EP2051982A1 - 6,6-bicyclische, ringsubstituierte schwefelhaltige heterobicyclische proteinkinaseinhibitoren - Google Patents

6,6-bicyclische, ringsubstituierte schwefelhaltige heterobicyclische proteinkinaseinhibitoren

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Publication number
EP2051982A1
EP2051982A1 EP06801288A EP06801288A EP2051982A1 EP 2051982 A1 EP2051982 A1 EP 2051982A1 EP 06801288 A EP06801288 A EP 06801288A EP 06801288 A EP06801288 A EP 06801288A EP 2051982 A1 EP2051982 A1 EP 2051982A1
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EP
European Patent Office
Prior art keywords
alkyl
compound
ioalkyl
cycloc
substituents
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP06801288A
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English (en)
French (fr)
Inventor
Qun-Sheng Ji
Mark Joseph Mulvihill
Arno G. Steinig
Qinghua Weng
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OSI Pharmaceuticals LLC
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OSI Pharmaceuticals LLC
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Publication date
Application filed by OSI Pharmaceuticals LLC filed Critical OSI Pharmaceuticals LLC
Publication of EP2051982A1 publication Critical patent/EP2051982A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention is directed to novel sulfur-containing heterobicyclic compounds, their salts, compositions comprising them, and combined treatment of patients with those compounds and an epidermal growth factor receptor (EGFR) kinase inhibitor.
  • EGFR epidermal growth factor receptor
  • the present invention is directed to novel sulfur-containing heterobicyclic compounds that inhibit the activity of tyrosine kinase enzymes in animals, including humans, for the treatment and/or prevention of various diseases and conditions such as cancer.
  • PTKs Protein tyrosine kinases
  • endothelial-cell specific receptor PTKs such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in supporting the progression of cancers and other diseases involving inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, infantile hemangiomas).
  • Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
  • the Receptor Tyrosine Kinases comprise a large family of transmembrane receptors with at least nineteen distinct RTK subfamilies having diverse biological activities.
  • the RTK family includes receptors that are crucial for the growth and differentiation of a variety of cell types (Yarden and Ullrich, Ann. Rev. Biochem. 57:433-478, 1988; Ullrich and Schlessinger, Cell 61:243-254, 1990).
  • the intrinsic function of RTKs is activated upon ligand binding, which results in phosphorylation of the receptor and multiple cellular substrates, and subsequently results in a variety of cellular responses (Ullrich & Schlessinger, 1990, Cell 61:203-212).
  • RTK mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity and receptor trans- phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate a corresponding cellular response such as cell division, differentiation, metabolic effects, and changes in the extracellular microenvironrnent (Schlessinger and Ullrich, 1992, Neuron 9:1-20). [4] Malignant cells are associated with the loss of control over one or more cell cycle elements.
  • IGF-I insulin growth factor-I
  • IGF-2 insulin growth factor-2
  • IGF-IR plays an important role in the establishment and maintenance of the malignant phenotype.
  • IGF-IR exists as a heterodimer, with several disulfide bridges. The tyrosine kinase catalytic site and the ATP binding site are located on the cytoplasmic portion of the beta subunit. Unlike the epidermal growth factor (EGF) receptor, no mutant oncogenic forms of the IGF-IR have been identified. However, several oncogenes have been demonstrated to affect IGF-I and IGF-IR expression. The correlation between a reduction of IGF-IR expression and resistance to transformation has been seen. Exposure of cells to the mRNA antisense to IGF-IR RNA prevents soft agar growth of several human tumor cell lines.
  • Apoptosis is a ubiquitous physiological process used to eliminate damaged or unwanted cells in multicellular organisms. Misregulation of apoptosis is believed to be involved in the pathogenesis of many human diseases. The failure of apoptotic cell death has been implicated in various cancers, as well as autoimmune disorders. Conversely, increased apoptosis is associated with a variety of diseases involving cell loss such as neurodegenerative disorders and AIDS. As such, regulators of apoptosis have become an important therapeutic target. It is now established that a major mode of tumor survival is escape from apoptosis. IGF-IR abrogates progression into apoptosis, both in vivo and in vitro.
  • IGF-IR is a transmembrane RTK that binds primarily to IGF-I but also to IGF-II and insulin with lower affinity.
  • IGF-I Binding of IGF-I to its receptor results in receptor oligomerization, activation of tyrosine kinase, intermolecular receptor autophosphorylation and phosphorylation of cellular substrates (major substrates are IRSl and She).
  • the ligand-activated IGF-IR induces mitogenic activity in normal cells and plays an important role in abnormal growth.
  • IGF- 1 pathway in human tumor development has an important role : 1 ) IGF- 1 R overexpression is frequently found in various tumors (breast, colon, lung, sarcoma) and is often associated with an aggressive phenotype. 2) High circulating IGFl concentrations are strongly correlated with prostate, lung and breast cancer risk. Furthermore, IGF-IR is required for establishment and maintenance of the transformed phenotype in vitro and in vivo (Baserga R. Exp.
  • IGF-IR The kinase activity of IGF-IR is essential for the transforming activity of several oncogenes: EGFR, PDGFR, SV40 T antigen, activated Ras, Raf, and v-Src.
  • the expression of IGF-IR in normal fibroblasts induces neoplastic phenotypes, which can then form tumors in vivo.
  • IGF-IR expression plays an important role in anchorage-independent growth. IGF-IR has also been shown to protect cells from chemotherapy-, radiation-, and cytokine-induced apoptosis.
  • IGF-IR endogenous growth factor-IR
  • triple helix formation or antisense expression vector has been shown to repress transforming activity in vitro and tumor growth in animal models.
  • Many of the tyrosine kinases, whether an RTK or non-receptor tyrosine kinase, have been found to be involved in cellular signaling pathways involved in numerous disorders, including cancer, psoriasis, fibrosis, atherosclerosis, restenosis, auto-immune disease, allergy, asthma, transplantation rejection, inflammation, thrombosis, nervous system diseases, and other hyperproliferative disorders or hyper-immune responses.
  • inhibitors of protein-tyrosine kinases are useful as selective inhibitors of the growth of mammalian cancer cells.
  • GleevecTM also known as imatinib mesylate, or STI571
  • STI571 2-phenylpyrimidine tyrosine kinase inhibitor that inhibits the kinase activity of the BCR-ABL fusion gene product
  • This compound in addition to inhibiting BCR-ABL kinase, also inhibits KIT kinase and PDGF receptor kinase, although it is not effective against all mutant isoforms of KIT kinase.
  • WO 00/71129 describes pyrrolotriazine inhibitors of kinases.
  • International Patent Publication No. WO 97/28161 describes pyrrolo[2,3- ⁇ 5T]pyrimidines and their use as tyrosine kinase inhibitors.
  • 07/133280 describes a cephem compound, its production and antimicrobial composition.
  • A. Albert et al. Journal of the Chemical Society, 1_1 : 1540-1547 (1970) describes pteridine studies and pteridines unsubstituted in the 4-position, a synthesis from pyrazines via 3,4-dhydropteridines.
  • A. Albert et al., Chem. Biol. Pteridines Proc. Int. Symp., 4th, 4: 1-5 (1969) describes a synthesis of pteridines (unsubstituted in the 4-position) from pyrazines, via 3-4-dihydropteridines.
  • IGF-IR performs important roles in cell division, development, and metabolism, and in its activated state, plays a role in oncogenesis and suppression of apoptosis.
  • IGF-IR is known to be overexpressed in a number of cancer cell lines (IGF-IR overexpression is linked to acromegaly and to cancer of the prostate).
  • IGF-IR overexpression is linked to acromegaly and to cancer of the prostate.
  • down-regulation of IGF-IR expression has been shown to result in the inhibition of tumorigenesis and an increased apoptosis of tumor cells.
  • the compounds of Formula I inhibit the IGF-IR enzyme and are useful for the treatment and/or prevention of hyperproliferative diseases such as cancer, inflammation, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system.
  • hyperproliferative diseases such as cancer, inflammation, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system.
  • the present invention relates to a compound of Formula I:
  • Xi, X 2 , and X 3 are each independently N or C-(E 1 Xa;
  • X 11 , X 12 , X 13 , X 14 , Xi S , and X 16 are each independently N, C-(E ⁇ ) bb , or N + -O " ; [29] wherein at least one of X 11 , X 12 , X 13 , X 14 , X 15 , and X 16 is N or N + -O " ;
  • E 1 , E 11 , G 1 , and G 41 are each independently halo, -CF 3 , -OCF 3 , -OR 2 , -NR 2 R 3 CR 2 ⁇ 1 ,
  • R 2 , R 2a , R 3 , R 3a , R 222 , R 222a , R 333 , and R 333a are each independently Cwoalkyl, C 2- l oalkenyl, C 2-10 allcynyl, Ci.ioalkoxyQ.ioalkyl, C 1-10 alkoxyC 2- i 0 alkenyl, Ci- l oalkylthioCi.ioalkyl, Ci.i 0 alkylthioC 2- i 0 alkynyl, cycloC 3-8 alkyl, cycloC 3- 8 alkenyl, cycloC 3-8 all ⁇ ylCi -10 alkyl, cycloQ-salkenylCi-ioalkyl, CyCIoC 3 - S aIlCyIC 2-I o alkenyl, cycloC 3- 8 alkenylC 2- i O alkenyl, cycloC 3-8
  • W 1 and Y 1 are each independently -0-, -NR 7 -, -S(0) j7 - -CR 5 R 6 -, -N(C(O)OR 7 )-,
  • R 5 with R 6 are optionally taken together with the carbon atom to which they are attached to form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted with one or more independent R 69 substituents and wherein said ring optionally includes one or more heteroatoms;
  • R 7 , R 7a , and R 8 are each independently acyl, C 0- ioalkyl, C 2- i 0 alkenyl, aryl, heteroaryl, heterocyclyl or cycloQ.ioalkyl, any of which is optionally substituted by one or more independent G 111 substituents;
  • R 4 is Co-ioalkyl, C 2 . 10 alkenyl, C 2- i 0 alkynyl, aryl, heteroaryl, cycloC 3- i 0 alkyl, heterocyclyl, cycloC 3-8 alkenyl, or heterocycloalkenyl, any of which is optionally substituted by one or more independent G 41 substituents;
  • R 69 is aryl-C o .ioalkyl, aryl-C 2- i 0 alkenyl, aryl-C 2- i 0 alkynyl, hetaryl-C o- ioalkyl, hetaryl-C 2-10 alkenyl, hetaryl-C 2- i 0 alkynyl, mono(Ci. 6 alkyl)aminoCi. 6 alkyl, di(Ci.6alkyl)ammoCi..
  • ⁇ alkyl mono(aryl)aminoCi -6 alkyl, di(aryl)aminoCi -6 alkyl, or -N(Ci -6 alkyl)-Ci.6alkyl-aryl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 778 , Ci -lo alkyl, C 2-10 alkenyl, C 2- i O alkynyl, haloCi -10 alkyl, haloC 2 .
  • R 77 , R 78 , R 87 , R 88 , R 778 , and R 88S are each independently aryl-C o- i O alkyl, aryl-C 2- l oalkenyl, aryl-C 2- i 0 alkynyl, hetaryl-C O -ioalkyl, hetaryl-C 2- i 0 alkenyl, hetaryl-C 2- ioalkynyl, mono(Ci -6 alkyl)aminoCi -6 alkyl, di(Ci.6alkyl)aminoCi -6 alkyl, mono(aryl)aminoCi -6 alkyl, di(aryl)aminoCi.
  • n, m, jl, jla,j2a,j5a,j7, andj ⁇ are each independently O, 1, or 2;
  • aa and bb are each independently O or 1.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi, X 2 , and X 3 are C-(E ] ) aa ; and the other variables are described as above for Formula I.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi is N; X 2 and X 3 are C-(E 1 ⁇ a ; and the other variables are described as above for Formula I.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 2 is N; Xi and X 3 are C-(E 1 ) ⁇ ; and the other variables are described as above for Formula I.
  • a compound is represented by Formula I 5 or a pharmaceutically acceptable salt thereof, wherein X 3 is N; Xi and X 2 are C-(E 1 X 3 ; and the other variables are described as above for Formula I.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are N; X 3 is C-(E 1 X a ; and the other variables are described as above for Formula I.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi and X 3 are N; X 2 is C-(E 1 X 3 ; and the other variables are described as above for Formula I.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 2 and X 3 are N; X 2 is C-(E 1 XaJ and the other variables are described as above for Formula I.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , and X 3 are N; and the other variables are described as above for Formula I.
  • Formula I or a pharmaceutically acceptable salt thereof, wherein X 11 , X 12 , and X 14 are N; X 13 , X 15 , and X 16 are C-(E ⁇ ) bt> ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 11 , X 12 , and X 15 are N; X 13 , X 14 , and X 16 are C-(E 11 V; and the other variables are as described in each of the above aspects.
  • a compound is represented by
  • Formula I or a pharmaceutically acceptable salt thereof, wherein Xn, Xi 2 , an d Xi ⁇ are N; Xi 3 , X] 4 , and X 15 are C-(E 11 ⁇ b J and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein Xn, X 13 , and X 14 are N; X 12 , X15, and X 16 are C-(E 1 l ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 11 , X 13 , and X 15 are N; X 12 , X 14 , and X 16 are C-(E ⁇ ) bb ; and the other variables are as described in each of the above aspects.
  • Formula I or a pharmaceutically acceptable salt thereof, wherein X 11 , X 13 , and Xi 6 are N; Xi 2 , Xw, and Xi 5 are C-(E n ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein Xn, Xi 4 , and Xi 5 are N; Xi 2 , X X3 , and Xi 6 are C-(E 1 x ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein Xn, Xi 4 , and Xi 6 are N; Xi 2 , Xi 3 , and Xi 5 are C-(E 1 l ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein Xn, Xi 5 , and Xi 6 are N; Xi 2 , Xi 3 , and Xi 4 are C-(E 1 ] ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi 2 , Xi 3 , and X 14 are N; Xn, Xi 5 , and X 16 are C-(E ⁇ ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 12 , X 13 , and X 15 are N; X 11 , X 14 , and Xi 6 are C-(E ⁇ ) bb ; and the other variables are as described in each of the above aspects.
  • Formula I or a pharmaceutically acceptable salt thereof, wherein X 12 , X 13 , and X 16 are N; X 11 , X 14 , and X 15 are C-(E ⁇ ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 12 , X J4 , and X i5 are N; X n , Xi 3 , and Xi 6 are C-(E n ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein Xj 2 , Xw, and X 16 are N; X 11 , Xn, and X 15 are C-(E n ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 12 , X 15 , and X 16 are
  • N; X 11 , X 13 , and X 14 are C-(E u ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 13 , X 14 , and X 15 are N; X 11 , X 12 , and X 16 are C-(E ⁇ ) bb ; and the other variables are as described in each of the above aspects.
  • Formula I or a pharmaceutically acceptable salt thereof, wherein X 13 , X 14 , and X 16 are N; X n , X 12 , and X 15 are C-(E n ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 14 , X 15 , and X 16 are N; X 11 , X 12 , and X 13 are C-(E 1 ⁇ b ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 13 , X 15 , and X 16 are N; X 11 , X 12 , and X 14 are C-(E 11 ⁇ 1 ,; and the other variables are as described in each of the above aspects.
  • a compound is ' represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 11 and Xi 2 are N;
  • Xi 3> Xi 4 , Xi 5> and X 16 are C-(E ⁇ ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 11 and X 13 are N; X 12 , X 14 , X 15 , and
  • Xi 6 are C-(E 11 ⁇ ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 11 and X 14 are N; X 12 , X 13 , X ]5 , and X 16 are C-(E 1 ! ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 11 and X 15 are N;
  • Xi 2> Xi3 > Xi 4> and X 16 are C-(E ⁇ ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 11 and X 16 are N; X 12 , X 13 , X 14 , and X 15 are C-(E 1 % b ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X !2 and Xi 3 are N; Xn, Xi 4 , Xis, and Xi 6 are C-(E n ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 12 and X M are N; Xn, Xu, Xis, and X] 6 are C-(E n ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 12 and Xi 5 are N; Xn, Xi 3 , X M , and Xi 6 are C-(E 1 l ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 12 and Xi 6 are N;
  • Xn, Xi3 > Xi 4» and Xis are C-(E ⁇ )bb; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 13 and X 14 are N; Xn, Xi 2 , X 1 5, and Xi 6 are C-(E ⁇ ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi 3 and Xi 5 are N; Xn, X 12 , Xi 4 , and Xi 6 are C-(E 11 ⁇ b J and the other variables are as described in each of the above aspects.
  • Formula I or a pharmaceutically acceptable salt thereof, wherein Xi 3 and X 16 are N; Xn, Xi 2 , Xi 4 , and Xis are C-(E 11 ⁇ t ,; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X J4 and X 15 are N; Xn, Xi 2 , Xi 3 , and Xi 6 are C-(E u ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 14 and X 16 are N; X n , X 12 , X13, and X] 5 are C-(E ⁇ ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by
  • Formula I or a pharmaceutically acceptable salt thereof, wherein X n is N; X 12 , Xi 3 , Xi 4 , Xi 5 , and X 16 are C-(E ⁇ ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X )2 is N; Xn, X 13 , X 14 , Xi 5 , and X 16 are C-(E u ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X 13 is N; Xn, X] 2 , Xi 4 , X 15 , and Xi 6 are C-(E 1 ⁇ ⁇ ,; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein X u is N; Xn, Xi 2 , Xi3, X 1 S, and Xi 6 are C-(E ⁇ ) bb ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi 5 is N; Xn, Xi 2 , X 13 , X M , and Xi 6 are C-(E 11 ⁇ ; and the other variables are as described in each of the above aspects.
  • a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi 6 is N; Xn, X J2 , X 13 , Xi 4 , and Xi 5 are C-(E n ) bb ; and the other variables are as described in each of the above aspects.
  • Formula I or a pharmaceutically acceptable salt thereof, wherein Xn and Xi 6 are N; X 12 , X 13 , X M , and X 15 are C-(E 11 ⁇ ; and the other variables are as described in each of the above aspects.
  • Formula I or a pharmaceutically acceptable salt thereof, wherein X 16 is N; Xn, Xn, X 13 , X M , and X 15 are C-(E n ) bb ; and the other variables are as described in each of the above aspects.
  • R 2 , R 2a , R 3 , R 3a , R 222 , R 222a , R 333 , R 333a , R 21 , R 2al , R 31 , R 3al , R 2221 , R 222al , R 3331 , and R 333al are each independently C o- ioalkyl, C 2- i 0 alkenyl, C 2- i 0 alkynyl, Ci.ioalkoxyCi.ioalkyl, Q- i
  • R 2 and R 3 are optionally taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted by one or more independent G 1111 substituents and wherein said ring optionally includes one or more heteroatoms other than the nitrogen to which R 2
  • G 1 is Co-ioalkyl, cycloC 3 . 8 alkyl, or heterocyclyl-Co-ioalkyl, any of which is optionally substituted with one or more independent halo, oxo, -CF 3 , -OCF 3 , -OR 222 ,
  • E 1 is cycloC 3-10 alkyl, bicycloC 5-10 alkyl, aryl, heteroaralkyl, heterocyclyl, heterobicycloCs.ioalkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents; or [137] wherein E 1 is Co-ioalkyl, heteroaralkyl, or aralkyl, any of which is optionally substituted by one or more independent G 11 substituents; or
  • E 1 is cycloC 3-10 alkyl, bicycloC 5-10 alkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents; or [139] wherein E 1 is heterocyclyl or heterobicycloC 5-10 alkyl, of which is optionally substituted by one or more independent G 11 substituents; or [140] wherein E 1 is aryl or heteroaryl, any of which is optionally substituted by one or more independent G 11 substituents; or [141] wherein E 1 is Q-ioalkyl, cycloC 3- i 0 alkyl, bicycloCs-ioalkyl, aralkyl, heteroaralkyl, heterocyclyl, heterobicycloCs-ioalkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents; or [142] wherein
  • G 11 is oxo, -OCF 3 , OR 21 , -NR 2I R 31 (R 2al ) j4 , -C(O)R 21 , -CO 2 R 21 ,
  • G 11 is hetaryl-C O -ioalkyl, any of which is optionally substituted with one or more independent halo, -CF 3 , -OCF 3 , -OR 2221 , -NR 2221 R 3331 (R 222al ) j5a , -C(O)R 2221 , -CO 2 R 2221 , -C(O)NR 2221 R 3331 , -NO 2
  • G 11 is hetaryl-C O -i O alkyl, any of which is optionally substituted with one or more independent halo, -CF 3 , -OCF 3 , OR 2221 , -NR 2221 R 3331 (R 222al ) jSa , -C(O)R 2221 , -CO 2 R 2221 , -C(O)NR 2221 R 3331 , -NO 2 ,
  • any three of Xi i_i 6 is N; or [157] wherein any one of Xn 1 Xw, Xi 5 , or Xi 6 is N; or
  • E 1 is cycloC 3 .ioall ⁇ yl, bicycloCs-ioalkyl, aryl, heteroaralkyl, heterocyclyl, heterobicycloCs-ioallcyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents; or
  • E 1 is C o- ioalkyl, heteroaralkyl, or aralkyl, any of which is optionally substituted by one or more independent G 11 substituents; or
  • E 1 is cycloC 3 .i 0 alkyl, bicycloC 5- i 0 allcyl, spiroallcyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G ⁇ substituents; or [176] wherein E 1 is heterocyclyl or heterobicycloCs. ⁇ alkyl, of which is optionally substituted by one or more independent G 11 substituents; or [177] wherein E 1 is aryl or heteroaryl, any of which is optionally substituted by one or more independent G 11 substituents; or
  • E 1 is C o .ioalkyl, cycloC 3- i 0 alkyl, bicycloC 5-1 oalkyl, aralkyl, heteroaralkyl, heterocyclyl, heterobicycloC 5- ioalkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents; or [179] wherein X 16 is N; or
  • G 11 is oxo, OR 21 , -NR 21 R 31 (R 2al ) j4 , -CO 2 R 21 , -C(O)NR 21 R 31 , C 0 . 10 alkyl, heterocyclyl-Co- ⁇ alkyl, any of which is optionally substituted with one or more independent halo, oxo, -OR 2221 , or -NR 2221 R 3331 (R 222al ) j4a substituents; or G 11 is hetaryl-C O - lo alkyl, any of which is optionally substituted with one or more independent halo, -CF 3 , -OCF 3 , -OR 2221 , -NR 2221 R 3331 (R 222al ) j5a , -C(O)R 2221 , -CO 2 R 2221 , -C(O)NR 2221 R 3331 , -NO 2 , -CN, -S(O
  • E 1 is C o- ioalkyl, cycloQ.ioalkyl, bicycloCs-ioalkyl, aryl, heteroaralkyl, heterocyclyl, heterobicycloC 5 .i 0 alkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents; or
  • G 1 is -OR 2 , -NR 2 R 3 CR 2 V -S(O) j iR 2 , C o- i O alkyl, cycloC ⁇ alkyl, heterocyclyl-Co-ioalkyl, any of which is optionally substituted with one or more independent halo, oxo , -CF 3 , -OCF 3 , -OR 222 , -NR 222 R 333 (R 222a ) jla , -C(O)R 222 , -CO 2 R 222 , -C(O)NR 222 R 333 , -NO 2 , -CN, -S(O) jla R 222 , -SO 2 NR 222 R 333 , -NR 222 C(O)R 333 , -NR 222 C(O)OR 333 , -NR 222 C(O)NR 333 R 222 ", -NR 222 222 ",
  • G 1 is aryl-C o- i O alkyl or hetaryl-Co-ioalkyl, any of which is optionally substituted with one or more independent halo, -CF 3 , -OCF 3 , -OR 222 , -NR 222 R 333 (R 222a ) j2a , -C(O)R 222 , -CO 2 R 222 , -C(O)NR 222 R 333 , -NO 2 , -CN, -S(O) j2a R 222 , -
  • G 1 is aryl-C o- i O alkyl or
  • E 1 is cycloC 3- i 0 alkyl, bicycloC 5- i 0 alkyl, aryl, heteroaralkyl, heterocyclyl, heterobicycloC 5 _ioalkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents; or
  • E 1 is C o- ioalkyl, heteroaralkyl, or aralkyl, any of which is optionally substituted by one or more independent G u substituents; or
  • E 1 is cycloC 3- i 0 alkyl, bicycloC 5 .i 0 alkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents; or [213] wherein E 1 is heterocyclyl or heterobicycloC 5- ioalkyl, of which is optionally substituted by one or more independent G 11 substituents; or
  • E 1 is aryl or heteroaryl, any of which is optionally substituted by one or more independent G 11 substituents;
  • E 1 is C o- ioalkyl, cycloC 3- i 0 alkyl, bicycloC 5 .i 0 alkyl, aralkyl, heteroaralkyl, heterocyclyl, heterobicycloCs. ⁇ alkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents; or
  • G 11 is oxo, -OCF 3 , -OR 21 , -NR 21 R 31 (R 2al ) j4 , -C(O)R 21 , -CO 2 R 21 ,
  • G 11 is hetaryl-C 0 .
  • G 11 is oxo, -OR 21 , -NR 21 R 3 '(R 2 " 1 ) ⁇ -CO 2 R 21 , -C(O)NR 21 R 31 , C 0-10 alkyl, heterocyclyl-Co-ioallcyl, any of which is optionally substituted with one or more independent halo, oxo, -OR 2221 , or -NR 2221 R 3331 (R 222al ) j4a substituents; or G 11 is hetaryl-C O -ioalkyl, any of which is optionally substituted with one or more independent halo, -CF 3 , -OCF 3 , -OR 2221 ,
  • G 1 is -OR 2 , -NR 2 R 3 (R 2a ) jl5 -S(O)J 1 R 2 , C 0-10 alkyl, cycloCa.galkyl, heterocyclyl-Co-ioalkyl, any of which is optionally substituted with one or more independent halo, oxo, -CF 3 , -OCF 3 , OR 222 , -NR 222 R 333 (R 222a ) jla , -C(O)R 222 , -CO 2 R 222 , -C(O)NR 222 R 333 , -NO 2 , -CN, -S(O) jla R 222 , -SO 2 NR 222 R 333 , -NR 222 C(O)R 333 , -NR 222 C(O)OR 333 , -NR 222 C(O)NR 333 R 2223 , -NR 222
  • G 1 is aryl-C o- i O alkyl or hetaryl-C o .ioalkyl, any of which is optionally substituted with one or more independent halo, -CF 3 , -OCF 3 , -OR 222 , -NR 222 R 333 (R 222a ) j2a ,
  • G 1 is aryl-C o- ioalkyl or hetaryl-C o- ioalkyl, any of which is optionally substituted with one or more independent halo, -CF 3 , -OCF 3 , -OR 222 , -NR 222 R 333 (R 222a ) j2a ,
  • E 1 is cycloC 3- i 0 alkyl, bicycloC 5- i 0 alkyl, aryl, heteroaralkyl, heterocyclyl, heterobicycloCs-ioalkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G u substituents; or
  • E 1 is C o .ioalkyl, heteroaralkyl, or aralkyl, any of which is optionally substituted by one or more independent G 11 substituents; or
  • E 1 is cycloC 3- i 0 alkyl, bicycloC 5- i 0 alkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents; or
  • E 1 is heterocyclyl or heterobicycloC 5- i 0 alkyl, of which is optionally substituted by one or more independent G 11 substituents;
  • E 1 is aryl or heteroaryl, any of which is optionally substituted by one or more independent G 11 substituents; or [252] wherein E 1 is C o .ioalkyl, cycloC 3- i 0 alkyl, bicycloC 5- i 0 allcyl, aralkyl, heteroaralkyl, heterocyclyl, heterobicycloC 5- ioalkyl, spiroallcyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents; or [253] wherein X )6 is N; or [254] wherein X 14 and Xi 6 are N; or
  • G 11 is hetaryl-C o .i O alkyl > any of which is optionally substituted with one or more independent halo, -CF 3 , -OCF 3 , -OR 2221 , -NR 2221 R 3331 (R 222al ) j5a , -C(O)R 2221 , -CO 2 R 2221 , -C(O)NR 2221 R 3331
  • G 11 is oxo, -OCF 3 , -OR 21 , -NR 21 R 31 (R 2al ) j4 , -C(O)R 21 , -CO 2 R 21 ,
  • G 11 is hetaryl-C o- i O alkyl, any of which is optionally substituted with one or more independent halo, -CF 3 , -OCF 3 , -OR 2221 , -NR 2221 R 3331 (R 222al ) j5a , -C(O)R 2221 , -CO 2 R 2221 , -C(O)NR 2221 R 3331 , -NO 2
  • E 1 is Co-ioalkyl, cycloC 3- i 0 alkyl, bicycloC 3- i 0 alkyl, aryl, heteroaralkyl, heterocyclyl, heterobicycloC 5 .i 0 alkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents; or [264] wherein G 1 is -OR 2 , -NR 2 R 3 (R 2i V -S(O)J 1 R 2 , C 0 -i 0 alkyl, cycloC 3 .
  • any three OfX 11-16 is N; or [268] wherein any one of X 11; X 14, X 15 _ or X 16 is N; or
  • any two OfX 11 , X 14 , X 15 , or X 16 is N;
  • any two OfX 14 , X 15 , or X 16 is N;
  • E 1 is cycloC 3- ioallcyl, bicycloC 5 .i 0 alkyl, aryl, heteroaralkyl, heterocyclyl, heterobicycloC 5- i 0 alkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G n substituents; or
  • E 1 is C o- ioalkyl, heteroaralkyl, or aralkyl, any of which is optionally substituted by one or more independent G 11 substituents; or
  • E 1 is cycloC 3- i 0 alkyl, bicycloC 5-1 oalkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents; or [287] wherein E 1 is heterocyclyl or heterobicycloC 5 .ioalkyl, of which is optionally substituted by one or more independent G 11 substituents; or [288] wherein E 1 is aryl or heteroaryl, any of which is optionally substituted by one or more independent G 11 substituents; or
  • E 1 is C o- ioalkyl, cycloC 3-10 alkyl, bicycloC 5 . 10 alkyl, aralkyl, heteroaralkyl, heterocyclyl, heterobicycloC 5- i 0 alkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents; or [290] wherein X 16 is N; or
  • G 11 is oxo, -OR 21 , -NR 21 R 3 '(R 2 " 1 ) ⁇ -CO 2 R 21 , -C(O)NR 21 R 31 , C o- i O alkyl, heterocyclyl-Co- ⁇ oalkyl, any of which is optionally substituted with one or more independent halo, oxo, -OR 2221 , or -NR 2221 R 3331 (R 222al ) j4a substituents; or G 11 is hetaryl-C 0-10 alkyl, any of which is optionally substituted with one or more independent halo, -CF 3 , -OCF 3 , -OR 2221 , -NR 2221 R 3331 (R 222al ) j5a , -C(O)R 2221 , -CO 2 R 2221 , -C(O)NR 2221 R 3331 , -NO 2 , -CN,
  • E 1 is C o- ioalkyl, cycloQ-ioalkyl, bicycloC 5-10 alkyl, aryl, heteroaralkyl, heterocyclyl, heterobicycloC 5 _i 0 alkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents; or
  • G 1 is -OR 2 , -NR 2 R 3 (R 2a ) j i, -S(O)J 1 R 2 , C o- i O alkyl, cycloC 3-8 alkyl, heterocyclyl-Co-ioalkyl, any of which is optionally substituted with one or more independent halo, oxo, -CF 3 , -OCF 3 , -OR 222 , -NR 222 R 333 (R 222a ) jla , -C(O)R 222 , -CO 2 R 222 , -C(O)NR 222 R 333 , -NO 2 , -CN, -S(O) jla R 222 , -SO 2 NR 222 R 333 , -NR 222 C(O)R 333 , -NR 222 C(O)OR 333 , -NR 222 C(O)NR 333 R 222a
  • G 1 is aryl-Co 4O alkyl or hetaryl-Co-ioalkyl, any of which is optionally substituted with one or more independent halo, -CF 3 , -OCF 3 , -OR 222 , -NR 222 R 333 (R 222a ) j2a , -C(O)R 222 , -CO 2 R 222 , -C(O)NR 222 R 333 , -NO 2 , -CN, -S(O) j2a R 222 , -SO 2 NR
  • X 1 , X 2 , and X 3 are C-(E 1 X 2 ; and wherein any one OfXn 1 Xw, Xis, or X 16 is N; or [315] wherein X 1 , X 2 , and X 3 are C-(E 1 X 3 ; and wherein any two OfX 111 X 141 X 151 Or X 16 is N; or
  • X 15i or X 16 is N;
  • X 15i or X 16 is N;
  • X 15, or X 16 is N;
  • X n-16 is N;
  • X n-26 is N; or [338] wherein X 2 and X 3 are N and Xi is C-(E 1 )., ⁇ and wherein any one of X ⁇ i X 14i X 15i or
  • G 1 is aryl-Co-ioalkyl or hetaryl-C o- ioalkyl, any of which is optionally substituted with one or more independent
  • X 3 is N and wherein Xi and X 2 are C-(E') aa ; and wherein any one, two, or three OfX n-16 is N; and wherein G 1 is -OR 2 , -NR 2 R 3 (R 2a ) jl; -S(O)jiR 2 , C o .i O alkyl, cycloC 3-8 alkyl, heterocyclyl-Co-ioallcyl, any of which is optionally substituted with one or more independent halo, oxo, -CF 3 , -OCF 35 -OR 222 , -NR 222 R 333 (R 222a )jia, -C(O)R 222 , -CO 2 R 222 , -C(O)NR 222 R 333 , -NO 2 , -CN 3 -S(O) jla R 222 , -SO 2 NR 222 R 333
  • X n-I6 is N; and wherein G 1 is -OR 2 , -NR 2 R 3 (R 2a ) j i, -S(O)J 1 R 2 , C o-lo alkyl, cycloC 3-8 alkyl, heterocyclyl-Co-ioalkyl, any of which is optionally substituted with one or more independent halo, oxo, -CF 3 , -OCF 3 , -OR 222 , -NR 222 R 333 (R 222a ) j i a , -C(O)R 222 , -CO 2 R 222 , -C(O)NR 222 R 333 , -NO 2 , -CN, -S(O) jla R 222 , -SO 2 NR 222 R 333 , -NR 222 C(O)R 333 , -NR 222 C(O)OR 333 , -NR 222 C
  • G 1 is aryl-C 0-10 alkyl or hetaryl-Co-ioalkyl, any of which is optionally substituted with one or more independent halo, -CF 3 , -OCF 3 , -OR 222 , -NR 222 R 333 (R 222a ) j2a , -C(O)R 222 , -CO 2 R 222 , -C(O)NR 222 R 333 , -NO 2 , -CN, -S(O) j2a R 222 , -SO 2
  • G 1 is aryl-C 0 - 10 alkyl or hetaryl-C o-1 oalkyl, any of which is optionally substituted with one or more independent halo, -CF 3 , -OCF 3 , -OR 222 , -NR 222 R 333 (R 222a ) j2a , -C(O)R 222 , -CO 2 R 222 , -C(O)NR 222 R 333 , -NO 2 , -CN, -S(O) j2a R 222 , -SO 2 NR 222 R 333 , -NR 222 C(O
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof wherein said protein kinase is IGF-IR.
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof wherein the condition mediated by protein kinase activity is a hyperproliferative disorder.
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof wherein the activity of said protein kinase influences angiogenesis, vascular permeability, immune response, cellular apoptosis, tumor growth, or inflammation.
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof wherein the protein kinase is a protein serine/threonine kinase or a protein tyrosine kinase.
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof wherein the condition mediated by protein kinase activity is one or more ulcers; or one or more ulcers caused by a bacterial or fungal infection; or Mooren ulcers; or one or more ulcers which are a symptom of ulcerative colitis.
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof wherein the condition mediated by protein kinase activity is Lyme disease, sepsis or infection by Herpes simplex, Herpes Zoster, human immunodeficiency virus, parapoxvirus, protozoa, toxoplasmosis, von Hippel Lindau disease, pemphigoid, psoriasis, Paget's disease, polycystic kidney disease, fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthma, exudtaes, ascites, pleural effusions, pulmonary edema, cerebral edema or edema following burns, trauma
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof wherein the condition mediated by protein kinase activity is an ocular condition wherein the ocular condition is ocular or macular edema, ocular neovascular disease, seleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser treatment complications, conjunctivitis, Stargardt's disease, Eales disease, retinopathy, or macular degeneration.
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof wherein the condition mediated by protein kinase activity is a cardiovascular condition.
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof wherein the condition mediated by protein kinase activity is a cardiovascular condition wherein the condition mediated by protein kinase activity is atherosclerosis, restenosis, ischemia/reperfusion injury, vascular occlusion, venous malformation, or carotid obstructive disease.
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof wherein the condition mediated by protein kinase activity is cancer.
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof wherein the condition mediated by protein kinase activity is cancer wherein the cancer is a solid tumor, a sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, a rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, an hematopoietic malignancy, malignant ascites, Kaposi's sarcoma, Hodgkin's disease, lymphoma, myeloma, or leukemia.
  • cancer is a solid tumor, a sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, a
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof wherein the condition mediated by protein kinase activity is a diabetic condition wherein the diabetic condition is insulin-dependent diabetes mellitus glaucoma, diabetic retinopathy, or microangiopathy.
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof wherein the protein kinase activity is involved in T cell activation, B cell activation, mast cell degranulation, monocyte activation, signal transduction, apoptosis, the potentiation of an inflammatory response or a combination thereof.
  • the present invention includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention includes a method of inhibiting protein kinase activity according to the present invention comprises administering a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the method includes wherein the protein kinase is IGF-IR.
  • the method includes wherein the activity of the protein kinase affects hyperproliferative disorders.
  • the method includes wherein the activity of the protein kinase influences angiogenesis, vascular permeability, immune response, cellular apoptosis, tumor growth, or inflammation.
  • the present invention includes a method of treating a patient having a condition which is mediated by protein kinase activity, comprises administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the method includes wherein the protein kinase is IGF-IR.
  • the method includes wherein the condition mediated by protein kinase activity is a hyperproliferative disorder.
  • the method includes wherein the activity of the protein kinase influences angiogenesis, vascular permeability, immune response, cellular apoptosis, tumor growth, or inflammation.
  • the method includes wherein the protein kinase is a protein serine/threonine kinase or a protein tyrosine kinase.
  • the method includes wherein the condition mediated by protein kinase activity is one or more ulcers.
  • the method includes wherein the ulcer or ulcers are caused by a bacterial or fungal infection; or the ulcer or ulcers are Mooren ulcers; or the ulcer or ulcers are a symptom of ulcerative colitis.
  • the method includes wherein the condition mediated by protein kinase activity is Lyme disease, sepsis or infection by Herpes simplex, Herpes Zoster, human immunodeficiency virus, parapoxvirus, protozoa, or toxoplasmosis.
  • the method includes wherein the condition mediated by protein kinase activity is von Hippel Lindau disease, pemphigoid, psoriasis, Paget's disease, or polycystic kidney disease.
  • the method includes wherein the condition mediated by protein kinase activity is fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthma, exudtaes, ascites, pleural effusions, pulmonary edema, cerebral edema or edema following burns, trauma, radiation, stroke, hypoxia, or ischemia.
  • the method includes wherein the condition mediated by protein kinase activity is ovarian hyperstimulation syndrome, preeclampsia, menometrorrhagia, or endometriosis.
  • the method includes wherein the condition mediated by protein kinase-activity is chronic inflammation, systemic lupus, glomerulonephritis, synovitis, inflammatory bowel disease,
  • the method includes wherein the condition mediated by protein kinase activity is sickle cell anaemia.
  • the method includes wherein the condition mediated by protein kinase activity is an ocular condition.
  • the method includes wherein the ocular condition is ocular or macular edema, ocular neovascular disease, seleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser treatment complications, conjunctivitis, Stargardt's disease, Eales disease, retinopathy, or macular degeneration.
  • the method includes wherein the condition mediated by protein kinase activity is a cardiovascular condition.
  • the method includes wherein the condition mediated by protein kinase activity is atherosclerosis, restenosis, ischemia/reperfusion injury, vascular occlusion, venous malformation, or carotid obstructive disease.
  • the method includes wherein the condition mediated by protein kinase activity is cancer.
  • the method includes wherein the cancer is a solid tumor, a sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, a rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, an hematopoietic malignancy, or malignant ascites.
  • the method includes wherein the cancer is Kaposi's sarcoma, Hodgkin's disease, lymphoma, myeloma, or leukemia. Further, the method includes wherein the condition mediated by protein kinase activity is Crow-Fukase (POEMS) syndrome or a diabetic condition. The method includes wherein the diabetic condition is insulin-dependent diabetes mellitus glaucoma, diabetic retinopathy, or microangiopathy. The method also includes wherein the protein kinase activity is involved in T cell activation, B cell activation, mast cell degranulation, monocyte activation, signal transduction, apoptosis, the potentiation of an inflammatory response or a combination thereof.
  • POEMS Crow-Fukase
  • the present invention includes the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of a disease which responds to an inhibition of the IGF-IR-dependent cell proliferation.
  • the present invention includes the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of a disease which responds to an inhibition of the IGF-IR tyrosine kinase.
  • the present invention includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention includes a method of inhibiting protein kinase activity that comprises administering such pharmaceutical composition.
  • the invention includes a method of treating a patient having a condition which is mediated by protein kinase activity by administering to the patient a therapeutically effective amount of such pharmaceutical composition.
  • the present invention includes a pharmaceutical composition comprising an EGFR kinase inhibitor and the compound of Formula 1 in a pharmaceutically acceptable carrier.
  • the present invention includes a pharmaceutical composition comprising an EGFR kinase inhibitor and the compound of Formula 1 in a pharmaceutically acceptable carrier wherein the EGFR kinase inhibitor is erlotinib.
  • the present invention includes a pharmaceutical composition comprising an EGFR kinase inhibitor and the compound of Formula 1 in a pharmaceutically acceptable carrier wherein the EGFR kinase inhibitor is erlotinib present as a hydrochloride salt.
  • the present invention includes a pharmaceutical composition comprising an EGFR kinase inhibitor and the compound of Formula 1 in a pharmaceutically acceptable carrier additionally comprising one or more other anti-cancer agents.
  • the present invention includes a pharmaceutical composition comprising an EGFR kinase inhibitor and the compound of Formula 1 in a pharmaceutically acceptable carrier wherein the EGFR kinase inhibitor is erlotinib, additionally comprising one or more other anti-cancer agents.
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of an EGFR kinase inhibitor and the compound of Formula 1.
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of the EGFR kinase inhibitor erlotinib and the compound of Formula 1.
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of an EGFR kinase inhibitor and the compound of Formula 1 wherein the patient is a human that is being treated for cancer.
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of the EGFR kinase inhibitor erlotinib and the compound of Formula 1 wherein the patient is a human that is being treated for cancer.
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of an EGFR kinase inhibitor and the compound of Formula 1 wherein the EGFR kinase inhibitor and the compound of Formula 1 are co-administered to the patient in the same or different formulations.
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of the EGFR kinase inhibitor erlotinib and the compound of Formula 1 wherein the erlotinib and the compound of Formula 1 are co-administered to the patient in the same or different formulations.
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of an EGFR kinase inhibitor and the compound of Formula 1 wherein the EGFR kinase inhibitor and the compound of Formula 1 are co-administered to the patient by the same or different routes.
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of the EGFR kinase inhibitor erlotinib and the compound of Formula 1 wherein the erlotinib and the compound of Formula 1 are co-administered to the patient by the same or different routes.
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of an EGFR kinase inhibitor and the compound of Formula 1 wherein the EGFR kinase inhibitor or the compound of Formula 1 are administered to the patient by parenteral or oral administration.
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of the EGFR kinase inhibitor erlotinib and the compound of Formula 1 wherein the erlotinib or the compound of Formula 1 are administered to the patient by parenteral or oral administration.
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of an EGFR kinase inhibitor and the compound of Formula 1, additionally comprising one or more other anti-cancer agents.
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of the EGFR kinase inhibitor erlotinib and the compound of Formula 1, additionally comprising one or more other anti-cancer agents.
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of an EGFR kinase inhibitor and the compound of Formula 1, additionally comprising one or more other anti-cancer agents, wherein the other anti-cancer agents are one or more agents selected from an alkylating agent, cyclophosphamide, chlorambucil, cisplatin, busulfan, melphalan, carmustine, streptozotocin, triethylenemelamine, mitomycin C, an anti-metabolite, methotrexate, etoposide, 6-mercaptopurine, 6-thiocguanine, cytarabine, 5-fluorouracil, raltitrexed, capecitabine, dacarbazine, an antibiotic, actinomycin D, doxorubicin, daunorubicin, bleomycin, mithramycin, an alkaloid, vinblastine,
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of the EGFR kinase inhibitor erlotinib and the compound of Formula 1, additionally comprising one or more other anti-cancer agents, wherein the other anti-cancer agents are one or more agents selected from an alkylating agent, cyclophosphamide, chlorambucil, cisplatin, busulfan, melphalan, carmustine, streptozotocin, triethylenemelamine, mitomycin C, an anti-metabolite, methotrexate, etoposide, 6-mercaptopurine, 6-thiocguanine, cytarabine, 5-fluorouracil, raltitrexed, capecitabine, dacarbazine, an antibiotic, actinomycin D, doxorubicin, daunorubicin, bleomycin, mithramycin, an
  • the present invention includes a method of preparing a pharmaceutical composition useful for treating tumors or tumor metastases in a patient, comprising combining the compound of Formula 1 with an EGFR kinase inhibitor.
  • the present invention includes a method of preparing a pharmaceutical composition useful for treating tumors or tumor metastases in a patient, comprising combining the compound of Formula 1 with an EGFR kinase inhibitor wherein the EGFR kinase inhibitor is erlotinib.
  • the present invention includes a method of preparing a pharmaceutical composition useful for treating tumors or tumor metastases in a patient, comprising combining the compound of Formula 1 with an EGFR kinase inhibitor, further comprising combining a pharmaceutically acceptable carrier with the compound of Formula 1 and erlotinib.
  • the present invention includes a pharmaceutical composition comprising an EGFR kinase inhibitor and the compound of Formula 1 in a pharmaceutically acceptable carrier, additionally comprising one or more other anti-cancer agents.
  • the present invention includes a pharmaceutical composition comprising an EGFR kinase inhibitor and the compound of Formula 1 in a pharmaceutically acceptable carrier wherein the EGFR kinase inhibitor is erlotinib, additionally comprising one or more other anti-cancer agents.
  • the present invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising an EGFR kinase inhibitor and the compound of Formula 1 in a pharmaceutically acceptable carrier, additionally comprising one or more other anti-cancer agents, wherein said other anti-cancer agent is a member selected from the group consisting of alkylating drugs, antimetabolites, microtubule inhibitors, podophyllotoxins, antibiotics, nitrosoureas, hormone therapies, kinase inhibitors, activators of tumor cell apoptosis, and antiangiogenic agents.
  • the present invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising an EGFR kinase inhibitor and the compound of Formula 1 in a pharmaceutically acceptable carrier wherein the EGFR kinase inhibitor is erlotinib, additionally comprising one or more other anti-cancer agents, wherein said other anti- cancer agent is a member selected from the group consisting of alkylating drugs, antimetabolites, microtubule inhibitors, podophyllotoxins, antibiotics, nitrosoureas, hormone therapies, kinase inhibitors, activators of tumor cell apoptosis, and antiangiogenic agents.
  • the present invention includes a method for the treatment of cancer, comprising administering to a subject in need of such treatment (i) an effective or sub-therapeutic first amount of the EGFR kinase inhibitor erlotinib, or a pharmaceutically acceptable salt thereof; and (ii) an effective or sub-therapeutic second amount of the compound of Formula 1.
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of an EGFR kinase inhibitor and the compound of Formula 1, wherein the tumors or tumor metastases to be treated are colorectal tumors or tumor metastases.
  • the present invention includes a method for treating tumors or tumor metastases in a patient, comprising administering to said patient simultaneously or sequentially a therapeutically effective amount of the EGFR kinase inhibitor erlotinib and the compound of Formula 1, wherein the tumors or tumor metastases to be treated are colorectal tumors or tumor metastases.
  • the present invention includes the following core structures wherein said core structures contain between one and four N and the Q 1 substituent is as defined above:
  • the compounds of the present invention include:
  • connection of compound name moieties are at the rightmost recited moiety. That is, the substituent name starts with a terminal moiety, continues with any bridging moieties, and ends with the connecting moiety. For example, has a heteroaryl group connected through a thio sulfur to a Ci -4 alkyl that connects to the chemical species bearing the substituent.
  • Co ⁇ alkyl is used to mean an alkyl having 0-4 carbons
  • alkyl having no carbon is hydrogen when the alkyl is a terminal group.
  • An alkyl having no carbon is a direct bond when the alkyl is a bridging (connecting) group.
  • C o alkyl includes being a substituted bond — that is, for example, -X-Y-Z is -C(O)-C 2-4 alkyl when X is C o alkyl, Y is C o alkyl, and Z is -C(O)-C 2-4 alkyl.
  • the term "alkyl" includes both branched and straight chain alkyl groups.
  • Typical alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, fer/-butyl, «-pentyl, isopentyl, n-hexyl, «-heptyl, isooctyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl, and the like.
  • halo refers to fluoro, chloro, bromo, or iodo.
  • haloalkyl refers to an alkyl group substituted with one or more halo groups, for example chloromethyl, 2-bromoethyl, 3-iodopropyl, trifluoromethyl, perfluoropropyl, 8- chlorononyl, and the like.
  • Examples include, but are not limited to, (bi)(cyclo)alkylketo, (cyclo)alkenylketo, alkynylketo, arylketo, hetarylketo, heterocyclylketo, heterobicycloalkylketo, spiroalkylketo, and the like.
  • cycloalkyl refers to a 3-8 carbon cyclic aliphatic ring structure, optionally substituted with for example, alkyl, hydroxy, oxo, and halo, such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyl, cyclohexyl, 4- chlorocyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • bicycloalkyl refers to a structure consisting of two cycloalkyl moieties that have two or more atoms in common. If the cycloalkyl moieties have exactly two atoms in common they are said to be "fused". Examples include, but are not limited to, bicyclo[3.1.0]hexyl, perhydronaphthyl, and the like. If the cycloalkyl moieties have more than two atoms in common they are said to be "bridged”. Examples include, but are not limited to, bicyclo[2.2.1]heptyl ("norborayl”), bicyclo[2.2.2]octyl, and the like.
  • spiroalkyl refers to a structure consisting of two cycloalkyl moieties that have exactly one atom in common. Examples include, but are not limited to, spiro[4.5]decyl, spiro[2.3]hexyl, and the like.
  • heterocycloalkyl refers to a bicycloalkyl structure in which at least one carbon atom is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur.
  • heterospiroalkyl refers to a spiroalkyl structure in which at least one carbon atom is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur.
  • alkylcarbonyloxyalkyl refers to an ester moiety, for example acetoxymethyl, n-butyryloxyethyl, and the like.
  • alkynylcarbonyl refers to an alkynylketo functionality, for example propynoyl and the like.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, for example hydroxymethyl, 2,3-dihydroxybutyl, and the like.
  • alkylsulfonylalkyl refers to an alkyl group substituted with an alkylsulfonyl moiety, for example mesylmethyl, isopropylsulfonylethyl, and the like.
  • alkylsulfonyl refers to a sulfonyl moiety substituted with an alkyl group, for example mesyl, ra-propylsulfonyl, and the like.
  • acetylaminoalkyl refers to an alkyl group substituted with an amide moiety, for example acetylaminomethyl and the like.
  • acetylaminoalkenyl refers to an alkenyl group substituted with an amide moiety, for example 2-(acetylamino)vinyl and the like.
  • alkenyl refers to an ethylenically unsaturated hydrocarbon group, straight or branched chain, having 1 or 2 ethylenic bonds, for example vinyl, allyl, 1-butenyl, 2-butenyl, isopropenyl, 2-pentenyl, and the like.
  • haloalkenyl refers to an alkenyl group substituted with one or more halo groups.
  • cycloalkenyl refers to a cyclic aliphatic 3 to 8 ring structure, optionally substituted with alkyl, hydroxy and halo, having 1 or 2 ethylenic bonds such as methylcyclopropenyl, trifluoromethylcyclopropenyl, cyclopentenyl, cyclohexenyl, 1,4- cyclohexadienyl, and the like.
  • alkynyl refers to an unsaturated hydrocarbon group, straight or branched, having at least one acetylenic bond, for example ethynyl, propargyl, and the like.
  • haloalkynyl refers to an alkynyl group substituted with one or more independent halo groups.
  • alkylcarbonyl refers to an alkylketo functionality, for example acetyl, n- butyryl, and the like.
  • alkenylcarbonyl refers to an alkenylketo functionality, for example, propenoyl and the like.
  • aryl refers to phenyl or naphthyl which may be optionally substituted.
  • aryl examples include, but are not limited to, phenyl, 4-chlorophenyl, 4-fluorophenyl, A- bromophenyl, 3-nitrophenyl, 2-methoxyphenyl, 2-methylphenyl, 3-methyphenyl, 4-methylphenyl, A- ethylphenyl, 2-methyl-3-methoxyphenyl, 2,4-dibromophenyl, 3,5-difluorophenyl, 3,5- dimethylphenyl, 2,4,6-trichlorophenyl, 4-methoxyphenyl, naphthyl, 2-chloronaphthyl, 2,4- dimethoxyphenyl, 4-(trifluoromethyl)phenyl, and 2-iodo-4-methylphenyl.
  • heteroaryl or “hetaryl” or “heteroar-” or “hetar-” refer to a substituted or unsubstituted 5- or 6-membered unsaturated ring containing one, two, three, or four independently selected heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur or to a bicyclic unsaturated ring system containing up to 10 atoms including at least one heteroatom selected from oxygen, nitrogen, and sulfur.
  • hetaryls include, but are not limited to, 2-, 3- or 4-pyridinyl, pyrazinyl, 2-, A-, or 5-pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, imidazolyl, 2- or 3-thienyl, 2- or 3-furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzotriazolyl, indolyl, benzofuranyl, and benzothienyl.
  • the heterocyclic ring may be optionally substituted with one or more substituents.
  • aryl-alkyl or “arylalkyl” or “aralkyl” are used to describe a group wherein the alkyl chain can be branched or straight chain forming a bridging portion with the terminal aryl, as defined above, of the aryl-alkyl moiety.
  • aryl-alkyl groups include, but are not limited to, optionally substituted benzyl, phenethyl, phenpropyl and phenbutyl such as A- chlorobenzyl, 2,4-dibromobenzyl, 2-methylbenzyl, 2-(3-fluorophenyl)ethyl, 2-(4-methylphenyl)ethyl, 2-(4-(trifluoromethyl)phenyl)ethyl, 2-(2-methoxyphenyl)ethyl, 2-(3-nitrophenyl)ethyl, 2-(2,4- dichlorophenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl, 3-phenylpropyl, 3-(3-chlorophenyl)propyl, 3-(2- methylphenyl)propyl, 3-(4-methoxy ⁇ henyl)propyl, 3-(4-(trifluoromethyl)phenyl)propy
  • aryl-cycloalkyl or “arylcycloalkyl” are used to describe a group wherein the terminal aryl group is attached to a cycloalkyl group, for example phenylcyclopentyl and the like.
  • aryl-alkenyl or “arylalkenyl” or “aralkenyl” are used to describe a group wherein the alkenyl chain can be branched or straight chain forming a bridging portion of the aralkenyl moiety with the terminal aryl portion, as defined above, for example styryl (2-phenylvinyl), phenpropenyl, and the like.
  • aryl-alkynyl or “arylalkynyl” or “aralkynyl” are used to describe a group wherein the alkynyl chain can be branched or straight chain forming a bridging portion of the aryl-alkynyl moiety with the terminal aryl portion, as defined above, for example 3-phenyl-l- propynyl, and the like.
  • aryl-oxy or “aryloxy” or “aroxy” are used to describe a terminal aryl group attached to a bridging oxygen atom. Typical aryl-oxy groups include phenoxy, 3,4- dichlorophenoxy, and the like.
  • aryl-oxyalkyl or “aryloxyalkyl” or “aroxyalkyl” are used to describe a group wherein an alkyl group is substituted with a terminal aryl-oxy group, for example pentafluorophenoxymethyl and the like.
  • heterocycloalkenyl refers to a cycloalkenyl structure in which at least one carbon atom is replaced with a heteroatom selected from oxygen, nitrogen, and sulfur.
  • heteroaryl-oxy or “heteroaryl-oxy” or “hetaryloxy” or “heteroaryloxy” or “heteroaryloxy” or
  • hetaryloxy or “heteroaroxy” are used to describe a terminal hetaryl group attached to a bridging oxygen atom. Typical hetaryl-oxy groups include 4,6-dimethoxypyrimidin-2-yloxy and the like. [469] The terms “hetarylalkyl” or “heteroarylalkyl” or “hetaryl-alkyl” or
  • heteroaryl-alkyl or “hetaralkyl” or “heteroaralkyl” are used to describe a group wherein the alkyl chain can be branched or straight chain forming a bridging portion of the heteroaralkyl moiety with the terminal heteroaryl portion, as defined above, for example 3-furylmethyl, thenyl, furfuryl, and the like.
  • heteroarylalkenyl or “heteroarylalkenyl” or “hetaiyl-alkenyl” or
  • heteroaryl-alkenyl or “hetaralkenyl” or heteroaralkenyl” are used to describe a group wherein the alkenyl chain can be branched or straight chain forming a bridging portion of the heteroaralkenyl moiety with the terminal heteroaryl portion, as defined above, for example 3-(4-pyridyl)-l-propenyl.
  • heteroarylalkynyl or “heteroarylalkynyl” or “hetaryl-alkynyl” or “heteroaryl-alkynyl” or “hetaralkynyl” or “heteroaralkynyl” are used to describe a group wherein the alkynyl chain can be branched or straight chain forming a bridging portion of the heteroaralkynyl moiety with the heteroaryl portion, as defined above, for example 4-(2-thienyl)-l-butynyl.
  • heterocyclyl refers to a substituted or unsubstituted A-, 5-, or 6-membered saturated or partially unsaturated ring containing one, two, or three heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen and sulfur; or to a bicyclic ring system containing up to 10 atoms including at least one heteroatom independently selected from oxygen, nitrogen, and sulfur wherein the ring containing the heteroatom is saturated.
  • heterocyclyls include, but are not limited to, tetrahydrofuranyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, 4-pyranyl, tetrahydropyranyl, thiolanyl, morpholinyl, piperazinyl, dioxolanyl, dioxanyl, indolinyl, and 5-methyl-6-chromanyl.
  • heterocyclylalkyl or “heterocyclyl-alkyl” or “hetcyclylalkyl” or
  • heterocyclyl-alkyl are used to describe a group wherein the alkyl chain can be branched or straight chain forming a bridging portion of the heterocyclylalkyl moiety with the terminal heterocyclyl portion, as defined above, for example 3-piperidinylmethyl and the like.
  • heterocyclylalkenyl or “heterocyclyl-alkenyl” or “hetcyclylalkenyl” or
  • heterocyclyl-alkenyl are used to describe a group wherein the alkenyl chain can be branched or straight chain forming a bridging portion of the heterocyclylalkenyl moiety with the terminal heterocyclyl portion, as defined above, for example 2-morpholinyl-l-propenyl and the like.
  • heterocyclylalkynyl or “heterocyclyl-alkynyl” or “hetcyclylalkynyl” or “hetcyclyl-alkynyl” are used to describe a group wherein the alkynyl chain can be branched or straight chain forming a bridging portion of the heterocyclylalkynyl moiety with the terminal heterocyclyl portion, as defined above, for example 2-pyrrolidinyl-l-butynyl and the like.
  • carboxylalkyl refers to a terminal carboxyl (-COOH) group attached to branched or straight chain alkyl groups as defined above.
  • carboxylalkenyl refers to a terminal carboxyl (-COOH) group attached to branched or straight chain alkenyl groups as defined above.
  • Carboxylalkynyl refers to a terminal carboxyl (-COOH) group attached to branched or straight chain alkynyl groups as defined above.
  • carboxylcycloalkyl refers to a terminal carboxyl (-COOH) group attached to a cyclic aliphatic ring structure as defined above.
  • Carboxylcycloalkenyl refers to a terminal carboxyl (-COOH) group attached to a cyclic aliphatic ring structure having ethylenic bonds as defined above.
  • cycloalkylalkyl or “cycloalkyl-alkyl” refer to a terminal cycloalkyl group as defined above attached to an alkyl group, for example cyclopropylmethyl, cyclohexylethyl, and the like.
  • cycloalkylalkenyl or "cycloalkyl-alkenyl” refer to a terminal cycloalkyl group as defined above attached to an alkenyl group, for example cyclohexylvinyl, cycloheptylallyl, and the like.
  • cycloalkylalkynyl or "cycloalkyl-alkynyl” refer to a terminal cycloalkyl group as defined above attached to an alkynyl group, for example cyclopropylpropargyl, 4- cyclopentyl-2-butynyl, and the like.
  • cycloalkenylalkyl or “cycloalkenyl-alkyl” refer to a terminal cycloalkenyl group as defined above attached to an alkyl group, for example 2-(cyclopenten-l- yl)ethyl and the like.
  • cycloalkenylalkenyl or “cycloalkenyl-alkenyl” refer to terminal a cycloalkenyl group as defined above attached to an alkenyl group, for example l-(cyclohexen-3- yl)allyl and the like.
  • cycloalkenylalkynyl or “cycloalkenyl-alkynyl” refer to terminal a cycloalkenyl group as defined above attached to an alkynyl group, for example l-(cyclohexen-3- yl)propargyl and the like.
  • carboxylcycloalkylalkyl refers to a terminal carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkyl group as defined above.
  • carboxylcycloalkylalkenyl refers to a terminal carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkenyl group as defined above.
  • carboxylcycloalkylalkynyl refers to a terminal carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkynyl group as defined above.
  • carboxylcycloalkenylalkyl refers to a terminal carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkyl group as defined above.
  • carboxylcycloalkenylalkenyl refers to a terminal carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkenyl group as defined above.
  • carboxylcycloalkenylalkynyl refers to a terminal carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkynyl group as defined above.
  • alkoxy includes both branched and straight chain terminal alkyl groups attached to a bridging oxygen atom. Typical alkoxy groups include methoxy, ethoxy, «-propoxy, isopropoxy, tert-butoxy and the like.
  • haloalkoxy refers to an alkoxy group substituted with one or more halo groups, for example chloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroisobutoxy, and the like.
  • alkoxyalkoxyalkyl refers to an alkyl group substituted with an alkoxy moiety which is in turn is substituted with a second alkoxy moiety, for example methoxymethoxymethyl, isopropoxymethoxyethyl, and the like.
  • alkylthio includes both branched and straight chain alkyl groups attached to a bridging sulfur atom, for example methylthio and the like.
  • haloalkylthio refers to an alkylthio group substituted with one or more halo groups, for example trifluoromethylthio and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group, for example isopropoxymethyl and the like.
  • alkoxyalkenyl refers to an alkenyl group substituted with an alkoxy group, for example 3-methoxyallyl and the like.
  • alkoxyalkynyl refers to an alkynyl group substituted with an alkoxy group, for example 3-methoxypropargyl.
  • alkoxycarbonylalkyl refers to a straight chain or branched alkyl substituted with an alkoxycarbonyl, for example ethoxycarbonylmethyl, 2-(methoxycarbonyl)propyl and the like.
  • alkoxycarbonylalkenyl refers to a straight chain or branched alkenyl as defined above substituted with an alkoxycarbonyl, for example 4-(ethoxycarbonyl)-2-butenyl and the like.
  • alkoxycarbonylalkynyl refers to a straight chain or branched alkynyl as defined above substituted with an alkoxycarbonyl, for example 4-(ethoxycarbonyl)-2-butynyl and the like.
  • haloalkoxyalkyl refers to a straight chain or branched alkyl as defined above substituted with a haloalkoxy, for example 2-chloroethoxymethyl, trifluoromethoxymethyl and the like.
  • haloalkoxyalkenyl refers to a straight chain or branched alkenyl as defined above substituted with a haloalkoxy, for example 4-(chloromethoxy)-2-butenyl and the like.
  • haloalkoxyalkynyl refers to a straight chain or branched alkynyl as defined above substituted with a haloalkoxy, for example 4-(2-fluoroethoxy)-2-butynyl and the like.
  • alkylthioalkyl refers to a straight chain or branched alkyl as defined above substituted with an alkylthio group, for example methylthiomethyl, 3-(isobutylthio)heptyl, and the like.
  • alkylthioalkenyl refers to a straight chain or branched alkenyl as defined above substituted with an alkylthio group, for example 4-(methylthio)-2-butenyl and the like.
  • alkylthioalkynyl refers to a straight chain or branched alkynyl as defined above substituted with an alkylthio group, for example 4-(ethylthio)-2-butynyl and the like.
  • haloalkylthioalkyl refers to a straight chain or branched alkyl as defined above substituted with an haloalkylthio group, for example 2-chloroethylthiomethyl, trifluoromethylthiomethyl and the like.
  • haloalkylthioalkenyl refers to a straight chain or branched alkenyl as defined above substituted with an haloalkylthio group, for example 4-(chloromethylthio)-2-butenyl and the like.
  • haloalkylthioalkynyl refers to a straight chain or branched alkynyl as defined above substituted with a haloalkylthio group, for example 4-(2-fiuoroethylthio)-2-butynyl and the like.
  • dialkoxyphosphorylalkyl refers to two straight chain or branched alkoxy groups as defined above attached to a pentavalent phosphorous atom, containing an oxo substituent, which is in turn attached to an alkyl, for example diethoxyphosphorylmethyl and the like.
  • an "oxo" requires a second bond from the atom to which the oxo is attached. Accordingly, it is understood that oxo cannot be substituted onto an aryl or heteroaryl ring.
  • oligomer refers to a low-molecular weight polymer, whose number average molecular weight is typically less than about 5000 g/mol, and whose degree of polymerization (average number of monomer units per chain) is greater than one and typically equal to or less than about 50.
  • Compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the above Formula I is shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • the invention also encompasses a pharmaceutical composition that is comprised of a compound of Formula I in combination with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier Preferably the composition is comprised of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of Formula I as described above (or a pharmaceutically acceptable salt thereof).
  • the invention encompasses a pharmaceutical composition for the treatment of disease by inhibiting kinases, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above (or a pharmaceutically acceptable salt thereof).
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable nontoxic bases, including inorganic bases and organic bases.
  • Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc, and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
  • organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N',N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylameine, trimethylamine, tripropylamine, tromethamine and the like.
  • ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N',N'- dibenzylethylenediamine, diethylamine, 2-
  • the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids Particularly preferred are formic and hydrochloric acid.
  • compositions of the present invention comprise a compound represented by Formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds represented by Formula I, or a prodrug, or a metabolite, or a pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion.
  • the compound represented by Formula I, or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both.
  • the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt, of Formula I.
  • the compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Unit dosage fo ⁇ ns will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or lOOOmg.
  • Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds. [534] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof may also be prepared in powder or liquid concentrate form.
  • dosage levels on the order of from about O.Olmg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 7g per patient per day.
  • inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
  • Anti-angiogenic agents include, for example: VEGFR inhibitors, such as SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, Calif., USA), or as described in, for example International Application Nos. WO 99/24440, WO 99/62890, WO 95/21613, WO 99/61422, WO 98/50356, WO 99/10349, WO 97/32856, WO 97/22596, WO 98/54093, WO 98/02438, WO 99/16755, and WO 98/02437, and U.S. Patent Nos.
  • VEGF inhibitors such as DVI862 (Cytran Inc. of Kirkland, Wash., USA); angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.); and antibodies to VEGF, such as bevacizumab (e.g.
  • AvastinTM Genentech, South San Francisco, CA
  • a recombinant humanized antibody to VEGF a recombinant humanized antibody to VEGF
  • integrin receptor antagonists and integrin antagonists such as to ⁇ v ⁇ 3] (I v P 5 and ⁇ v ⁇ 6 integrins, and subtypes thereof, e.g. cilengitide (EMD 121974), or the anti-integrin antibodies, such as for example ⁇ v ⁇ 3 specific humanized antibodies (e.g. Vitaxin®); factors such as IFN-alpha (U.S. Patent Nos. 41530,901, 4,503,035, and 5,231,176); angiostatin and plasminogen fragments (e.g.
  • PF4 platelet factor 4
  • plasminogen activator/urokinase inhibitors plasminogen activator/urokinase inhibitors
  • urokinase receptor antagonists heparinases
  • fumagillin analogs such as TNP-4701
  • suramin and suramin analogs angiostatic steroids
  • bFGF antagonists flk-1 and flt-1 antagonists
  • anti-angiogenesis agents such as MMP-2 (matrix- metalloprotienase 2) inhibitors and MMP-9 (matrix-metalloprotienase 9) inhibitors.
  • MMP-2 matrix- metalloprotienase 2 inhibitors
  • MMP-9 matrix-metalloprotienase 9 inhibitors.
  • useful matrix metalloproteinase inhibitors are described in International Patent Publication Nos.
  • MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-I. More preferred, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix- metalloproteinases (i.e. MMP-I, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-IO, MMP-I l, MMP-12, and MMP-13).
  • MMP-I matrix- metalloproteinases
  • additional other cytotoxic, chemotherapeutic or anticancer agents include, for example: alkylating agents or agents with an alkylating action, such as cyclophosphamide (CTX; e.g. Cytoxan®), chlorambucil (CHL; e.g. leukeran®), cisplatin (CisP; e.g. platinol®), oxaliplatin (e.g. EloxatinTM), busulfan (e.g.
  • alkylating agents or agents with an alkylating action such as cyclophosphamide (CTX; e.g. Cytoxan®), chlorambucil (CHL; e.g. leukeran®), cisplatin (CisP; e.g. platinol®), oxaliplatin (e.g. EloxatinTM), busulfan (e.g.
  • CX cyclophosphamide
  • CHL chlorambuci
  • myleran® myleran®
  • melphalan carmustine (BCNU)
  • streptozotocin triethylenemelamine (TEM)
  • mitomycin C and the like
  • anti-metabolites such as methotrexate (MTX), etoposide (VP 16; e.g. vepesid®), 6-mercaptopurine (6MP), 6-thiocguanine (6TG), cytarabine (Ara-C), 5-fluorouracil (5-FU), capecitabine (e.g.Xeloda®), dacarbazine (DTIC), and the like
  • antibiotics such as actinomycin D, doxorubicin (DXR; e.g.
  • adriamycin® daunorubicin (daunomycin), bleomycin, mithramycin and the like
  • alkaloids such as vinca alkaloids such as vincristine (VCR), vinblastine, and the like
  • antitumor agents such as paclitaxel (e.g. taxol®) and pactitaxel derivatives, the cytostatic agents, glucocorticoids such as dexamethasone (DEX; e.g.
  • decadron® and coiticosteroids such as prednisone, nucleoside enzyme inhibitors such as hydroxyurea, amino acid depleting enzymes such as asparaginase, leucovorin, folinic acid, raltitrexed, and other folic acid derivatives, and similar, diverse antitumor agents.
  • the following agents may also be used as additional agents: arnifostine (e.g. ethyol®), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, lornustine (CCNU), doxorubicin lipo (e.g. doxil®), gemcitabine (e.g.
  • gemzar® daunorubicin lipo (e.g. daunoxome®), procarbazine, mitomycin, docetaxel (e.g. taxotere®), aldesleukin, carboplatin, cladribine, camptothecin, 10-hydroxy 7-ethyl-camptothecin (SN38), floxuridine, fludarabine, ifosfamide, idarubicin, mesna, interferon alpha, interferon beta, mitoxantrone, topotecan, leuprolide, megestrol, melphalan, mercaptopurine, plicamycin, mitotane, pegaspargase, pentostatin, pipobroman, plicamycin, tamoxifen, teniposide, testolactone, thioguanine, thiotepa, uracil mustard, vinorelbine, chlorambucil. [539]
  • the IGF-IR inhibitory of a compound of Formula I can be shown in a tyrosine kinase assay using purified GST fusion protein containing the cytoplasmic kinase domain of human IGF-IR expressed in Sf9 cells.
  • This assay is carried out in a final volume of 90 ⁇ L containing 1-10OnM (depending on the specific activity) in an Immulon-4 96-well plate (Thermo Labsystems) pre-coated with l ⁇ g/well of substrate poly-glu-tyr (4:1 ratio) in kinase buffer (5OmM Hepes, pH 7.4, 125mM NaCl, 24mM MgCl 2 , ImM MnCl 2 , 1% glycerol, 200 ⁇ M Na 3 VO 4 , and 2mM DTT).
  • the enzymatic reaction was initiated by addition of ATP at a final concentration of lOO ⁇ M.
  • HRP horse radish peroxidase
  • the bound anti-phosphotyrosine antibody was detected by incubation with lOO ⁇ L/well ABTS (Kirkegaard & Perry Labs, Inc.) for 30min at rt. The reaction was stopped by the addition of lOO ⁇ L/well 1% SDS, and the phosphotyrosine dependent signal was measured by a plate reader at 405/490 nm.
  • All EXAMPLES showed inhibition of IGF-IR.
  • the following examples showed efficacy and activity by inhibiting IGF-IR in the biochemical assay with IC 50 values less than 20 ⁇ M to less than 5OnM.
  • the IC 50 value is less than 5 ⁇ M.
  • the IC 50 value is less than IuM. More advantageously, the IC 50 value is less than 20OnM. Even more advantageously, the IC 50 value is less than 10OnM. Still more advantageously, the IC 50 value is less than 5OnM.
  • the most preferred EXAMPLES are selective towards IGF-IR.
  • an aldehyde Q ! -CHO may be reacted with a methyl transfer reagent such as methyllithium or a methyl Grignard reagent, followed by oxidation of the resulting secondary alcohol Q ⁇ CH ⁇ OBQ-CHs to the methyl ketone of Formula II.
  • a methyl transfer reagent such as methyllithium or a methyl Grignard reagent
  • Further methods for the preparation of compounds of Formula II may be found in: Larock, R. C. Comprehensive Organic Transformations, 2 nd ed.; Wiley and Sons: New York, 1999, pp. 1199-1620.
  • aminocyanopyrroles of Formula III can be prepared from compounds of Formula III
  • Typical amine bases include, but are not limited to, morpholine, diethylamine, diisopropylamine, and triethylamine.
  • Typical solvents include, but are not limited to, alcohols such as methanol, ethanol, isopropanol; amides such as DMF and formamide. The reaction is typically conducted at temperatures of, but not limited to, about 25 0 C to about 90 0 C.
  • compounds of Formula II may be reacted first with malononitrile in the presence of ammonium acetate and acetic acid in benzene or toluene and then reacted with sulfur and an amine base as described above.
  • the compounds of Formula I-BB can be prepared from compounds of Formula III by cyclization under typical cyclization conditions. These conditions include, but are not limited to, heating with formamide neat to about 150-180 0 C; heating with formamidine acetate or a trialkylorthoformate followed by treatment with ammonia.
  • compounds of Formula II are reacted with sulfur and an alkyl cyanoacetate in a typical solvent in the presence of a typical amine base to give compounds of Formula IV.
  • Typical amine bases include, but are not limited to, morpholine, diethylamine, diisopropylamine, and triethylamine.
  • Typical solvents include, but are not limited to, alcohols such as methanol, ethanol, isopropanol; amides such as DMF and formamide.
  • the reaction is typically conducted at temperatures of, but not limited to, about 25 0 C to about 90 0 C.
  • compounds of Formula II may be reacted first with an alkyl cyanoacetate in the presence of ammonium acetate and acetic acid in benzene or toluene and then reacted with sulfur and an amine base as described above.
  • Compounds of Formula V can be prepared from compounds of Formula IV thus obtained by cyclization under typical cyclization conditions. These conditions include, but are not limited to, heating with formamidine acetate in an alcoholic solvent to about reflux temperature of said solvent; heating with a mixture of formamide, DMF, and formic acid to about 80-180 0 C, preferably to about 140-160 0 C.
  • Compounds of Formula VI may be prepared from compounds of Formula V by chlorination using typical chlorinating reagents including, but not limited to, POCl 3 (either neat or in solution) or the Vilsmeier reagent (in solution of a suitable solvent such as DMF).
  • the compounds of Formula I-BB can then be prepared from compounds of Formula VI by reaction with ammonia in a typical solvent under typical reaction conditions.
  • Typical solvents include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile; alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, and the like.
  • the preferred solvent is isopropanol.
  • the reaction can be carried out at temperatures between about 20 0 C and about 120 0 C, preferably between 8O 0 C and about 100 0 C.
  • compounds of Formula I-BB may be reacted with a brominating agent such as Br 2 or NBS to give the 6-bromo compound of Formula I-B-6-Br, which can be further reacted to give compounds of Formula I-B-6-E 1 by, e.g., Suzuki or Stille coupling with a boronic acid derivative or a trialkyltin derivative, respectively.
  • a brominating agent such as Br 2 or NBS
  • compounds of Formula I-B-6-Br may be further reacted to give compounds of Formula I-B-6-E 1 by, e.g., Suzuki or Stille coupling with a boronic acid derivative or a trialkyltin derivative, respectively.
  • Compounds of Formula I-B-2-E 1 may be prepared from compounds of Formula III or
  • Scheme Ib shows an alternative method of preparing compounds of Formula I-BB, wherein Q 1 is as previously defined, A 1 is halogen such as Cl, Br, or I, and B(OR 1 ) 2 is a suitable boronic acid/ester wherein R 1 is C o- ioalkyl, cycloC 3 _ 10 alkyl, bicycloC 5- i 0 alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterobicycloC 5 .i 0 alkyl, spiroalkyl, or heterospiroalkyl: Scheme Ib
  • Compounds of Formula IX may be prepared from compounds of Formula VIII by halogenation with reagents such as PPh 3 -I 2 , PPh 3 -Br 2 , POCl 3 , POBr 3 , and the like. Cyclization of compounds of Formula IX to give compounds of Formula X can be accomplished by methods described above for the conversion of compounds of Formula III to compounds of Formula I-BB.
  • compounds of Formula I-BB can be prepared from compounds of Formula X by Suzuki coupling with a boronate derivate Q I -B(OR 1 ) 2 (compound of Formula XI) or by Stille coupling with a trialkyltin derivative Q'-SnBu 3 (compound of Formula XII), respectively, under typical coupling conditions well known to someone skilled in the art.
  • the compounds of Formula XI (Q'-BfpR 1 ⁇ ) of Scheme Ib may be prepared from compounds of Formula Q ! -A n (wherein A 11 is chloro, bromo, iodo, triflate, and the like) by reacting with a suitable metal catalyst and a suitable boronating agent under suitable reaction conditions.
  • Suitable metal catalyst agents include, but are not limited to, Pd(OAc) 2 in the presence of l,3-bis(2,6- diisopropylphenyl)imidazolium chloride; Pd(Cl) 2 dppf, optionally in the presence of additional dppf.
  • Suitable boronating agents include, but are not limited to, t ⁇ (pinacolato)diboron.
  • Suitable reaction conditions for use in the above process include, but are not limited to, heating a mixture of the metal catalyst agent, KOAc, and ⁇ zs(pinacolato)diboron in a suitable solvent such as, but not limited to, THF, 1,4-dioxane, DMSO.
  • the above process may be carried out at temperatures between about 2O 0 C and about 12O 0 C.
  • the reaction is carried out at 6O 0 C to 8O 0 C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired.
  • 2-3 equivalents of KOAc, 1—1.5 equivalents of t ⁇ (pinacolato)diboron, 0.03-1 equivalent of metal catalyst agent are used although higher or lower amounts were used if desired.
  • compounds of Formula Q ⁇ -A 11 and XI are commercially available or synthesized according to literature procedures. In cases where neither are available, compounds of Formula Q ⁇ -A 11 and XI (Q 1 -B(OR 1 ) 2 ) were synthesized via procedures described in the experimental section herein.
  • Scheme 2 shows a method that can be used to prepare compounds of Formula I-AA, wherein Q 1 is as previously defined, A 1 is halogen such as Cl, Br, or I, and B(OR J ) 2 is a suitable boronic acid/ester wherein R ! is C O -ioalkyl, cycloCa.ioalkyl, bicycloC 5 .i 0 alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterobicycloCs.ioalkyl, spiroalkyl, or heterospiroalkyl: [567] Scheme 2
  • the starting aldehydes of Formula XIII are known in the literature, commercially available, or can be prepared by methods known to someone skilled in the art.
  • the compounds of Formula XIV can be prepared from the aldehydes of Formula XIII in a known four-step sequence consisting of Knoevenagel condensation with malonic acid and subsequent decarboxylation, conversion of the resulting acid to its acyl azide, thermal rearrangement of said azide to give an isocyanate, and thermal cyclization of this isocyanate to give compounds of Formula XIV.
  • This type of sequence has repeatedly been described in the literature, e.g., Ger. Offen. DE2059386 (1971), Ger. Offen. DE1965710 (1970), WO2004/000828A1.
  • Compounds of Formula XV may be prepared from compounds of Formula XIV by chlorination using typical chlorinating reagents including, but not limited to, POCl 3 (either neat or in solution).
  • the compounds of Formula XVI can then be prepared from compounds of Formula XV by reaction with ammonia in a typical solvent under typical reaction conditions as described above for the conversion of compounds of Formula V to compounds of Formula VI.
  • compounds of Formula I-AA can be prepared from compounds of Formula XVI by Suzuki coupling with a boronate derivate Q '-B(OR 1 ) 2 (compound of Formula XI) or by Stille coupling with a trialkyltin derivative Q ⁇ -SnBu 3 (compound of Formula XII), respectively, under typical coupling conditions well known to someone skilled in the art. It will be appreciated by someone skilled in the art that the Suzuki or Stille coupling with a compound of Formula XI or compound of Formula XII, respectively, may be performed alternatively, at an earlier stage, with any of the compounds of Formulas XIII, XIV, or XV, if one deems appropriate.
  • Scheme 2a shows how compounds of Formula I-A that are substituted at C-7 can be prepared, wherein Q 1 and E 1 are as previously defined, and A 1 and A 2 are halogen such as Cl, Br, or I: [571] Scheme 2a
  • NBS, or NIS to give the 7-halo compound of Formula I-A-7-A 2 , which can be further reacted to give compounds of Formula I-A-7-E 1 by, e.g., Suzuki or Stille coupling with a boronic acid derivative or a trialkyltin derivative, respectively, as described above.
  • compounds of Formula XIV may be reacted with a halogenating agent such as NCS, NBS, or NIS to give the 7-halo compound of Formula XIV-7-A 2 .
  • a halogenating agent such as NCS, NBS, or NIS
  • the compounds of Formula XrV-7-A 2 can then be converted to compounds of Formula XV-7-A 2 and further to compounds of Formula XVI-7-A 2 in substantially the same way as described above for the conversion of compounds of Formula XIV to compounds of Formula XV and compounds of Formula XVI.
  • Compounds of Formula XVI-7-A 2 may be converted to compounds of Formula I-A-7-A 2 by, e.g., Suzuki or Stille coupling with a boronic acid derivative of Formula XI or a trialkyltin derivative of Formula XII, respectively, as described above, and the compounds of Formula I-A-7-A 2 can be further reacted to give compounds of Formula I-A-7-E 1 , as described above.
  • Compounds of Formula XVI-7-A 2 may also be converted to compounds of Formula XVI-7-E 1 , as described above, which can be further reacted to give compounds of Formula I-A-7-E 1 by, e.g., Suzuki or Stille coupling with a boronic acid derivative of Formula XI or a trialkyltin derivative of Formula XII, respectively, as described above.
  • compounds of Formula I-A-7-E 1 may be prepared from compounds of
  • Formula XIH-E 1 under substantially similar conditions as described above for the conversion of compounds of Formula XIII to compounds of Formula I- AA.
  • the starting compounds of Formula XIII-E 1 can be prepared by methods well known to someone skilled in the art.
  • Scheme 3 shows a method that can be used to prepare compounds of Formula I-CC, wherein Q 1 is as previously defined.
  • a carboxylic acid Q ⁇ -CO 2 H may be reacted with a chlorinating reagent such as, but not limited to, SOCl 2 , PCl 3 , PCl 5 , PPh 3 -CCl 4 , or the Vilsmeier reagent, either neat or in a suitable solvent such as, but not limited to, CH 2 Cl 2 , CHCl 3 , of DMF.
  • a chlorinating reagent such as, but not limited to, SOCl 2 , PCl 3 , PCl 5 , PPh 3 -CCl 4 , or the Vilsmeier reagent, either neat or in a suitable solvent such as, but not limited to, CH 2 Cl 2 , CHCl 3 , of DMF.
  • Compounds of Formula XVII can be treated with malononitrile in the presence of a
  • Typical bases include, but are not limited to, NaOH and KOH.
  • Typical reaction conditions include, but are not limited to, using a two-phase system Of CH 2 Cl 2 and water in the presence of a phase-transfer catalyst such as a tetraburylammonium halide, a benzyltriethylammonium halide, and the like, at temperatures between about -5 0 C and about 35 0 C.
  • Compounds of Formula XIX can be prepared from compounds of Formula XVIII by reaction with a chlorinating reagent such as PCl 5 in a typical solvent at a typical reaction temperature.
  • Typical solvents include, but are not limited to, halogenated solvents such as CH 2 Cl 2 , CHCl 3 , and CCl 4 .
  • Typical reaction temperatures range from about O 0 C to about 40 0 C.
  • Compounds of Formula XX can be prepared from compounds of Formula XIX by reaction with ammonia in a typical solvent at a typical reaction temperature. Ammonia may be used as concentrated aqueous solution, or as solution in another suitable solvent.
  • Typical solvents include, but are not limited to, methanol, ethanol, and isopropanol.
  • Typical reaction temperatures range from about 0 0 C to about 40 0 C.
  • Compounds of Formula XXI can be prepared from compounds of Formula XX by reaction with a typical sulfur source under typical reaction conditions.
  • Typical sulfur sources and reaction conditions include, but are not limited to, diethyl dithiophosphate in an alcoholic solvent such as methanol or ethanol optionally containing water at about 70 0 C to about 80 0 C, and hydrogen sulfide gas in pyridine containing an amide base such as triethylamine at about 70 0 C to about 90 0 C.
  • Compounds of Formula XXII can be prepared from compounds of Formula XXI under typical oxidative cyclization conditions.
  • the line positions or multiplets are given in ppm ( ⁇ ) and the coupling constants (J) are given as absolute values in Hertz, while the multiplicities in 1 H NMR spectra are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), m e (centered multiplet), br (broadened), AA'BB'.
  • the signal multiplicities in 13 C NMR spectra were determined using the DEPT135 pulse sequence and are abbreviated as follows: + (CH or CH3), - (CH 2 ), Cqua r t (C).
  • LOMS analysis was performed using a Gilson 215 autosampler and Gilson 819 autoinjector attached to a Hewlett Packard HPl 100 and a MicromassZQ mass spectrometer, or a Hewlett Packard HP 1050 and a Micromass Platform II mass spectrometer. Both setups used XTERRA MS Cl 8 5 ⁇ 4.6x50mm columns with detection at 254 nm and electrospray ionization in positive mode. For mass-directed purification (MDP), a Waters / MicromassZQ system was used. [583] The tables below list the mobile phase gradients (solvent A: acetonitrile; solvent B:

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