title compound was prepared as a TFA salt according to the procedure outlined in Example 39 substituting benzylamine with N ⁇ N'-dimethylpropane-l ⁇ -diamine.
  • Example 36B substituting pyrimidin-2-amine for thiazol-2-amine.
  • Example 44B tert-Butyl 5 -acetyl- 1 H-indazole- 1 -carboxylate
  • Example 44A (5.12 g, 17.2 mmol), tributyl (1-ethoxyvinyl) tin (7.0 mL, 20.7 mmol), and dichlorobis(triphenylphosphine)palladium(II) (672 mg, 0.957 mmol) were combined in toluene (85 mL). Nitrogen was bubbled into the mixture for 5 minutes, and the mixture was heated to 100 0 C in a sealed tube overnight.
  • Example 44C tert-Butyl 5 -(2-bromoacetyl)- 1 H-indazole- 1 -carboxylate
  • Example 44B (1.60 g, 6.15 mmol) and pyridinium tribromide (1.98 g, 6.19 mmol) were combined in tetrahydrofuran and heated to 40 0 C for 2 hours. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0- 40% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 360.9 (M+Na) + .
  • Example 44C (71 mg, 0.208 mmol) and l-phenyl-2-thiourea (33 mg, 0.217 mmol) were combined in ethanol (300 mL) in a 4 mL vial. The vial was shaken at 80 0 C overnight. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of methanol in dichloromethane (0-5%) to afford the title compound.
  • Example 55 methyl N-[2-(lH-indazol-5-yl)imidazo[l,2-a]pyridin-3-yl]glycinate
  • the title compound was prepared as a TFA salt according to the procedure outlined in Example 36B substituting 2-aminopyridine for 2-aminothiazole and methyl 2-isocyanoacetate for cyclohexyl isocyanide.
  • Example 36B The title compound was prepared according to the procedure outlined in Example 36B substituting 2-aminopyridine for 2-aminothiazole and benzyl isocyanide for cyclohexyl isocyanide. The final product precipitated out of solution and was isolated after filtration.
  • Example 59 tert-butyl 4-[4-(4-fluorophenyl)-5-(lH-indazol-5-yl)-lH-imidazol-l-yl]piperidine-l- carboxylate
  • the title compound was prepared according to the procedure outlined in Example 39 substituting tert-butyl 4-aminopiperidine-l-carboxylate for benzylamine.
  • Example 6OB tert-butyl S-bromo-S-phenyl-lH-indazole-l-carboxylate and tert-butyl 5-bromo-3-iodo-lH- indazole- 1 -carboxylate To a solution of Example 6OA (2.1 g, 5 mmol) in toluene (10 mL) was added
  • Example 6OB (1 g, 2.55 mmol), dichlorobis(triphenylphosphine)palladium(II) (89 mg, 0.13 mmol), triethylamine (1.78 mL, 12.75 mmol), trimethylsilyl acetylene (0.432 mL, 3.06 mmol), and CuI (24 mg, 0.13 mmol) were combined in dimethylformamide (10 mL) and stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed with water, and purified by silica gel chromatography to afford the title compounds.
  • Example 6OC To a solution of Example 6OC (350 mg, 0.85 mmol) in tetrahydrofuran (5mL) was added a IM solution of TBAF in tetrahydrofuran (2 mL, 2 mmol). After 10 minutes, the solvent was evaporated under reduced pressure and the crude mixture was purified by silica gel chromatography eluting with 5% ethyl acetate in hexanes to afford the title compounds.
  • Example 61 A tert-Butyl 3-phenyl-5-((trimethylsilyl)ethynyl)-lH-indazole-l-carboxylate and tert-butyl 5- bromo-3 -phenyl- 1 H-indazole- 1 -carboxylate
  • Example 6OB (1 g, 2.55 mmol), dichlorobis(triphenylphosphine)palladium(II) (89mg,
  • Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 70 mL) was added to a solution of Example 62A (5.05 g, 23.2 mmol) in tetrahydrofuran (50 mL) and allowed to stir for 20 minutes. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. 1 H
  • Example 62B (1.68 g, 11.6 mmol) was dissolved in tert-butanol (14 mL). Benzyl azide (2.14 g, 15.8 mmol) was added and the mixture was transferred to 14 microwave vials (1.0 mL each). Water (0.5 mL), a small piece of copper wire, and a 1 M solution of copper (II) sulfate (0.5 mL) were added to each microwave vial and the vials were heated in a CEM- Discover microwave at 125 0 C using 100 Watts for 10 minutes each. The vials were recombined, diluted with ethyl acetate, and washed with water and brine.
  • Example 62C Hydrazine hydrate (18 mL) was added to Example 62C (1.93 g, 6.94 mmoL) in ethanol (10 mL). The mixture was heated to 95 0 C overnight. The mixture was diluted with ethyl acetate and washed with water. Some of the product precipitated in the separatory funnel and was filtered to afford the title compound. The ethyl acetate layer was concentrated under reduced pressure and the resulting solid was triturated with methanol to afford additional title compound.
  • Example 62D (44 mg, 0.152 mmol), 1 -methylpiperdine-4-carboxylic acid hydrochloride (27 mg, 0.150 mmol), and HATU (61 mg, 0.160 mmol) were combined in tetrahydrofuran (2 mL).
  • Diisopropylethylamine (110 mL, 0.631 mmol) was added and the mixture was heated to 90 0 C for 30 minutes.
  • the mixture was diluted with methylene chloride and washed with 1 N sodium hydroxide.
  • the organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-15% methanol in dichloromethane to afford the title compound.
  • Example 62D (1.80 g, 6.20 mmol) was suspended in methylene chloride (100 mL) with a catalytic amount of dimethylaminopyridine. A solution of di-tert-buty ⁇ dicarbonate (1.36 g, 6.23 mmol) in methylene chloride (50 mL) was added dropwise over 1 hour. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-5% methanol in dichloromethane to afford the title compound. MS (ESI+) m/z 391.1 (M+H) + .
  • Example 64B N-[5-(l-benzyl-lH-l,2,3-triazol-4-yl)-lH-indazol-3-yl]-2-methoxyacetamide
  • Example 64A 45 mg, 0.115 mmol was dissolved in methylene chloride (1.5 mL) and pyridine (0.5 mL). Methoxy acetyl chloride (18 uL, 0.197 mmol) was added and the mixture was stirred at ambient temperature for 2 hours.
  • Example 64A (81 mg, 0.207 mmol) was dissolved in methylene chloride (2 mL) and pyridine (0.5 mL). Dimethylaminoacetylchloride hydrochloride, 80% (120 mg, 0.607 mmol) was added in three portions over 2 hours and the mixture was stirred at ambient temperature overnight. Trifluoroacetic acid (2 mL) was added and the mixture was stirred for 3 hours. The mixture was diluted with methylene chloride and washed with 1 N sodium hydroxide. The organic layer was absorbed on silica gel and purified using silica gel chromatography eluting with a gradient of 5-15% methanol in dichloromethane to afford the title compound.
  • Example 64A (76 mg, 0.195 mmol) was dissolved in methylene chloride (2 mL) and pyridine (0.2 mL). Butyryl chloride (26 uL, 0.250 mmol) was added and the mixture was stirred at ambient temperature for 2 hours. Trifluoroacetic acid (1 mL) was added and the mixture was stirred for 3 hours. The mixture was diluted with methylene chloride and washed with water.
  • Example 3C (1.83 g, 12.9 mmol) was dissolved in toluene (60 mL) and triethylamine (2.2 mL) and warmed to 90 0 C.
  • Ethyl 2-chloro-2-(hydroxyimino)acetate (1.89 g, 12.5 mmol) was dissolved in toluene (15 mL) and was added dropwise over 30 minutes. Following the addition, the mixture was diluted with ethyl acetate and washed with 1 N hydrochloric acid. The organic layer was concentrated under reduced pressure and the resulting residue was triturated with methanol to afford the title compound.
  • Example 70 (1.50 g, 5.83 mmol) was dissolved in tetrahydrofuran (100 mL), methanol (10 mL), and water (10 mL). Potassium hydroxide (680 mg, 12.1 mmol) was added, and the mixture was stirred at ambient temperature for 2 hours. The solvents were removed under reduced pressure, and the resulting residue was triturated with a mixture of 1 N hydrochloric acid and methanol to provide a solid that was filtered to afford the title compound.
  • Example 71A (46 mg, 0.201 mmol), HATU (88 mg, 0.231 mmol), and diisopropylethylamine (133 uL, 0.764 mmol) were combined in tetrahydrofuran (2 mL). Monomethylamine (40% solution in water) (50 uL) was added, and the reaction was stirred at 50 0 C for 2 hours. The mixture was diluted with methylene chloride and washed with 1 N sodium hydroxide, 1 N hydrochloric acid, and brine.
  • Phenylacetaldehyde (90+ %) (266 mg, 2.38 mmol) was dissolved in tert-butanol (1 mL) and water (1 mL). Hydroxylamine hydrochloride (79 mg, 1.14 mmol) was added followed by a 6N solution of sodium hydroxide (19 uL, 31.7 mmol). The mixture was stirred for 30 minutes. Chloramine-T trihydrate (308 mg, 1.09 mmol) was added slowly over 5 minutes followed by the addition of copper (II) sulfate and a small piece of copper wire.
  • Example 3C (154 mg, 1.08 mmol) was added and the mixture was stirred at 5O 0 C for 2 hours then ambient temperature overnight. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title compound.
  • Example 75B The title compound was prepared according to the procedure outlined in Example 3A, substituting methyl 4-amino-3-methylbenzoate for 4-iodo-2-methylaniline. During the final workup, addition of 6 N HCl until pH 6 resulted in the formation of a solid, which was filtered, washed twice with water and dried in vacuo to afford the title compound.
  • Example 75B Example 75B
  • Example 75A To a suspension of Example 75A (1.6 g, 10 mmol) and N,O-dimethylhydroxylamine (1.1 g, 11 mmol) in dichloromethane (40 mL) and dimethylformamide (10 mL) was added triethylamine (1.67 mL, 12 mmol) and EDC (2.1 g, 11 mmol), and the mixture was stirred at room temperature for 24 hours. The solvents were evaporated under reduced pressure, and the resulting residue was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and purified by silica gel column chromatography in ethyl acetate to afford the title compound. MS (ESI+) m/z 206.0 (M+H) + .
  • Example 75B A solution of Example 75B (900 mg, 4.39 mmol) in tetrahydrofuran (10 mL) was cooled under argon with an ice bath and treated with a 2M solution of benzyl magnesium chloride in tetrahydrofuran (6.6 mL, 13.16 mmol). The reaction was stirred overnight at room temperature followed by the addition of one more equivalent of benzyl magnesium chloride. The mixture was heated at 70 0 C for 9 hours. One more equivalent of benzylmagnesium chloride was added, and the reaction was heated at 70 0 C for another 90 minutes and was allowed to cool to room temperature.
  • Example 75C To a suspension of Example 75C (236 mg, 1 mmol) in dichloromethane (2 mL) was added di-tert-butyl dicarbonate (327 mg, 1.5 mmol) and a pinch of dimethylaminopyridine ( ⁇ 2 mg). The mixture was stirred for 15 minutes, and passed through a bed of silica gel and eluted with dichlormethane. The solvent was evaporated under reduced pressure to afford the title compound. MS (ESI+) m/z 337.0 (M+H) + .
  • N-benzyl-4-(lH-indazol-5-yl)-5-phenyl-l,3-thiazol-2-amine A vial containing Example 75E (50 mg, 0.16 mmol) and 1 -benzylthiourea (26 mg, 0.16 mmol) in ethanol (1 mL) was capped and heated in a heater shaker at 80 0 C for 2 hours. The solution of the crude product was purified by reverse-phase HPLC using an acetonitrile/water 0.1% TFA gradient elution method to afford the title compound as a TFA salt.
  • Example 77A tert-butyl 5 -(cyclopropylethynyl)- 1 H-indazole- 1 -carboxylate
  • Example 44A (2.31 g, 7.77 mmol), cyclopropyl acetylene (620 mg, 9.37 mmol), dichlorobis(triphenylphosphine)palladium(II) (170 mg, 0.242 mmol), and copper (I) iodide (92 mg, 0.483 mmol) were combined in triethylamine (10 mL) under an inert atmosphere of nitrogen. The mixture was heated to 100 0 C in a sealed tube for 4 hours.
  • Example 77A (145 mg, 0.51 mmol) and benzyl azide (82 mg, 0.62 mmol) were heated neat in a CEM-Discover microwave at 150 0 C and 150 Watts, for 10 minutes. The crude mixture was dissolved in dichloromethane and purified by silica gel column chromatography using 50% ethyl acetate in hexanes as the eluent.
  • Example 8OA 122 mg, 0.864 mmol
  • Example 3C 150 mg, 0.619 mmol
  • a small piece of copper wire followed by copper(II) sulfate 5 mg, 0.02 mmol was added, and the vial was stirred in a microwave (CEM-Discover) at 125 0 C at 100 W for 10 minutes.
  • the mixture was diluted with methylene chloride and washed with 1 N hydrochloric acid.
  • Example 70 (1.50 g, 5.83 mmol) was dissolved in tetrahydrofuran (100 mL), methanol (10 mL), and water (10 mL). Potassium hydroxide (680 mg, 12.1 mmol) was added and the mixture was stirred at ambient temperature for 2 hours. The solvents were removed under reduced pressure, and the resulting residue was triturated with a mixture of 1 N hydrochloric acid and methanol to provide a solid that was filtered to afford the title compound.
  • Example 81A 110 mg, 0.480 mmol
  • piperidine 55 uL, 0.556 mmol
  • HATU 101 mg, 0.266 mmol
  • dimethylformamide 2 mL
  • Diisopropylethylamine 133 uL, 0.764 mmol
  • the mixture was diluted with ethyl acetate and washed with 1 N sodium hydroxide, 1 N hydrochloric acid, water (3 times), and brine.
  • the organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-5% methanol in dichloromethane to afford the title compound.
  • Example 84 5-[3-(piperidin- 1 -ylmethyl)isoxazol-5-yl]-lH-indazole
  • Example 8 IB (22 mg, 0.0742 mmol) was dissolved in tetrahydrofuran (2.5 mL) under an inert atmosphere of nitrogen. Lithium aluminum hydride (1.0 M solution in tetrahydrofuran) (250 uL) was added and the mixture was heated to 70 0 C for 20 minutes. Methanol was added, and the mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of methanol in dichloromethane (0-7%) to afford the title compound.
  • Example 70 (84 mg, 0.366 mmol) was dissolved in tetrahydrofuran (8 mL). Lithium aluminum hydride (1.0 M solution in tetrahydrofuran) (3.0 mL) was added in 1.0 mL portions over 2 hours. After the final addition, the mixture was stirred for an additional 30 minutes. The mixture was diluted with methylene chloride and washed with water and the organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-20% methanol in dichloromethane to afford the title compound.
  • Lithium aluminum hydride 1.0 M solution in tetrahydrofuran
  • Phenylethynyltri-n-butyltm (8.25 g, 21.1 mmol) and benzyl azide (2.3 mL, 18.4 mmol) were combined and heated to 150 0 C overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 526.3 (M+H) + .
  • Example 87A (139 mg, 0.486 mmol), Example 87B (284 mg, 0.542 mmol), dichlorobis(triphenylphosphine)palladium(II) (40 mg, 0.057 mmol) and copper thiophene-2- carboxylate (167 mg, 0.876 mmol) were combined in toluene (1.5 mL) in a microwave vial under an inert atmosphere of nitrogen.
  • the vial was heated in a microwave (CEM-Discover) to 150 0 C at 125 Watts for 20 minutes.
  • the mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound.
  • MS (ESI+) m/z 394.1 (M+H) + .
  • Example 87C (95 mg, 0.242 mmol) was dissolved in tetrahydrofuran (2.0 rnL), methanol (1.0 mL) and water (1.0 rnL), and potassium hydroxide (64 mg, 1.14 mmol) was added. The mixture was stirred for 2 hours, and diluted with ethyl acetate and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-5% methanol in dichloromethane to afford the title compound.
  • Example 87A (969 mg, 3.39 mmol), 3 -phenyl- 1-propyne (392 mg, 3.37 mmol), sodium azide (278 mg, 4.28 mmol), sodium ascorbate (68 mg, 3.43 mmol), sodium carbonate (75 mg, 0.708 mmol), and L-proline (78 mg, 8.98 mmol) were combined in a 1 :1 mixture of dimethyl sulfoxide and water (10 mL). Copper(II) sulfate pentahydrate (46 mg, 0.184 mmol) was added and the mixture was stirred at 65 0 C for 3 hours. 6N Sodium hydroxide (1 mL) was added, and the mixture was stirred for 30 minutes to deprotect the indazole.
  • Example 89A (211 mg, 1.14 mmol) and benzyl azide (143 uL, 1.14 mmol) were combined in a microwave (CEM-Discover) vial and heated to 160 0 C using 100 Watts for 26 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 20-60% ethyl acetate in hexanes to afford a mixture of inseparable triazole regiomers.
  • the mixture of regiomers were treated with hydrazine hydrate (3.0 mL) and ethanol (3.0 mL) and heated to 90 0 C for 1 hour.
  • the mixture was diluted with methylene chloride and washed with water.
  • the organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 1-6% methanol in dichloromethane to afford the title compound.
  • Example 9 5-(3-isobutylisoxazol-5-yl)-lH-indazol-3-amine
  • hydrazine hydrate 1.5 mL
  • ethanol 1.0 mL
  • the mixture was heated to 70 0 C overnight in a sealed vial.
  • the mixture was diluted with methylene chloride and washed with water.
  • the organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-5% methanol in dichloromethane to afford the title compound.
  • Example 72 The title compound was prepared according to the procedure outlined in Example 72 substituting Example 62B for Example 3C. The crude product was used in the next step without further purification or characterization.
  • Example 92A (65 mg, 0.234 mmol) was added hydrazine hydrate (1.5 mL) in ethanol (1.0 mL). The mixture was heated to 70 0 C overnight in a sealed vial. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-20% methanol in dichloromethane to afford the title compound.
  • Example 96 5- ⁇ 4-(4-fluorophenyl)- 1 -[2-(4-methylpiperidin- 1 -yl)ethyl]- lH-imidazol-5-yl ⁇ - lH-indazole
  • the title compound was prepared according to the procedure outlined in Example 39 substituting 2-(4-methylpiperidin- 1 -yl)ethanamine for benzylamine.
  • Example 100 has been removed and is not part of this document. .
  • Example 102B 5 ( 1 -benzyl-5 -phenyl- IH-1 ,2,3 -triazol-4-yl)- 1 H-indazol-3 -amine
  • Example 102A 120 mg, 0.339 mmol
  • hydrazine hydrate 1.0 mL
  • ethanol 1.0 mL
  • the mixture was diluted with methylene chloride and washed with water.
  • the organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-5% methanol in dichloromethane to afford the title compound.
  • Example 109 l- ⁇ [l-(lH-indazol-5-yl)-lH-l,2,3-triazol-4-yl]methyl ⁇ -lH-l,2,3-benzotriazole
  • the title compound was prepared according to the procedure outlined in Example 88 substituting 1-propargyl-lH-benzotriazole for 3-phenyl-l-propyne.
  • Example 119A tert-Butyl 5 -ethynyl- 1 H-indazole- 1 -carboxylate
  • dichloromethane 10 mL
  • di-tert-butyl dicarbonate 459 mg, 2.1 mmol
  • dimethylaminopyridine ⁇ 3 mg
  • Example 87A (235 mg, 0.821 mmol), Example 122A (380 mg, 0.822 mmol), dichlorobis(triphenylphosphine)palladium(II) (60 mg, 0.085 mmol), and copper thiophene-2- carboxylate (325 mg, 1.23 mmol) were combined in toluene (2.0 mL) in a microwave vial under an inert atmosphere of nitrogen.
  • the vial was heated in a microwave (CEM-Discover) to 150 0 C at 125 Watts for 20 minutes.
  • the mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound.
  • MS (ESI+) m/z 332.2 (M+H) + .
  • Example 122B (109 mg, 0.329 mmol) was dissolved in tetrahydrofuran (3.0 mL) and water (0.5 mL), and potassium hydroxide (53 mg, 0.945 mmol) was added. The mixture was stirred for 2 hours, diluted with ethyl acetate, and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0- 5% methanol in dichloromethane to afford the title compound.
  • Example 122A (415 mg, 0.792 mmol), 5-bromo-2-fluorobenzonitrile (158 mg, 0.790 mmol), dichlorobis(triphenylphosphine)palladium(II) (52 mg, 0.074 mmol), and copper thiophene-2-carboxylate (226 mg, 1.19 mmol) were combined in toluene (2 mL) in a microwave vial under an inert atmosphere of nitrogen. The vial was heated in a microwave (CEM-Discover) at 150 0 C at 125 Watts for 20 minutes.
  • CEM-Discover microwave
  • Example 123A (120 mg, 0.339 mmol) was treated with hydrazine hydrate (1.0 mL) in ethanol (1.0 mL) and heated to 60 0 C overnight. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of methanol in dichloromethane (0-5%) to afford the title compound.
  • Example 121 (42 mg, 0.120 mmol) and a solution of 7 N ammonia in methanol (1.0 mL) were combined and heated to 60 0 C overnight. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of methanol in dichloromethane (1-7%) to afford the title compound.

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Abstract

L'invention concerne des composés de formule (I) ou des sels pharmaceutiquement acceptables, où A, R1, R2, R3 et m sont définis dans la description. L'invention concerne également des procédés de préparation desdits composés ainsi que des compositions contenant lesdits composés servant à inhiber les kinases telles que la glycogène synthase kinase 3 (GSK-3), la Rho kinase (ROCK), les Janus kinases (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurore, pim 1 et nek 2.
PCT/US2008/065727 2007-06-08 2008-06-04 Indazoles à substitution 5-hétéroaryle servant d'inhibiteurs de kinases WO2008154241A1 (fr)

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CN200880102038A CN101790526A (zh) 2007-06-08 2008-06-04 用作激酶抑制剂的5-杂芳基取代的吲唑化合物
AU2008262038A AU2008262038A1 (en) 2007-06-08 2008-06-04 5-heteroaryl substituted indazoles as kinase inhibitors
EP08770094A EP2167491A1 (fr) 2007-06-08 2008-06-04 Indazoles à substitution 5-hétéroaryle servant d'inhibiteurs de kinases
BRPI0811065-4A2A BRPI0811065A2 (pt) 2007-06-08 2008-06-04 Indazóis 5-heteroaril substituídos como inibidores de quinase
MX2009013213A MX2009013213A (es) 2007-06-08 2008-06-04 Indazoles 5-sustituidos 5-heteroarilo como inhibidores de cinasa.
CA002689117A CA2689117A1 (fr) 2007-06-08 2008-06-04 Indazoles a substitution 5-heteroaryle servant d'inhibiteurs de kinases
JP2010511293A JP5451602B2 (ja) 2007-06-08 2008-06-04 キナーゼ阻害薬としての５−ヘテロアリール置換インダゾール類
RU2009149696/04A RU2487873C2 (ru) 2007-06-08 2008-06-04 5-замещенные индазолы в качестве ингибиторов киназы
IL202318A IL202318A0 (en) 2007-06-08 2009-11-24 5-heteroaryl substituted indazoles as kinase inhibitors
ZA2009/08624A ZA200908624B (en) 2007-06-08 2009-12-04 5-heteroaryl substituted indazoles as kinase inhibitors

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EP2194045A1 (fr) * 2007-08-30 2010-06-09 Takeda Pharmaceutical Company Limited Dérivé de pyrazole substitué
US7807672B2 (en) 2006-02-16 2010-10-05 Schering Corporation Compounds that are ERK inhibitors
WO2011019651A1 (fr) * 2009-08-10 2011-02-17 Epitherix, Llc Composés d’indazole inhibant la voie de signalisation des wnt et utilisations thérapeutiques de ceux-ci thereof
US7897619B2 (en) 2007-07-17 2011-03-01 Amgen Inc. Heterocyclic modulators of PKB
US7919504B2 (en) 2007-07-17 2011-04-05 Amgen Inc. Thiadiazole modulators of PKB
JP2011520838A (ja) * 2008-05-15 2011-07-21 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ プロドラッグとしての２環式カルボニルアミノ−ピラゾールのカルバモイル誘導体
WO2011136264A1 (fr) * 2010-04-28 2011-11-03 第一三共株式会社 Composé [5,6] hétérocyclique
WO2012084704A1 (fr) * 2010-12-20 2012-06-28 Merck Serono S.A. Dérivés d'indazolyl triazole en tant qu'inhibiteurs d'irak
KR101233082B1 (ko) 2010-02-25 2013-02-14 주식회사 이큐스앤자루 신규한 이미다졸피라진 유도체 화합물 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 항바이러스 치료용 약학적 조성물
EP2566333A1 (fr) * 2010-05-07 2013-03-13 The Board of Trustees of The Leland Stanford Junior University Identification de stabilisants de protéines multimériques
US8450340B2 (en) 2009-12-21 2013-05-28 Samumed, Llc 1H-pyrazolo[3,4-b]pyridines and therapeutic uses thereof
JP2013521260A (ja) * 2010-03-03 2013-06-10 プロビオドルグ エージー グルタミニルシクラーゼの阻害剤
WO2013098229A2 (fr) 2011-12-27 2013-07-04 Bayer Intellectual Property Gmbh Dérivés d'hétéroarylpipéridine et d'hétéroarylpipérazine utilisés comme fongicides
WO2013124158A1 (fr) * 2012-02-21 2013-08-29 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Composés 1h-indazole-3-carboxamide en tant qu'inhibiteurs de la glycogène synthase kinase 3 bêta
US8546404B2 (en) 2005-12-13 2013-10-01 Merck Sharp & Dohme Compounds that are ERK inhibitors
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RU2009149696A (ru) 2011-07-20
BRPI0811065A2 (pt) 2014-12-02
SG182187A1 (en) 2012-07-30
CN101790526A (zh) 2010-07-28
RU2487873C2 (ru) 2013-07-20
AU2008262038A1 (en) 2008-12-18
CA2689117A1 (fr) 2008-12-18
MX2009013213A (es) 2010-03-30
KR20100032886A (ko) 2010-03-26
IL202318A0 (en) 2010-06-30
EP2167491A1 (fr) 2010-03-31

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