MXPA06007302A - Fused pyrrolocarbazoles and methods for the preparation thereof - Google Patents

Abstract

The present invention relates generally to selected fused pyrrolocarbazoles, including pharmaceutical compositions thereof and methods of treating diseases therewith. The present invention is also directed to intermediates and processes for making these fused pyrrolocarbazoles.

Description

FUSED PiRROLOCARBAZOLES AND METHODS FOR PREPARATION Cross Reference for Related Requests This application claims the priority of United States Provisional Application No. 60 / 532,252, filed on December 23, 2003, which is hereby incorporated by reference in its entirety for all purposes. Field of the Invention The present invention relates generally to fused pyrrolocarbazoles, including pharmaceutical compositions, diagnostic kits, assay standards or reagents containing the same, and methods for using the same as therapeutics. The invention is also directed to intermediates and processes for manufacturing these novel compounds. BACKGROUND OF THE INVENTION The publications cited fully in this description are incorporated herein by reference in their entirety. Various synthetic small organic molecules have been prepared which are biologically active and generally known in the art as "fused pyrrolocarbazoles" (See U.S. Patent Nos. 5,475,110, 5,591,855, 5,594,009, 5,616,724, and 6,630,500). In addition, U.S. Patent 5,705,511 discloses fused pyrrolocarbazole compounds that possess a variety of functional pharmacological activities. The fused pyrrolocarbazoles were described as being used in a variety of ways, including: improving the function and / or survival of cells of the neuronal lineage, either singly or in combination with the neutrophilic factor (s) (s) ) and / or indolocarbazoles; improvement of the activity induced by the trophic factor; inhibition of protein kinase C ("PKC") activity; inhibition of the activity of the tyrosine kinase trk; inhibition of the proliferation of a prostate cancer cell line; inhibition of the cellular trajectory involved in the inflammation process; and improvement of the survival of neuronal cells at risk of dying. However, a need remains for novel pyrrolocarbazole derivatives that possess beneficial properties. This invention is directed to this, as well as to other important terminals. Brief Description of the Invention The present invention in one aspect is directed to fused pyrrolocarbazole compounds of Formula I: and their stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, wherein the constituent members are defined infra. The fused pyrrolocarbazoles of the present invention can be used in a variety of ways, including: for the inhibition of angiogenesis; as antitumor agents; to improve the function and / or survival of cells of the neuronal lineage, either singly or in combination with the neurotrophic factor (s) and / or indolocarbazoles; to improve the activity induced by the trophic factor; inhibition of kinase activity, such as trk tyrosine kinase ("trk"), vascular endothelial growth factor receptor ("VEGFR") receptor, preferably VEGFR1 and VEGFR2, mixed lineage kinase ("MLK"), kinase that leads to double closing of leucine ("DLK"), platelet-derived growth factor receptor kinase ("PDGFR"), protein kinase C ("PKC"), Tie-2, or CDK-1, -2, - 3, -4, -5, -6; for the inhibition of trk phosphorylation stimulated by NGF; for the inhibition of the proliferation of a prostate cancer cell line; for the inhibition of cellular trajectories involved in the inflammation process; and for the improvement of the survival of neuronal cells at risk of dying. In addition, the fused pyrrolocarbazoles may be useful for the inhibition of internal tandem duplications containing mutated c-met, c-kit and Flt-3 in the juxtamembrane domain. Due to these varied activities, the described compounds found utility in a variety of fixations, including research and therapeutic environments. In other embodiments, the compounds of the present invention are useful for the treatment or prevention of angiogenic and angiogenesis disorders such as cancer of solid tumors, endometriosis, retinopathy, diabetic retinopathy, psoriasis, hemangioblastoma, ocular disorders or macular degeneration. In another embodiment, the compounds of the present invention are useful for the treatment or prevention of neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, healing of abnormal wounds, atherosclerosis, or restenosis. In other embodiments, the compounds of the present invention are useful for the treatment or prevention of neurodegenerative disorders and diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, fulminating attack or crisis, ischemia, Huntington's disease, dementia AIDS, epilepsy, multiple sclerosis, peripheral neuropathy, peripheral neuropathy induced by chemotherapy. Peripheral neuropathy related to AIDS, or injuries to the brain or spinal cord. In additional embodiments, the compounds of the present invention are useful for the treatment or prevention of prostate disorders such as prostate cancer or benign prostatic hyperplasia. In still other embodiments, the compounds of the present invention are useful for the treatment or prevention of multiple myeloma and leukemias including, but not limited to, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymnocytic leukemia, and chronic lymphocytic leukemia. In another aspect, the present invention is directed to pharmaceutical compositions comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of a compound of the present invention. Detailed Description of the Invention Thus, in a first embodiment, the present invention provides a novel compound of Formula I: I wherein: ring A together with the carbon atoms to which it is attached is selected from: (a) a phenylene ring in which 1 to 3 carbon atoms can be replaced by nitrogen atoms; and (b) a 5-membered aromatic ring in which 1 to 2 carbon atoms can be replaced by nitrogen atoms; A1 and A2 are independently selected from H, H; and a group wherein A1 and A2 together form a selected portion of = O; B1 and B2 are independently selected from H, H; and a group wherein B1 and B2 together form a selected portion of = O; with the proviso that at least one of the pairs A1 and A2, or B1 and B2 form = O; R1 is H or optionally substituted alkyl, wherein the optional substituents are groups of one to three R10; R2 is selected from H, C (= O) R2a, C (= O) NR2cR2d, SO2R2b, CO2R2b, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, wherein the optional substituents they are groups of one to three R10; R2a is selected from optionally substituted alkyl, optionally substituted aryl, OR2b, NR2cR2d, (CH2) pNR2cR2d, and O (CH2) pNR2cR2d, wherein the optional substituents are groups of one to three R10; R2b is selected from H and optionally substituted alkyl, wherein the optional substituents are groups of one to three R10; R2c and R2d are each independently selected from H and optionally substituted alkyl, or together with the nitrogen to which they are attached form an optionally substituted heterocycloalkyl, wherein the optional substituents are groups of one to three R10; at least one of R3, R4, R5, and R6 is selected from OR14; C (= O) R22; CH = NR26; NR11C (= O) R20; NR11C (= O) OR15; OC (= O) R20; OC (= O) NR 11 R 20; O- (alkylene) -R24; Z - (alkylene) -R23), wherein Z1 is selected from CO2, O2C, C (= O), NR11, NR11C (= O), and NR 1C (= O) O; Y (alkyl) -Z - (alkylene) -R? wherein it is selected from O, S (O) and, C (= O) NR1 \ NR11C (= O), NR11C (= O) NR11, OC (= O) NR11, NR11C (= O) O; wherein the alkylene groups are optionally substituted with one to three R10 groups; the other portions R3, R4, R5, or R6 can be independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl, wherein the optional substituents are groups of one to three R10; Q is selected from an optionally substituted C-α-2 alkylene, wherein the optional substituents are groups of one to three R 10; 10 is selected from alkyl, cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkoxy, F, Cl, Br, I, CN, CF3, NR27AR27BJ NQ2I OR25, OCF3, = O, = NR25, = N-OR25, = NN (R25) 2l OC (= O) R25, OC (= O) NHR1 \ O-YES (R16) 4, O-tetrahydropyranyl, ethylene oxide, NR16C (= O) R25, NR16CO2R25, NR16C (= O) NR27AR27B, NHC (= NH) NH2, NR16S (O) 2R25, S (O) and R25, CO2R25, C (= O) NR27AR27B, C (= O) R25, CH2OR25, (CH2) pOR25, CH = NNR27AR27B, CH = NOR25, CH = NR25, CH = NNHCH (N = NH) NH2, S (= O) 2NR27AR27B, P (= O) (OR25) 2, OR13, and a monosaccharide wherein each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl, alkylcarbonyloxy, or alkoxy; R 11 is selected from H and optionally substituted alkyl, wherein the optional substituents are groups of one to three R 10; R 12 is selected from optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein the optional substituents are groups of one to three R 10; R 13 is the residue of an amino acid after removal of the hydroxyl portion of the carboxyl group thereof; R 14 is optionally substituted heteroaryl, wherein the optional substituents are groups of one to three R 10; R 15 is optionally substituted alkyl, wherein the optional substituents are groups of one to three R 10; R 16 is H or alkyl; R17 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, wherein the optional substituents are groups of one to three R10; R 18 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, wherein the optional substituents are groups of one to three R 10; R 19 is selected from optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl, wherein optional substituents are groups of one to three R 10; R 2o is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, wherein the optional substituents are groups of one to three R 10; R 21 is selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, wherein the optional substituents are groups of one to three R10; R 22 is selected from optionally substituted aryl, and optionally substituted heteroaryl, wherein the optional substituents are groups of one to three R 10; R 23 is selected from optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, OR21, O (CH2) pOR21, (CH2) pOR21, SR18, SOR17, SO2R18, CN, N (R20) 2, CHOH (CH2) pN (R1) 2, C (= O) N (R18) 2) NR18C (= O) R18, NR18C (= O) N (R18) 2, C (= NR18) OR18, C (R12) = NOR18, NHOR21, NR18C (= NR18) N (R18) 2, NHCN, CONR18OR18, CO2R18, OCOR17, OC (= O) N (R18) 2, NR18C (= O) OR17, and C (= O) R18, wherein the optional substituents are groups of one to three R10; R 24 is selected from optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, CN, OR21, O (CH2) pOR21, (CH2) pOR21 SR19, SOR17, SO2R18, N (R18) 2 , CHOH (CH2) pN (R11) 2 NR18C (= O) R18, NR18C (= O) N (R18) 2, C (= NR18) OR18 NHOR21, NR18C (= NR18) N (R18) 2, NHCN, C (= O) N (R18) 2 C (= O) NR27AR27B, C (= O) NR11R28, C (= O) NR 8OR18 C (= O) NR11N (R 1) 2, C (= O) NR11 (alkylene) ) -NR27AR27B CO2R18, OCOR17, OC (= O) N (R18) 2, NR 8C (= O) OR17 C (= O) NR11R18 and C (= O) R18, wherein the optional substituents are groups of one to three R10; R 25 is H, alkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; R is selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, wherein the optional substituents are groups of one to three R10; R27A and R27B are each independently selected from H and alkyl, or together with the nitrogen to which they are attached form an optionally substituted heterocycloalkyl, wherein the optional substituents are selected from alkyl, aryl heteroaryl; R28 is optionally substituted arylalkyl, wherein the optional substituents are groups of one to three R10; p is independently selected from 1, 2, 3 and 4; and is independently selected from 0, 1 and 2; and a stereoisomer or a pharmaceutically acceptable salt form thereof. In another embodiment, the compounds of Formula I as defined herein are not intended to include any compounds described in PCT Publication No. WO 98/07433. In particular, when A1, A2 is = O; B1, B2 are independently H or OH, or B1, B2 combined form = O; rings A and B are each phenylene; Q is CH-Ra; and one of R2 or Ra is H and the other is optionally substituted wherein W is optionally substituted C-i alkyl, or NR27AR27B; then any of R3, R4, R5 and R6 may not include OR14 or O- (alkyien) -R24. Other aspects of the present invention include compounds of Formula I as defined herein wherein ring A is phenylene; or a 5-membered aromatic ring containing a nitrogen atom, preferably pyrazolylene, and more preferably.

Additional aspects include those compounds wherein R 1 is H or optionally substituted alkyl. Another aspect includes those compounds wherein R2 is H, C (= O) R2a, C (= O) NR2cR2d, SO2R2b, CO2R2b, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted cycloalkyl, and preferably H optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted cycloalkyl, and most preferably R2 is H or optionally substituted alkyl. Additional aspects include those compounds wherein the A1A2 groups are H, H; and B1B2 together form = O. In still another aspect, the invention includes compounds wherein Q is selected from an optionally substituted C? -2 al alkylene, or preferably Q is CH 2, or CH 2 CH 2. Other aspects include those compounds wherein R14 is benzoxazole, benzothiazole, pyrimidine, pyrazine or triazine; R22 is a 5-membered heteroaryl group; R 20 is heterocycloalkyl or heteroaryl; R23 is heteroaryl or heterocycloalkyl; R24 is heteroaryl; and R26 is heterocycloalkyl. Additional aspects of the present invention include any combination of the above preferred substituents, such as, for example, a compound of Formula I with the preferred portions of the groups R1 and R2; or R1 and Q; or R1, R2; or Q; etc. In another embodiment of the present invention, compounds having a structure of Formula II are included: p In one aspect, compounds of Formula II are included wherein ring A is phenylene or pyrazolylene, preferably An additional aspect includes those compounds wherein R 1 is H or optionally substituted alkyl. Other aspects include those compounds wherein R2 is H, C (= O) R2a, C (= O) NR2cR2d, SO2R2b, CO2R2b, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted cycloalkyl, and preferably H optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted cycloalkyl, and most preferably R2 is H or optionally substituted alkyl. Additional aspects include compounds wherein Q is selected from an optionally substituted C? _ Al alkylene, or preferably Q is CH 2 or CH 2 CH 2. Additional aspects of the present invention include any combination of the above preferred substituents, such as, for example, a compound of Formula II with the preferred portions of the groups R1 and R2; or R1 and Q; or R1, R2; or Q; etc. In yet another embodiment of the present invention, compounds having a structure of Formula III are included: m where ring A is preferably phenylene or pyrazolylene, preferably , and R1 is H or optionally substituted alkyl; and Formula IV: RV and Formula V: and Formula VI SAW In certain aspects of the present invention, compounds of Formulas III-VI are included wherein R2 is H, C (= O) R2a, C (= O) NR2cR2d, SO2R2b, CO2R2b, optionally substituted alkyl, optionally substituted alkenyl, alkynyl optionally substituted, or optionally substituted cycloalkyl, and preferably H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted cycloalkyl, and most preferably R2 is H or optionally substituted alkyl. Other aspects include those compounds wherein Q is selected from an optionally substituted C -? - 2 alkylene, or preferably Q is CH2 or CH2CH2. Additional aspects of the present invention include any combination of the above preferred substituents for each of Formulas III-VI. The following paragraphs show further aspects of the invention for at least one of R3, R4, R5, and R6 for compounds of Formulas I-VI and their respective preferred embodiments described hitherto. 1. OR14; particularly those wherein R14 is optionally substituted benzoxazole, optionally substituted benzothiazole, optionally substituted pyrimidine, optionally substituted pyrazine or optionally substituted triazine. 2. C (= O) R22; particularly those wherein R22 is an optionally substituted 5-membered heteroaryl group. 3. CH = NR26; particularly those wherein R26 is optionally substituted heterocycloalkyl. 4. NR11C (= O) R20; particularly those wherein R 20 is optionally substituted heteroaryl. 5. NR11C (= O) OR15. 6. OC (= O) R20; particularly those wherein R 20 is optionally substituted heterocycloalkyl. OC (= O) NR 11 R 20; particularly those wherein R 20 is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl. O- (alkylene) -R24; particularly those wherein R24 is optionally substituted heterocycloalkyl. 9. Z1- (alkylene) -R23, wherein Z1 is selected from CO2, O2C, C (= O), NR11, NR11C (= O), and NR11C (= O) O; particularly those where Z1 is C (= O) or NR11. 10. (alkylene) -Z2- (alkylene) -R23, wherein Z2 is selected from O, S (O) and, C (= O) NR11, NR11C (= O), NR11C (= O) NR11, OC ( = O) NR11, NR11C (= O) O; particularly those where Z2 is O, C (= O) NR11, or NR11C (= O). The preceding paragraphs may be combined to further define additional preferred embodiments of compounds of Formulas I-VI. For example, such a combination for R3, R4, R5, or R6 may include OR14; C (= O) R22; NR11C (= O) R20; NR11C (= O) OR15; OC (= O) R20; or OC (= O) NR11 R20. Another such combination includes OR14; C (= O) R22; Y NR11C (= O) OR15. A third of such combination includes OR14, where R14 is benzoxazole, benzothiazole, pyrimidine, pyrazine or triazine; C (= O) R22, wherein R22 is a 5-membered heteroaryl group; NRnC (= 0) R, 2'0 wherein R 20 is heteroaryl; NR C (= 0) OR 15. OC (= O) R 'wherein R 20 is heterocycloalkyl; or OC (= O) NR R, wherein R20 is cycloalkyl, wherein each R14, R22 and R20 is optionally substituted as set forth above. The following terms and expressions used herein have the indicated meanings. In the formulas described and claimed herein, it is understood that when any symbol appears more than once in a particle or substituent formula, its meaning in each case is independent of the other. As used herein, the term "approximately" refers to a range of values of ± 10% of a specified value. For example, the phrase "approximately 50 mg" includes ± 10% of 50, or 45 to 55 mg. As used herein, a range of values in the form "x-y" or "x to y", or "x to y", includes integers x, y, and the integers among them. For example, the phrases "1-6", or "1 to 6" or "1 to 6" are intended to include integers 1, 2, 3, 4, 5 and 6. Preferred embodiments include each individual integer in the interval, as well as any sub-combination of integers. For example, preferred integers for "1-6" may include 1, 2, 3, 4, 5, 6, 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2 -5, 2-6, etc. As used in the present "stable compound" or "stable structure" it refers to a compound that is sufficiently solid for subsistence isolation to a useful degree of purity of a reaction mixture, and preferably capable of formulation in an agent effective therapeutic The present invention is directed only to stable compounds. As used herein, the term "alkyl" refers to a straight or branched chain alkyl group having from 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl , tert-butyl, pentyl, isoamyl, neopentyl, 1-ethylpropyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, hexyl, octyl, etc. The alkyl portion of alkyl-containing groups, such as alkoxy, alkoxycarbonyl, and alkylaminocarbonyl groups, has the same meaning as the alkyl defined above. Lower alkyl groups, which are preferred, are alkyl groups as defined above containing from 1 to 4 carbon atoms. A designation such as "C 1 -C 4 alkyl" refers to an alkyl radical containing 1 to 4 carbon atoms. As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon of chains of 2 to 8 carbon atoms having at least one carbon-carbon double bond. A designation "C2-C8 alkenyl" refers to an alkenyl radical containing from 2 to 8 carbon atoms. Examples of alkenyl groups include ethenyl, propenyl, isopropenyl, 2,4-pentadienyl, etc. As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon of chains of 2 to 8 carbon atoms having at least one carbon-carbon triple bond. A designation "C2-C8 alkynyl" refers to an alkynyl radical containing from 2 to 8 carbon atoms. Examples include ethynyl, propynyl, isopropynyl, 3,5-hexadiynyl, etc. As used herein, the term "alkylene" refers to a straight or branched chain hydrocarbon of 1 to 8 carbon atoms, which is formed by the removal of two hydrogen atoms. A designation such as "C -? - C4 alkylene" refers to an alkylene radical containing from 1 to 4 carbon atoms. Examples include methylene (-CH2-), propylidene (CH3CH2CH =), 1,2-ethanediyl (-CH2CH2-), etc. As used herein, the term "phenylene" refers to a phenyl group with an added hydrogen atom removed, that is, a portion with the structure of: As used herein, the term "cycloalkyl" refers to a saturated or partially saturated mono- or bicyclic alkyl ring system containing from 3 to 10 carbon atoms. A designation such as "C5-C7 cycloalkyl" refers to a cycloalkyl radical containing from 5 to 7 carbon atoms in the ring. Preferred cycloalkyl groups include those containing 5 or 6 carbon atoms in the ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, etc. As used herein, the term "spirocycloalkyl" refers to a cycloalkyl group attached to a carbon chain or carbon ring portion by a carbon atom common to the cycloalkyl group and the carbon or ring chain portion of carbon. For example, an alkyl group of C3 substituted with a group R wherein the group R is spirocycloalkyl containing 5 carbon atoms refers to: As used herein, the term "aryl" refers to an aromatic ring system, mono- or bicyclic hydrocarbon having from 6 to 12 carbon atoms in the ring. Examples include phenyl and naphthyl. Preferred aryl groups include phenyl or naphthyl groups. Included within the definition of "aryl" are fused ring systems, including, for example, ring systems wherein an aromatic ring is fused to a cycloalkyl ring. Examples of such fused ring system include, for example, indane and indene. As used herein, the terms "heterocycle," "heterocyclic," or "heterocyclyl" refer to a distinct mono-, di-, tri- or multicyclic aliphatic ring system that includes at least one heteroatom such as O, N , or S. The nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen may be optionally substituted on non-aromatic rings. The heterocycles are intended to include heteroaryl and heterocycloalkyl groups. Some heterocyclic groups containing one or more nitrogen atoms include pyrrolidine, pyrroline, pyrazoline, piperidine, morpholine, thiomorpholine, N-methyl-piperazine, indole, isoindole, imidazole, imidazoline, oxazoline, oxazole, triazole, thiazoline, thiazole, isothiazole groups. , thiadiazole, triazine, isoxazole, oxindole, pyrazole, pyrazolone, pyrimidine, pyrazine, quinoline, isoquinoline, and tetrazole. Some heterocyclic groups formed containing one or more oxygen atoms include furan groups, tetrahydrofuran, pyran, benzofurans, isobenzofurans and tetrahydropyran. Some heterocyclic groups containing one or more sulfur atoms include thiophene, tianaphthene, tetrahydrothiophene, tetrahydrothiapyran and benzothiophenes. As used herein, the term "heterocycloalkyl" refers to a cycloalkyl group in which one or more carbon atoms in the ring are replaced by at least one heteroatom such as -O-, -N-, or -S -, and includes ring systems containing a ring group saturated in bridge form or fused to one or more aromatic groups. Some heterocycloalkyl groups containing both aromatic and saturated rings include phthalamide, phthalic anhydride, indoline, soindoline, tetrahydroisoquinoline, chroman, isochroman and chromene. As used herein, the term "heteroaryl" refers to an aryl group containing from 5 to 10 carbon atoms in the ring in which one or more carbon atoms in the ring are replaced by at least one hetero atom such as -O-, -N-, or -S-. Some heteroaryl groups of the present invention include pyridyl, pyrimidyl, purinyl, pyrrolyl, pyridazinyl, pyrazinyl, triazinyl, imidazolyl, triazolyl, tetrazolyl, indolyl, isoindylyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinolinyl, phthalazinyl, benzoimidazolyl, pyrazolyl, thiazolyl group , thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, naphthyridinyl, oxindolyl, and benzothiazolyl.

As used herein, the term "arylalkyl" refers to an alkyl group that is substituted with an aryl group.

Examples of arylalkyl groups include, but are not limited to, benzyl, phenethyl, benzhydryl, diphenylmethyl, triphenylmethyl, diphenylethyl, naphthylmethyl, etc.

As used herein, the term "arylalkoxy" refers to an alkoxy group substituted with aryl, such as benzyloxy, diphenylmethoxy, triphenylmethoxy, phenylethoxy, diphenylethoxy, etc. As used herein, the term "monosaccharide" refers to a simple sugar of the formula (CH 2 O) n. The monosaccharides can be straight chain or ring systems, and can include a sucrose unit of the formula -CH (OH) -C (= O) -. Examples of monosaccharides include erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, iodine, galactose, talose, erythulose, ribulose, xiulose, psychose, fructose, sorbose, tagatose, erythropentulose, treopentulose, glycerotetrulose, glucopyranose, fructofuranose, etc. As used herein, the term "amino acid" refers to a group that contains both an amino group and a carboxyl group. Modalities of amino acids include -amino acids, β-amino acids, α-amino acids. The a-amino acids have a general formula HOOC-CH (side chain) -NH2. The amino acids can be either D, L or racemic configurations. Amino acids include portions that occur naturally or in a non-natural form. The amino acids that occur naturally include the 20 standard amino acids found in proteins, such as glycine, serine, tyrosine, proline, histidine, glutamine, etc. Amino acids that occur naturally may also include non-amino acids (such as β-alanine, α-aminobutyric acid, homocysteine, etc.), rare amino acids (such as 4-hydroxyproline, 5-hydroxylysine, 3-methylhistidine, etc. .) and non-protein amino acids (such as citrulline, ornithine, canavanine, etc.). Amino acids that do not occur naturally are well known in the art, and include natural amino acid analogs. See Lehninger, A. L. Biochemistry, 2nd ed .; Worth Publishers: New York, 1975; 71-77, the description of which is incorporated herein by reference. Amino acids that do not occur naturally also include α-amino acids wherein the side chains are replaced with synthetic derivatives. In certain embodiments, substituent groups for the compounds of the present invention include the residue of an amino acid after removal of the hydroxyl portion of the carboxyl group thereof; that is, groups of formula -C (= O) CH (Iateral chain) -NH2. Representative side chains of a-amino acids that occur naturally and occur in a non-naturally occurring form are shown below in Table A.

Table AH HS-CH2-CH3-H02C-CH (NH2) -CH2-SS-CH2-HO-CH2-CH3-CH2-C6H5-CH2-CH3-S-CH2-CH2-HO-C6H4-CH-CH3-CH2 -S-CH2-CH2- HO-CH2-CH2- CH3-CH (OH) - H02C-CH2-CH2- H2C (= 0) -CH2- H2N-C (= O) -NH-CH2-CH2-CH2- As used herein, the term "trk" refers to the family of high affinity neurotrophin receptors that currently comprises trk A, trk B and trk C, and other proteins associated with the membrane to which the neurotrophin can bind .

As used herein, the term "VEGFR" refers to the family of high affinity vascular endothelial growth factor receptors that currently comprises VEGFR1, VEGFR2, VEGFR3, and other proteins associated with the membrane to which the VEGF. As used herein, "MLK" refers to the family of high affinity mixed lineage kinases currently comprising MLK1, MLK2, MLK3, MLK4a & ß, DLK, LZK, ZAK a & ß, and other serine / threonine kinases classified within this family. As used herein, the terms "improve" or "improvement" when used to modify the terms "function" or "survival" mean that the present compound of the present invention has a positive effect on function and / or survival of a cell sensitive to the trophic factor compared to a cell in the absence of the compound. For example, and not in the form of limitation, with respect to the survival of, for example, a cholinergic neuron, a compound of the present invention would demonstrate improved survival of a cholinergic neuronal population at risk of dying (due, for example, to damage , a condition of the disease, a degenerative condition or natural progression) when compared to a cholinergic neuronal population not presented with such a compound, if the treated population has a comparatively greater period of functionality than the untreated population. As a further example, and again not by way of limitation, with respect to the function of, for example, a sensory neuron, a compound of the present invention would demonstrate improvement of the function (e.g., neurite outgrowth) of a neuronal population sensory when compared to a sensory neuronal population not presented with such a compound, if the neurite extension of the treated population is comparatively greater than the neurite extension of the untreated population. As used herein, the terms "inhibit" or "inhibition" refers to a specific response of a designated material (eg, enzyme activity) is comparatively decreased in the presence of a compound of the present invention. As used herein, the terms "cancer" or "cancerous" refers to any malignant proliferation of cells in a mammal. Examples include prostate cancers, benign prostatic hyperplasia, ovarian, breast, brain, lung, pancreatic, colorectal, gastric, stomach, solid tumors, head and neck, neuroblastoma, renal cell carcinoma, lymphoma, leukemia, other recognized malignancies of hematopoietic systems, and other recognized cancers. As used herein, the terms "neuron", "cells of the neuronal lineage" and "neuronal cell" refer to a heterogeneous population of neuronal types having single or multiple transmitters and / or single or multiple functions; preferably, those that are cholinergic and sensory neurons. As used herein, the phrase "cholinergic neuron" means neurons of the Central Nervous System (CNS) and Peripheral Nervous System (PNS) whose neurotransmitter is acetylcholine; Exemplary neurons are neurons of the basal forebrain and the spinal cord. As used herein, the phrase "sensory neuron" includes neurons responsive to environmental signals (e.g., temperature, movement) of, e.g., skin, muscle and joints; exemplary is a DRG neuron. As used herein, the term "trophic factor" refers to a molecule that directly or indirectly affects the survival or function of a cell responsive to the trophic factor. Exemplary trophic factors include Ciliary Neurotrophic Factor (CNTF), Basic Fibroblast Growth Factor (bFGF), insulin or insulin-like growth factors (eg, IGF-I, IGF-II, IG F-III), interferons, interleukins, cytokines, and neurotrophins, including Nerve Growth Factor (NGF), Neurotrophin-3 (NT-3), Neurotrophin-4/5 (NT-4/5) and Neurotrophic Factor Derivative of the Brain (BDNF).

As used herein, the term "trophic factor responsive cell" refers to a cell that includes a receptor to which a trophic factor can specifically bind; examples include neurons (e.g., cholinergic and sensory neurons) and non-neuronal cells (e.g., neoplastic cells and monocytes). As used herein, the terms "trophic factor activity" and "trophic factor induced activity" refer to both endogenous and exogenous trophic factors, where "endogenous" refers to a trophic factor normally present and "exogenous". "refers to a trophic factor added to a system. As defined, "activity induced by trophic factor" includes activity induced by (1) endogenous trophic factors; (2) exogenous trophic factors; and (3) a combination of endogenous and exogenous trophic factors. As used herein, the term "at risk of dying" in conjunction with a biological material, for example, a cell such as a neuron, refers to a condition or condition that negatively impacts the biological material such that the material has a decreased probability of dying due to such a condition or condition. For example, compounds described herein may "save" or improve the survival of motoneurons that are naturally at risk of dying in an in ovo model of programmed cell death. Similarly, for example, a neuron may be at risk of dying due to the natural aging process that causes the death of a neuron, or due to damage, such as a head trauma, which may be such that the neurons and / or glia, for example, impacted by such trauma may be at risk of dying. In addition, for example, a neuron may be at risk of dying as caused by ALS disease. In this way, improving the survival of a cell at risk of dying by the use of a compound of the claimed invention means that such a compound decreases or prevents the risk of cell death.

As used herein, the term "contacting" refers to directly or indirectly causing placement simultaneously to portions, such that the portions directly or indirectly enter into physical association with each other, thereby achieve a desired result. In this way, as used herein, one can "put in contact" a target cell with a compound as described herein even through the compound and the cell does not necessarily bind together physically (as, for example, it is the case where a ligand and a receptor physically bind together), since the desired result is achieved (e.g., improvement of cell survival). In this way contacting includes acting such as placing portions together in a container (e.g., adding a compound as described herein to a container comprising cells for in vitro studies) as well as administering the compound to an entity. target (e.g., injecting a compound as described herein in a laboratory animal for an in vivo test, or in a human being for therapy or treatment purposes). As used herein, a "therapeutically effective amount" refers to an amount of a compound of the present invention effective to prevent or treat the symptoms of a particular disorder. As used herein, the term "subject" refers to a warm-blooded animal such as a mammal, preferably a human being, or a human child, which is afflicted with, or has the potential to be afflicted with, the animal. one or more diseases and conditions described herein. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of firm medical judgment, suitable for contacting the tissues of humans and animals without excessive toxicityirritation, allergic response, or other problematic complications in proportion to a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by the preparation of acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, organic or mineral acid salts of basic residues such as amines; organic or alkaline salts of acidic residues such as carboxylic acids; and similar. The pharmaceutically acceptable salts include conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, of non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the prepared salts of organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroximic, phenylacetic, glutamic, benzoic, salicylic, sulfonic, 2-acetoxybenzoic, fumaric , toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like. The pharmaceutically acceptable salts of the present invention can be prepared from the main compound containing a basic or acid portion by conventional chemical methods. In general, such salts can be prepared by reacting the base or free acid forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the description of which is incorporated herein by reference. As used herein, the term "unit dose" refers to a single dose that is capable of being administered to a patient, and which can be easily handled and packaged, remaining as a physically and chemically stable unit dose that already comprises either the active compound itself, or as a pharmaceutically acceptable composition, as described hereinafter. As used herein, "prodrug" is intended to include any covalently linked carriers that release the active principal compound as defined in the present invention in vivo when such a prodrug is administered to a mammalian subject. Since prodrugs are known to improve numerous desirable qualities of pharmaceuticals (eg, solubility, bioavailability, manufacturing, etc.), the compounds of the present invention can be released in the form of a prodrug. In this way, the present invention contemplates prodrugs of the claimed compounds, compositions containing the same, and methods of releasing same. Prodrugs of a compound of the present invention can be prepared by modifying functional groups present in the compound in such a way that the modifications are dissociated, either in routine manipulation or in vivo, with the main compound. Accordingly, prodrugs include, for example, compounds of the present invention wherein a hydroxy, amino or carboxy group is attached to any group which, when the prodrug is administered to a mammalian subject, dissociates to form a free hydroxyl, amino free or carboxylic acid, respectively. Examples include, but are not limited to, acetate, formate and benzoate derived from alcohol and amine functional groups; and alkyl, carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, and phenethyl esters, and the like . It is recognized that the compounds of the present invention can exist in various stereoisomeric forms. As such, the compounds of the present invention include their respective diastereomers or enantiomers. The compounds are normally prepared as racemates and can conveniently be used as such, but individual diastereomers or enantiomers can be isolated or synthesized by conventional techniques if so desired. Such racemates and individual diastereomers or enantiomers and mixtures thereof form part of the present invention.

It is well known in the art how to prepare and isolate such optically active forms. Specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically pure or enantiomerically enriched starting materials. Specific stereoisomers of any starting materials or products can be resolved and recovered by techniques known in the art, such as resolution of racemic forms, reverse phase, normal, and chiral chromatography, recrystallization, enzymatic resolution, or fractional recrystallization of addition salts formed for reagents used for that purpose. Useful methods of resolution and recovery of specific stereoisomers described in Eliel, E. L .; Wilen, S.H. Stereochemistry of Organic Compounds; Wiley: New York, 1994, and Jacques, J, et al., Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, each incorporated by reference in the present in its totalities. It is further recognized that functional groups present in the compounds of the present invention may contain protecting groups. For example, the amino acid side chain substituents of the compounds of the present invention can be substituted with protecting groups such as benzyloxycarbonyl or t-butoxycarbonyl groups. Protective groups are known per se as chemical functional groups that can be selectively appended to and separated from functionalities, such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to give such inert functionality to chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups can be employed with the present invention. Preferred groups for protective lactams include silyl groups such as t-butyldimethylsilyl groups ("TBDMS"), dimethoxybenzhydryl ("DMB"), acyl, benzyl, and methoxybenzyl. Preferred groups for hydroxy protecting groups include TBS, acyl, benzyl ("Bn"), benzyloxycarbonyl ("CBZ"), t-butyloxycarbonyl ("Boc"), and methoxymethyl. Many different standard protecting groups employed by one skilled in the art can be found in Greene, T.W. and Wuts, P.G.M., "Protective Groups in Organic Synthesis" 2d. Ed., Wiley & Sons, 1991. Synthesis The general routes for preparing the examples shown in Tables 1-3 of the present invention are shown in Schemes 1-4. The intermediates used to prepare the examples and their mass spectral data are shown in Table B. Reagents and starting materials are commercially available, or easily synthesized by techniques well known to one of ordinary skill in the art. All processes described in association with the present invention are contemplated to be practiced on any scale, including milligrams, grams, multigrams, kilograms, multikilograms or commercial industrial scale. All substituents in the synthetic schemes, unless indicated otherwise, are as previously defined. Table B The general procedures for preparing the pyrrolocarbazoles of the present invention are described in U.S. Patent Nos. 5,705,511 ("the '511 patent") and 6,630,500, PCT Publication No. WO 00/47583, J. Heterocyclic Chemistry, 2001 , 38, 591, and J. Heterocyclic Chemistry, 2003, 40, 135. In general, the lactam nitrogen or intermediary alcohol groups of the intermediates described in Table B can be protected with such groups as acetyl, substituted silyl, benzyl, Boc, or dimethoxybenzhydrol. Intermediate I-23 (wherein R is hydrogen) used to prepare examples in Table 2 was prepared from the β-ketone, 2-methyl-1,4,6,7-tetrahydro-5H-indazol-5-one (Peet, NP; LeTourneau, ME; Heterocycles, 1991, 32, 41) using methods described in the '511 patent and in J. Heterocyclic Chemistry, 2003, 40, 135. Scheme 1 NC COaEt As shown in Scheme 1, N1-methyl-pyrazole derivatives were prepared in Table 3 from 1-methyl-α-ketone (J. Chem. Res., 1986, 1401). The N2-methy1-pyrazole intermediates were prepared according to the procedures in J. Heterocyclic Chem. 1992, 19, 1355.

Scheme 2 Intermediary 1-14 Examples 1-2, 70-72 Scheme 2 describes the route for preparing carbamate-type derivatives, such as Examples 1-2, and 70-72. An alternate method for preparing N, N-di-substituted carbamates is used in a nitrophenyl carbonate intermediate which can be treated with several primary or secondary amines. In a similar manner, urea, O-carbamate and N-carbamate derivatives may be prepared from the reaction of the appropriate amine or the phenol intermediate with an isocyanate or chloroformate or from nitrophenyl carbonate, nitrophenyl carbamate, or appropriate trichloromethylcarbonyl ( see J. Org. Chem. 2003, 68, 3733-3735).

Scheme 3 Example 19 Intermediary 1-29-1 Scheme 3 describes a route to prepare heteroaryl ethers from the corresponding phenol using a base such as sodium hydride and a heteroaryl chloride or bromide. Scheme 4 R = OR15 Examples 50-69 Intermediary 1-29 R = R20 Examples 74-82 Scheme 4 shows a route for the preparation of N-carbamates (Examples 50-69) or amides (Examples 74-82) from the corresponding aniline I-29 intermediates. Amino intermediates I-29 were prepared by alkylation of the appropriate cyano-esters with the appropriate alkyl bromide or iodide followed by nitration, and subsequent reduction of RaNi to provide the amino-lactam. The desired compounds were easily prepared from the amine. Heteroaryl ketones can be prepared using Friedel-Crafts type acylation reactions. Examples Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments as shown in the following Tables 1-5. The compounds of Tables 1-5 show activity in the targets described herein at concentrations ranging from 0.1 nM to 10 μM. These examples are given for illustration of the invention and are not intended to be limiting thereof.

Table 1 Table 2 * D R 1 is H, unless otherwise noted Table 3 Table 4 Example No. Structure EM m / e (M + 1) 98 555 99 487 100 459 101 500 Table 5 General procedure for Examples 1 and 2. A mixture of the intermediate phenol 1-14 (0.05 mmol), isocyanate (0.05 mmol), sodium hydrogen carbonate (0.5 mg) and tetrahydrofuran (0.5 ml) was stirred at room temperature for 1 day . The solvent was evaporated and the residue was stirred for 8 hours with ethyl acetate and 3N HCl. The ethyl acetate was removed by evaporation and the aqueous solution was decanted from the solid. The residue was triturated with methanol and the product was collected. Example 1. (26%) MS m / e 510 (M + 1); 1 H-NMR (DMSO-d 6) d 11.60 (s, 1 H), 8.33 (s, 1 H), 8.16 (d, 1 H), 7.63 (d, 1 H), 7.53 (s, 1 H), 7.51 (d, 1 H), 7.18 (d, 1H), 6.86 (s, 1H), 6.77 (d, 1h), 4.77 (s, 2H), 4.68 (m, 1H), 3.87 (m, 1H), 2.98 (t, 2H), 2.83 (t, 2H), 1.85 (m, 2H), 1.69 (m, 2H), 1.52 (m, 4H), 1.31 (d, 6H). Example 2. (36%) MS m / e 524 (M + 1); 1 H-NMR (DMSO-d 6) 11.59 (s, 1 H), 8.33 (s, 1 H), 8.16 (d, 1 H), 7.63 (s, 1 H), 7.52 (d, 1 H), 7.17 (d, 1 H), 6.86 (s, 1H), 6.78 (d, 1h), 4.77 (s, 2H), 4.68 (m, 1H), 3.00 (t, 2H), 2.83 (t, 2H), 1.87 (m, 2H), 1.72 ( m, 2H), 1.56 (d, 1H), 1.30 (d, 6H). Example 3. A suspension of sodium hydride (2.44 mg, 1.22 eq.) In 0.5 mL of THF was added dropwise under N2 as an intermediate of phenol 1-14 (20.6 mg, 0.05 mmol) in 2.0 mL of THF: DMF (1: 1). After 10 minutes of stirring, 2-bromopyrimidine (8.9 mg, 1.12 equivalents) in 0.5 mL of THF was added. The mixture was stirred at 60 ° C for 14 hours. The mixture was cooled to room temperature, diluted with CH2Cl2 / MeOH, filtered through celite and concentrated. Purification by preparative TLC (preparative thin layer chromatography) with CH2Cl2 / MeOH (9: 1) was achieved to produce the product (4.0 mg, 17%) (MS: 477 m / e (M + H) +). Example 4. The compound was prepared according to the procedure of Example 3 using the intermediate of phenol 1-14 and 2-chlorobenzoxazole; 40 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); 28% yield; MS: 516 m / e (M + 1) +. Example 5. The compound was prepared according to the procedure of Example 3 using intermediate 1-14 and 2-chlorobenzothiazole; 40 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); 13% yield; MS: 531 m / e (M + 1) +. Example 6. To a mixture of Example 3 (25.0 mg, 0.052 mmol) and cesium carbonate (81 mg, 5.0 eq.) In 2.0 mL of CH3CN was added n-propyl bromide (47 ul, 10.0 eq.) Under N2. . After stirring at 90 ° C for 14 hours, the mixture was diluted with CH 2 Cl 2, filtered through celite and concentrated. Purification by preparative TLC with 95% CH2Cl2 / MeOH produced the product (15.0 mg, 56%); MS: m / e 519 (M + 1) +. Example 7. The compound was prepared using the procedure of Example 3 using intermediate 1-14 and 2-bromopyrazine; Preparative TLC (10% MeOH in CH 2 Cl 2); MS 499 m / e (M + 1) +. Example 8. The compound was prepared according to the procedure of Example 6 using Example 7 as a starting material. MS m / e 519 (M + 1). Synthesis of the phenol intermediates 1-18 and 1-19. A mixture of AlCl 3 (800 mg, 6 mmol) in dichloromethane (8 mL) was stirred at 0 ° C as EtSH (1.40 mL) was added and followed by intermediate 1-41 (398 mg, 1 mmol). The reaction was stirred at 50 ° C for 48 hours. To the reaction mixture was added 5 mL of 1 N HCl and the mixture was stirred at room temperature for 0.5 hour. Filtration gave 240 mg (63%) of intermediate 1-18 (MS: 385 m / e (M + 1) +.) By a similar method, intermediate 1-19 was prepared from the NH methoxy derivative. 10. A suspension of sodium hydride (12.2 mg, 1.22 eq.) In 0.5 mL of THF was stirred under N2 as an intermediate of phenol 1-18 (76.8 mg, 0.2 mmol) in 4.0 mL of THF: DMF (1: 1). ) was added dropwise at room temperature.

After 10 minutes of stirring, chloro-benzothiazole (38 mg, 1.12 eq.) In 0.5 mL of THF was added. The mixture was then stirred at 60 ° C for 40 hours, diluted with CH2Cl2 / MeOH, filtered through celite and concentrated. Purification by preparative TLC with CH2Cl2 / MeOH (9: 1) yielded the mono product of Example 9 (6.0 mg, 6% yield) (MS: 517 m / e (M + H) +) and the dialkylated product of Example 10 (60 mg, 46% yield) (MS: 651 m / e (M + H) +). Example 11. The compound was prepared according to the procedure of Example 10 using the intermediate of phenol 1-18 and 2-chlorobenzoxazole; 36 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); 11% yield; MS: 502 m / e (M + 1) +. Example 12. The compound was prepared according to the procedure of Example 10 using intermediate 1-19 and 2-bromopyrimidine; 36 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); 25% yield; MS: 419 m / e (M + 1) +. Example 13. The compound was prepared according to the procedure of Example 3 using the intermediate of phenol I-22 and 2-bromopyrimidine; 30 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); 53% yield; MS: 423 m / e (M + 1) +. Example 14. The compound was prepared according to the procedure of Example 6 using Example 13 and iodoethane; 14 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); 19% yield; MS: 451 m / e (M + 1) +. Example 15. The compound was prepared according to the procedure of Example 6 using Example 13 and iodomethane; 14 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); 28% yield; MS: 459 m / e (M + 23) +. Example 16. The compound was prepared according to the procedure of Example 6 using Example 13 and cyclopentyl bromide; 14 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); 38% yield; MS: 513 m / e (M + 23) +.

Example 17. A mixture of the phenol intermediate I-22 (17.2 mg, 0.05 mmol), potassium t-butoxide (33.7 mg, 6 eq.) And t-butylammonium bromide (0.97 mg, 0.06 eq.) Was mixed and stirred for 5 minutes, then 1.0 mL of chloropyrazine, then stirred at room temperature for 5 minutes and at 90 ° C for 1 hour. The mixture was cooled to room temperature, the excess chloropyrazine was evaporated and the resulting residue was diluted with CH2Cl2 / MeOH. Preparative purification with CH2Cl2 / MeOH (9: 1) yielded the mono-product (11.0 mg, 52% yield) MS: 423 m / e (M + 1) +. Example 18. The compound was prepared according to the procedure of Example 6 using Example 13 and butyl bromide; 14 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); 38% yield; MS: 479 m / e (M + 1) +.

Example 19. The compound was prepared according to the procedure of Example 10 using Example 13 and 2-propyl bromide; 60 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); 10% yield; MS: 465 m / e (M + 1) +. Example 20. The compound was prepared according to the procedure of Example 6 using Example 13 and 2-cyclopropylmethyl bromide; 14 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); 5% yield; MS: 477 m / e (M + 1) +. Example 21. The compound was prepared according to the procedure of Example 6 using Example 13 and 2-cyclopropylmethyl bromide; 14 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); MS: 507 m / e (M + 1) +. Example 22. The compound was prepared according to the procedure of Example 6 using Example 13 and isobutyl bromide; Preparative TLC (10% MeOH in CH 2 Cl 2); MS: 493 m / e (M + 1) +. Example 23. The compound was prepared according to the procedure of Example 6 using Example 17 and ethyl iodide; Preparative TLC (10% MeOH in CH 2 Cl 2); MS: 451 m / e (M + 1) +. Example 24. The compound was prepared according to the procedure of Example 6 using Example 13 and 1-bromo-3,5-dimethoxytriazine; Preparative TLC (10% MeOH in CH 2 Cl 2); MS: 540 m / e (M + 1) +.

Example 25. To 25 mg (0.07 mmol) of intermediate 1-23-1 of N-ethyl in methylene chloride / nitromethane (3 mL / 2 mL) was slowly added 2-furoyl chloride (69 μL)., 0.7 mmol, 10 eq.) Followed by aluminum chloride (93 mg, 0.7 mmol, 10 eq.). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated, water and a few drops of 1 N HCl were added to the residue and the mixture was extracted with methylene chloride. The combined organic extracts were dried with sodium sulfate, the drying agents were removed by filtration, and the solvent was removed by evaporation. The crude mixture was dissolved in methanol / methylene chloride and purified by preparative TLC eluting with 10% methanol / methylene chloride. The desired band was collected, stirred with methylene chloride / methanol, filtered through a porous funnel, and concentrated. The sample was dried at 80 ° C under high vacuum overnight. MS: m / e 451 (M + 1) +. Example 26. The compound was prepared by the method described in Example 25. MS: m / e 438 (M + 1) +. Example 27. To the N-ethyl intermediate I-23-I (25 mg, 0.07 mmol) in nitromethane (5 mL) was added 2-thiophene-carbonyl chloride (75 μL, 0.7 mmol, 10 eq.) Followed by addition of small portions of aluminum chloride (94 mg, 0.7 mmol, 10 eq.). The reaction mixture was stirred at room temperature overnight. The reaction was then concentrated, stirred with water and a few drops of 1N HCl were added. The product was collected by filtration, dissolved in methylene chloride / methanol and purified by preparative TLC eluting with 10% methanol / methylene chloride. The desired band was collected, stirred with methylene chloride / methanol, filtered, and concentrated. The sample was dried at 80 ° C under vacuum overnight. MS: m / e 467 (M + 1). Examples 28-49 were prepared using the general method described by Example 27 using the appropriate N-alkyl I-23 intermediate, and heteroaryl acid chloride with AICI3 or FeCI3 as a catalyst. Example 28. MS m / e 423 Example 29. MS m / e 465 Example 30. MS m / e 479 Example 31. MS m / e 495 Example 32. MS m / e 463 Example 33. MS m / e 509 Example 34 MS m / e 481 Example 35. MS m / e 530 Example 36. MS m / e 495 Example 37. MS m / e 479 Example 38. MS m / e 574 Example 39. MS m / e 481 Example 40. MS m / e 481 Example 41. MS m / e 608 Example 42. MS m / e 588 Example 43. MS m / e 536 M + Example 44. MS m / e 520 M + Example 45. MS m / e 509 M + Example 46. MS m / e 592 M + Example 47. MS m / e 550 M + Example 48. MS m / e 550 M + Example 49. MS m / e 570; M + 1) Example 50. To a stirred solution of the intermediate I-29-2 of 3-amino (25 mg, 0.0649 mmol) in CH 2 Cl 2 (5 mL) was added isopropyl chloroformate (1.0 M in toluene, 125 μL, 0. 125 mmol) and pyridine (20 μL, 0.247 mmol). After shaking 3 hours at room temperature, the resulting precipitate was filtered and dried to give 28 mg (91%) of the desired product. H-NMR (DMSO-d6) d 9.51 (s, 1H), 8.85 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.61-7.49 (m, 2H), 4.98 (m, 1H) ), 4.68 (s, 2H), 4.51 (m, 2H), 3.86 (s, 3H), 3.45 (m, 2H), 2.83 (m, 2H), 1.80 (m, 2H), 1.29 (m, 6H) 0.89 (m, 3H); MS (m / e) 472 (M + 1).

Example 51. MS m / e 458 (M + H). Example 52. MS m / e 486 (M + H). Example 53. MS m / e 472 (M + H). Example 54. MS m / e 476 (M + H). Example 55. MS m / e 492 (M + H). Example 56. MS m / e 458 (M + H). Example 57. MS m / e 500 (M + H). Example 58. MS m / e 486 (M + H).

Example 59. MS m / e 486 (M + H). Example 60. MS m / e 472 (M + H). Example 61. MS m / e 472 (M + H). Example 62. MS m / e 536 (M + H). Example 63. MS m / e 490 (M + H). Example 64. MS m / e 506 (M + H). Example 65. MS m / e 550 (M + H). Example 66. MS m / e 486 (M + H). Example 68. To 25 mg (0.045 mmol) of the N-p-nitrophenyl intermediate was added N-piperidinyl ethane (500 μl). The reaction was stirred at room temperature for about 5 hours, diluted with methylene chloride, washed with water / brine and dried over sodium sulfate. The crude product was purified by preparative TLC eluting with 8-10% MeOH / CH 2 Cl 2. The crude product was collected, stirred with solvent, filtered, and concentrated. The sample was dried at 80 ° C under high vacuum. 1 H NMR (DMSO-d 6) d 9.80 (s, 1 H), 8.77 (s, 1H), 8.36 (s, 1H), 8.10 (s, 1H), 7.72 (d, 1H), 7.50 (d, 1H), 5.20 (m, 1H), 4.78 (s, 2H), 4.19 (m, 2H), 3.86 (s, 3H), 2.78 (m, 2H), 2.41 (m, 4H), 1.59 (d, 6H), 1.40 ( m, 10H); MS (m / e) 541 (M + 1).

Example 67. The compound was prepared by the method described for Example 68 using the intermediate of N-p-nitrophenyl and N-pyrrolidinyl ethanol. MS (m / e) 527 (M + 1). Example 69. The compound was prepared by the method described for Example 68 using the intermediate of N-p-nitrophenyl and N-pyrrolidinyl ethanol. MS (m / e) 538 (M + 1). Example 70. Step 1: O-Nitrophenylcarbonate Intermediate: A mixture of the 1-33-1 intermediate of phenol (192 mg, 0.525 mmol) and p-nitrophenyl carbonate (314 mg, 1.03 mmol) in DMF (4 mL) is heated at 100 ° C for 20 hours. The solvent was removed by rotary evaporation and the residue was extracted into CH2Cl2 and washed with aqueous NaHCO3. The organic layer was dried over MgSO 4, filtered and evaporated. The resulting residue was purified by column chromatography (silica gel, 3% MeOH in CH 2 Cl 2) to yield the carbonate intermediate (156 mg, 56%). 1 H NMR (CDCl 3) d 8.86 (s, 1 H), 8.34 (d, 2 H, J = 9.1), 7.69 (d, 1 H, J = 2.1), 7.53 (d, 2 H, J = 9.1), 7.49, (d , 1H, J = 8.8), 7.41, (d, 1H, J = 8.8), 6.01 (s, 1H), 4.84 (s, 2H), 4.62 (q, 2H, J = 7.1), 3.96 (s, 3H) ), 3.55 (t, 2H, 8.0), 3.01 (t, 2H, J = 8.0), 1.55 (t, 3H, J = 7.1). MS (m / e) 538 (M + H). Step 2: A suspension of the carbonate intermediate (52 mg, 97 umol) in THF (2 mL) was treated with pyrrolidine (20 uL, 227 umol). The mixture was heated at 40 ° C for 2 hours. The solvent was removed by rotary evaporation, and the residue was extracted into CH 2 Cl 2 and washed with dilute aqueous NaOH. The organic layer was dried over MgSO, filtered, and evaporated. The resulting residue was purified by trituration with water (2 x 1 mL) and ether (2 x 1 mL). 1 H NMR (CDCl 3) d 8.86 (s, 1 H), 7.55 (d, 1 H, J = 2.1), 7.40 (d, 1 H, J = 8.8), 7.26 (d, 1 H, J = 8.8), 6.01, (s , 1H), 4.78 (s, 2H), 4.57 (q, 2H, J = 7.1), 3.95 (s, 3H), 3.65 (t, 2H, 7.0), 3.55-3.45 (m, 4H), 2.99 (t , 2H, J = 7.0), 2.02-1.96 (m, 4H), 1.53 (t, 3H, J = 7.1). MS (m / e) 470 (M + H). Example 71. MS m / e 498 (M + H). Example 72. MS m / e 484 (M + H). Example 73. MS m / e 555 (M + H). Example 74. To 20 mg (0.052 mmol) of the intermediate 1-29-1 of amine in 2 mL of CH 2 Cl 2 / 12.6 μl of pyridine were added 28 mg (0.156 mmol, 3 eq.) Of nicotinoyl chloride. The reaction was heated to 49 ° C for 1 hour, cooled to room temperature, concentrated, was stirred with ether, and the solid was filtered. The solid was taken up in CH2Cl2 / MeOH and purified on preparative TLC by eluting with 10% MeOH / CH2Cl2. The pure product was collected and dried at 80 ° C under high vacuum. H NMR (DMSO-d6) d 10.53 (s, 1H), 9.18 (s, 1H), 8.79 (s, 2H), 8.40 (m, 3H), 7.83 (s, 2H), 7.6 (m, 1H), 5.25 (m, 1H), 4.74 (s, 2H), 3.87 (s, 3H), 3.41 (m, 2H), 2.80 (m, 2H), 1.61 (d, 6H). MS (m / e) 491 (M + 1). Examples 75-82 were prepared by the method described for Example 74 using the appropriate I-29 amine intermediate and acid chloride. Example 75. MS m / e 496 (M + H). Example 76. MS m / e 480 (M + H). Example 77. MS m / e 491 (M + H). Example 78. MS m / e 491 (M + H).

Example 79. MS m / e 510 (M + H). Example 80. MS m / e 494 (M + H). Example 81. MS m / e 481 (M + H). Example 82. MS m / e 495 (M + H). Example 83. The compound was prepared using the N-sec-butyl intermediate I-36 and 2-thiophenecarbonyl chloride by the general procedure described for Example 25. MS (m / e) 495 (M + H). Example 84. The compound was prepared using the intermediate of N-sec-butyl-indazole I-36 and 2-furoyl chloride by the general procedure described for Example 25. MS (m / e) 479 (M + H). Example 85. The compound was prepared using intermediate I-39 by the general procedure described for Example 13. MS (m / e) 479 (M + H). General Procedure A for Examples 136-140. A solution of diol intermediate I in the appropriate alcohol (0.05 M) in a sealable glass reaction tube was added camphorsulfonic acid (1.1 equiv.). The reaction tube was flushed with nitrogen and sealed. The reaction mixture was heated at 80 ° C for 2-26 hours and monitored for loss of starting material by CLAP (HPLC). After the completion of the reaction, the mixture was cooled to room temperature and poured into ether. The precipitate that formed was collected by filtration and purified by flash chromatography or preparative TLC on silica gel using ethyl acetate or a mixture of ethyl acetate and hexane to provide the pure products. The following Examples were prepared. Example 136. Tan solid (yield of 58%). 1 H NMR (CDCl 3, 300 MHz): d 2.03 (m, 2H), 2.13 (m, 2H), 2. 40 (m, 2H), 3.56 (m, 4H), 3.72 (m, 4H), 4.37 (s, 2H), 4.71 (s, 4H), 4.89 (s, 2H), 6.12 (s, 1H), 7.34 -7.62 (6H, m), 7.99 (s, 1H), 9.53 (d, 1H). MS (ESI): (m / e) 510 (M + 1) +; Example 137. (71% yield). 1 H NMR (CDCl 3, 300 MHz): d 1.97 (t, 2H), 3.61 (t, 2H), 3.79 (m, 4H), 4.14 (s, 2H), 4. 41 (m, 4H), 4.62 (s, 2H), 4.76 (s, 2H), 6.10 (s, 1H), 7.28-7.57 (m, 11 H), 7.68 (s, 1H), 9.47 (d, 1H) ). MS (ESI): (m / e) 533 (M + 1) +; 555 (M + Na) +. Example 138. (19% yield). 1 H NMR (CDCl 3, 300 MHz): d 1.66 (m, 1H), 2.01-2.22 (m, 3H), 2.67 (m, 1H), 3.51 (m, 2H), 3.74 (m, 4H), 3.88 (m, 2H), 4.38 ( s, 2H), 4.71 (s, 2H), 4.72 (m, 2H), 4.90 (s, 2H), 6.07 (s, 1H), 7.36 (t, 1H), 7.44-7.68 (m, 5H), 7.80 (s, 1H), 9.53 (d, 1H). MS (ESI): (m / e) 483 (M + 1) +; Example 139. (21.2 mg) 1 H-NMR (CDCl 3, 300 MHz): d 1.95 (m, 2 H), 2.04 (s, 3 H) 2.68 (t, 2 H), 3.49 (m, 2 H), 3.64 (t, 2 H) , 4.52 (s, 2H), 4.66 (s, 2H), 4.73 (m, 2H), 4.90 (s, 2H), 7.27-7.43 (m, 2H), 7.48 (d, 1H), 7.63 (d, 1H) ), 7.69 (d, 1H), 7.94 (s, 1H), 8.55 (s, 1H), 9.46 (d, 1H); MS (ESI): (m / e) 473 (M + 1) +; Example 140. Off white solid (25% yield). 1 H NMR (CDCl 3, 300 MHz): d 1.93 (m, 2 H), 3.22 (s, 3 H), 3.46 (m, 4 H), 3.58 (m, 2 H), 4.49 (s, 2 H), 4.64 (s, 2 H) ), 4.70 (m, 2H), 4.78 (m, 1H), 4.87 (s, 2H), 7.23-7.43 (m, 2H), 7.47 (d, 1H), 7.62 (d, 1H), 7.70 (d, 1H), 7.89 (s, 1H), 8.54 (s, 1H), 9.46 (d, 1H); General Procedure B of Examples 141-144. In a sealed reaction tube, a suspension of diol intermediate I (1 equivalent) in either the appropriate alcohol or methylene chloride or chloroform containing the appropriate alcohol, at room temperature was slowly added trifluoroacetic anhydride (1-2 equiv. ). The tube was flushed with nitrogen and tightly sealed. The mixture was stirred at room temperature for 1-2 hours then heated at 80 ° C for 2-60 hours and monitored for disappearance of the starting material by CLAP. After completion the reaction was allowed to cool to room temperature, concentrated and worked up by triturating the residue with ether and collecting the resulting precipitate by filtration, or extracting the product from the reaction mixture with a suitable organic solvent. The solid product was purified by trituration with ether or flash chromatography on silica gel using ethyl acetate or a mixture of ethyl acetate and hexane. The following Examples were prepared. Example 141. Light yellow solid (17% yield). 1 H NMR (DMSO-de, 300 MHz): d 1.93 (m, 2H), 3.45 (m, 6H), 3.58 (s, 4H), 4.53 (s, 2H), 4.56 (m, 1H), 4.65 (s) , 2H), 4.74 (m, 3H), 4.91 (s, 2H), 7.33-7.39 (m, 2H), 7.48 (d, 1H), 7.63-7.71 (m, 2H), 7.92 (s, 1H), 8.55 (s, 1H), 9.47 (d, 1H); MS (ESI): (m / e) 487 (M + 1) +, 509 (M + Na) +. Example 142. Pale yellow solid (26% yield). 1 H-NMR (CDCl 3, 300 MHz): d 1.33 (d, 3 H), 2.11 (m, 2 H), 3.19 (m, 1 H), 3.56-3.77 (m, 4 H), 4.30 (s, 2 H), 4.65 (m , 2H), 4.68 (s, 2H), 4.74 (s, 2H), 6.07 (s, 1H), 7.20-7.50 (m, 1H), 7.56 (d, 1H), 7.69 (s, 1H), 9.48 ( d, 1 H); MS (ESI): (m / e) 517 (M + 1) +, 539 (M + Na) +. Example 143. Orange residue (21% yield). 1 H NMR (300 MHz DMSO-d 6l): d 1.93 (m, 2H), 2.30 (m, 4H), 2.50 (m, 2H), 3.48 (m, 6H), 3.94 (s, 2H), 4.52 (s, 2H), 4.72 (m, 4H), 4.88 (s, 2H), 7.33-7.43 (m, 2H), 7.48 (d, 1H), 7.66 (m, 2H), 7.88 (s, 1H), 8.57 (s) , 1H), 9.46 (d, 1H); MS (ESI): (m / e) 528 (M + 1) +. Example 144. Light orange solid (9% yield). 1 H NMR (DMSO-d 6, 300 MHz): d 1.29 (m, 2 H), 1.39 (m, 4 H), 1.95 (m, 2 H), 2.26 (m, 4 H), 2.51 (m, 2 H), 3.47 (m , 2H), 3.94 (s, 2H), 4.52 (s, 2H), 4.72 (m, 4H), 7.88 (s, 2H), 7.33-7.39 (m, 2H), 7.47 (d, 1H), 7.66 ( m, 2H), 7.88 (s, 1H), 8.57 (s, 1H), 9.46 (d, 1H); MS (ESI): (m / e) 526 (M + 1) +. General Procedure C for Examples 145-156: To a well-stirred suspension of intermediates I, II or III of CH2OH in 7 mL of methylene chloride were added sequentially trifluoroacetic anhydride (5 equivalents) and N-methylmorpholino (5 eq.) at 5 ° C and under an argon atmosphere. The resulting suspension was stirred at room temperature for 3 hours and the low boiling solvents were removed under vacuum. A stirred solution of this trifluoroacetate intermediate in an appropriate alcohol was heated at 80 ° C for 6-48 hours in an oil bath. Gradually, the heterogeneous reaction mixture became homogeneous. When no starting material was observed by CLAP, the reaction mixture was worked up by removing the solvent in vacuo. The residue was purified by either trituration with water or ether or alternatively, flash chromatography or preparative plate chromatography on silica gel using ethyl acetate or a mixture of ethyl acetate / hexane. Example 145. (12.6 mg, 44% yield). 1 H-NMR (CDCl 3, 300 MHz): d 2.18 (m, 2 H), 2.09 (m, 1 H), 3.73 (m, 4 H), 4.42 (s, 2 H), 4.76 (s, 2 H), 4.80 (m, 2 H) ), 4.98 (s, 2H), 6.12 (s, 1H), 7.23 (m, 2H), 7.43 (m, 2H), 7.48 (m, 2H), 7.68 (m, 1H), 7.88 (s, 1H) 9.56 (d, 1H); MS (ESI): (m / e) 451 (M + 1) +, 473 (M + Na) +. Example 146. Light orange solid (35.3 mg, 74% yield). 1 H NMR (DMSO-d 6, 300 MHz): d 1.23 (m, 2 H), 1.50 (m, 4 H), 1.67 (m, 2 H), 1.93 (m, 2 H), 2.13 (m, 1 H), 3.35 (m , 2H), 3.48 (m, 2H), 4.52 (s, 2H), 4.62 (s, 2H), 4.72 (m, 2H), 4.89 (s, 2H), 7.33-7.39 (m, 2H), 7.47 ( d, 1H), 7.62-7.70 (m, 2H), 7.90 (d, 1H), 8.53 (s, 1H), 9.47 (d, 1H); MS (ESI): (m / e) 481 (M + 1) +. Example 147. Pale yellow solid (31 mg, 54% yield). 1 H NMR (DMSO-d 6, 300 MHz): d 0.05 (m, 2 H), 0.49 (m, 2 H), 1.06 (m, 1 H), 2.79 (m, 2 H), 3.82 (m, 5 H), 4.65 (m , 4H), 4.79 (s, 2H), 4.97 (t, 1H), 6.80 (d, 1H), 6.89 (s, 1H), 7.46 (d, 1H), 7.65 (d, 1H), 7.87 (s, 1H), 7.89 (d, 1H), 8.36 (s, 1H); MS (ESI): (m / e) 483 (M + 1) +. Example 148. Pale orange solid (12.4 mg, 24% yield). 1 H NMR (DMSO-d 6, 300 MHz): d 2.79 (m, 2 H), 3.12 (t, 2 H), 3.30 (m, 2 H), 3.72 (t, 2 H), 3.82 (m, 5 H), 4.65 (m , 2H), 4.70 (s, 2H), 4.76 (s, 2H), 4.97 (t, 2H), 6.79 (d, 1H), 6.90 (s, 1H), 6.93 (s, 1H), 6.97 (d, 2H), 7.35 (s, 1H), 7.46 (d, 1H), 7.65 (d, 1H), 7.89 (d, 2H), 8.39 (s, 1H); MS (ESI): (m / e) 539 (M + 1) +. Example 149. Pale yellow solid (42.6 mg, 57% yield). 1 H NMR (DMSO-d 6, 300 MHz): d 2.55 (m, 2 H), 2.80 (t, 2 H), 3.86 (m, 4 H), 3.98 (s, 2 H), 4.61 (s, 1 H), 4.73 (t , 1H), 4.80 (s, 2H), 4.98 (t, 1H), 6.78 (d, 1H), 6.89 (s, 1H), 7.50 (d, 1H), 7.68 (d, 1H), 7.88 (s, 1H), 7.90 (d, 1H), 8.38 (s, 1H); MS (ESI): (m / e) 489 (M + 1) +, 512 (M + Na) +. Example 150. Yellow-cinnamon solid (77% yield). 1 H NMR (DMSO-d 6, 300 MHz): d 0.2 (m, 2 H), 0.47 (m, 2 H), 1.05 (m, 1 H), 1.94 (m, 2 H), 3.49 (m, 2 H), 4.53 (s) , 2H), 4.64 (s, 2H), 4.75 (m, 2H), 4.92 (s, 2H), 7.32-7.45 (m, 2H), 7.49 (d, 1H), 7.62-7.77 (m, 2H), 7.93 (s, 1H), 8.64 (s, 1H), 9.47 (d, 1H); MS (ESI): (m / e) 453 (M + 1) +. Example 151. Solid tan color (32% yield). 1 H NMR (DMSO-d 6, 300 MHz): d 1.97 (m, 4 H), 3.51 (s, 2 H), 3.73 (t, 2 H), 4.56 (s, 2 H), 4.71 (s, 2 H), 4.77 (m , 2H), 4.91 (s, 2H), 6.98 (m, 2H), 7.35-7.43 (m, 3H), 7.52 (d, 1H), 7.70 (m, 2H), 7.96 (s, 1H), 8.60 ( s, 1H), 9.51 (d, 1H); MS (ESI): (m / e) 509 (M + 1) +. Example 152. Yellow solid (69%). 1 H NMR (DMSO-d 6, 300 MHz): d 1.62-2.00 (m, 8H), 2.54 (m, 1H), 3.38-3.50 (m, 4H), 4.51 (s, 2H), 4.61 (s, 2H) , 4.72 (m, 2H), 4.89 (s, 2H), 7.3-7.41 (m, 2H), 7.46 (d, 1H), 7.62-7.70 (m, 2H), 7.89 (s, 1H), 8.53 (s) , 1H), 9.47 (d, 1H); MS (ESI): (m / e) 467 (M + 1) +. Example 153. (80%). 1 H-NMR (DMSO-d 6, 300 MHz): d 1.55 (m, 3 H), 3.4-3.8 (m, 6 H), 4.14 (m, 2 H), 4.66 (s, 2 H), 4.91 (s, 2 H), 7.29 -7.73 (m, 5H), 7.98 (s, 1H), 8.55 (s, 1H), 9.39 (d, 1H), 11.94 (s, 1H). Example 154. (150 mg, 89% yield). 1 H NMR (DMSO-de, 300 MHz): d 1.80 (m, 4H), 3.58-3.78 (m, 4H), 4.02 (m, 1H), 4.18 (s, 2H), 4.69 (s, 2H), 4.93 (s) , 2H), 7.34-7.49 (m, 2H), 7.56 (t, 2H), 7.70 (d, 1H), 7.94 (s, 1H), 8.53 (s, 1H), 9.39 (d, 1H), 11.92 ( s, 1H). Example 155. 1 H NMR (DMSO-d 6, 300 MHz): d 3.24 (s, 3 H), 3.47 (m, 2 H), 3.58 (m, 2 H), 4.13 (m, 2 H), 4.62 (s, 2 H), 4.89 (s, 2H), 7.30-7.42 (m, 3H), 7.56 (d, 1H), 7.64 (d, 1H), 7.91 (s, 1H), 8.51 (s, 1H), 9.35 (d, 1H) 11.89 (s, 1H); MS (ESI): (m / e) 421 (M + Na) +. Example 156. (10%). MS (m / e) 429 (M + 1). 1H NMR (DMSO-de) 11-79 (s, 1H), 9.20 (d, 1H), 8.44 (s, 1H), 7.87 (s, 1H), 7.52 (d, 1H), 7.38 (d, 1H), 7.24 (s, 1H), 6.96 (d, 1H), 4.86 (s, 2H), 4.61 (s, 2H), 4.08 (s, 2H), 3.81 (s, 4H), 3.58 (d, 1H), 3.52 (s, d, 1H). Example 157. A stirred solution of Example 155 (370 mg, 0.93 mmol) in DMF (20 mL) was placed under vacuum and DMF (10 mL) was removed by distillation. The mixture was cooled to room temperature and sodium hydride (45 mg, 0.93 mmol) was added and stirred for 30 minutes. Glycidol mesylate (170 mg, 1.1 mmol) was added and the mixture was heated to 60 ° C. After 18 hours, the mixture was cooled to room temperature, filtered, and concentrated in vacuo. The solid was triturated with methanol, filtered, and purified by flash chromatography on silica gel using hexane / ethyl acetate (1: 1) then methanol / ethyl acetate (10%) to give the product (90 mg, yield 22%). MS (ESI): (m / e) 455 (M + 1) +. Example 158. To a stirred solution of Example 157 (80 mg, 0.18 mmol) in THF (10 mL) super hydride (724 uL, 0.72 mmol) was added dropwise at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction solvent was removed in vacuo and HCl was added. The mixture was stirred, filtered, triturated with methanol and collected by filtration. The solid was purified by flash chromatography using hexane / ethyl acetate (3: 1) to ethyl acetate (100%). Further purification of the solid crystallization involved ethyl acetate / methanol followed by acetonitrile to give the product (40 mg, 50% yield). MS (ESI): (m / e) 457 (M + 1) +. Example 159. Using the general procedure for the Example 158, an ester suspension (1.45 g, 2.27 mmol) in methylene chloride (30 mL) was cooled to 0 ° C and DIBAL-H (5.7 mL, 5.7 mmol) was added dropwise. The reaction mixture was warmed to room temperature for 2 hours, then quenched with methanol (20 mL). HCl (1N, 20 mL) was added and the reaction solvent was removed in vacuo to give the product as a yellow solid (1.2 g, 78% yield >). Alcohol (522 mg, 0.92 mmol), trifluoroacetic anhydride (130 uL), methoxyethanol (4 mL) and methylene chloride (6 mL) were combined and heated at 70 ° C for 18 hours. Additional trifluoroacetic anhydride (100 ul) was added and heated for 24 hours. The reaction solvent was removed in vacuo and the solid was triturated with methanol to give the product as a yellow solid (325 mg, 91% yield). A solution of the previous product (100 mg, 0.16 mmol) in methylene chloride (3 mL) / methanol (1 mL) / hexamethylphosphoramide (500 uL) was added cesium carbonate (212 mg.0.65 mmol). The reaction mixture was stirred at room temperature for 20 minutes, and acetaldehyde was added and the mixture was stirred for 18 hours. Additional cesium carbonate and acetaldehyde were added and the mixture was stirred for 3 hours. The mixture was diluted with methylene chloride, washed with water and brine, and purified by flash chromatography on silica gel using ethyl acetate / methylene chloride (10%) to give the product (45 mg, 43% yield ). The product (45 mg) was dissolved in methylene chloride (4 mL) and ethanethiol was added followed by trifluoroacetic anhydride at 0 ° C. After 1.5 hours, the reaction solvent was removed in vacuo and the material was purified by flash chromatography on silica gel using methanol / ethyl acetate (10% to give the product (11 mg, 37% yield). ESI): (m / e) 443 (M + 1) + Example 160. To trifluoroacetate (27 mg) prepared using the general method C was added 1 ml of 2-methoxyethanol and the reaction was heated to 90 ° C in a sealed tube for 2 hours The reaction was concentrated, the product was triturated with ether, collected and dried 1 H NMR (400MHz, DMSO) d 8.38 (1H, s), 7.89 (2H, d), 7.66 (1H , d), 7.47 (1H, d), 6.90 (1H, s), 6.81 (1H, d), 4.98 (2H, m), 4.79 (1H, s), 4.67 (3H, m), 3.96 (6H, m), 3.82 (2H, m), 3.62 (2H, m), 3.50 (3H, m), 3.10 (2H, m), 2.79 (2H, m) MS m / e 487 (M + 1) + Example 161 To the amino-methyl Xll intermediate CEP7668 (30 mg, 0.066 mmol) in THF (1 mL) was added TEA (9 μL, 0.066 mmol), followed by benzyl chloroformate (9 μL, 0.066 mmol) and the The reaction mixture was stirred at room temperature overnight. Additional TEA and benzyl chloroformate were added while heating at 50 ° C. The reaction was concentrated, dissolved in ethyl acetate, washed with sodium bicarbonate, brine and dried over magnesium sulfate. The drying agent was removed by filtration and the solvent was evaporated. The product was purified by preparative TLC using 2% methanol / methylene chloride. The product was collected and dried at 80 ° C overnight. MS m / e = 590 (m + 1) +. Example 162. This compound was prepared using the general procedure as Example 161 starting with the intermediate XIII of 3-aminomethyl-N-ethanol. MS m / e 540 (m + 1) +. Example 163. This compound was prepared from intermediate Xll and isocyanate-ethyl acetate. MS m / e 513 (m + 1) +. Example 164. The phenol X intermediate CEP 7143 (15 mg, 0.037 mmol), bromoethylethylether (66 mg, 0.57 mmol) (added in 3 portions), acetone (7 mL) and 10N sodium hydroxide (4 mL) were stirred at room temperature for 7 hours. The acetone was evaporated and the solution was acidified to pH 3. The solid was collected, triturated with hexane and then extracted with methylene chloride. The extract was evaporated to give the product (0.004 g) (23%). MS (m / e) 471 (M + 1); 1 H NMR (DMSO-d 6) 11.40 (s, 1 H), 8.33 (s, 1 H), 8.16 (d, 1 H), 7.47 (d, 2 H), 7.11 (d, 1 H), 6.86 (s, 1 H), 6.78 (d, 1H), 4.80 (s, 2H), 4.69 (m, 1H), 4.24 (m, 2H), 3.85 (m, 2H), 3.65 (t, 2H), 2.98 (t, 2H), 2.81 ( t, 2H), 1.30 (d, 6H), 1.23 (t, 3H). Example 165. A mixture of intermediate X (16.5 mg, 0.041 mmol) and cesium carbonate (88 mg, 1.1 eq.) In 2.0 mL of CH3CN was added cyclopentyl bromide (8.0 ul, 2.0 eq.) Under N2. After being stirred at 70 ° C for 24 hours, the mixture was diluted with CH 2 Cl 2 and filtered through celite and concentrated. Purification by preparation of TLC plate with CH2Cl2 / MeOH produced the product. MS m / e 533 (M + 1). Example 166. It was prepared by hydrogenation of Example 1C in DMF using Pd (OH) 2 and one drop of HCl. MS m / e 443 (M + 1) Example 1C. A suspension of sodium hydride (2.44 mg, 1.22 eq.) In 0.5 mL of THF was stirred under N2 as the intermediate of phenol X (3-hydroxy-10-isopropoxy-12,13-dihydro-6H.7H, 14H- Nephthyl (3,4-a) pyrrolo (3,3-pi rrol or (3,4-c) carbazole-7 (7H) one) (20.6 mg, 0.05 mmol) in 2.0 mL of THF: DMF (1: 1) ) was added in drops After 10 minutes of stirring, 2-bromopyrimidine (8.9 mg, 1.12 eq.) in 0.5 mL of THF was added.

The mixture was stirred at 60 ° C for 14 hours. Then, the mixture was cooled to room temperature, diluted with CH2Cl2 / MeOH, filtered through celite and concentrated. Purification was achieved by preparation of the TLC plate with CH2Cl2 / MeOH (9: 1) to yield the product (4.0 mg, 17%) (MS: 477 m / z (M + H) +). General Methods for the Synthesis of Examples 167-191. Method A: A mixture of the hydroxyl intermediate (0.2 mmol), potassium iodide (3.3 mg, 0.1 eq.), N-tetrabutylammonium bromide (0.1 eq.), Cesium hydroxide hydrate (3 eq.) And 20 mg of a 4A sieve in 2.0 mL of CH3CN was added the appropriate iodide or alkyl bromide under N2. After the mixture was stirred at 50 ° C for 14-72 hours, the reaction mixture was diluted with CH 3 CN and filtered through celite and concentrated. The residue was diluted with CH2Cl2 and washed with water and dried over magnesium sulfate. Purification by preparation of a TLC plate or crystallization with CH2Cl2 / MeOH produced the desired products. Method B: A mixture of the intermediate of hydroxy (0.2 mmol) and cesium carbonate (3 eq.) In 2.0 mL of CH3CN was added the appropriate iodide or alkyl bromide under N2. After the mixture was stirred at 50-80 ° C for 14-72 hours, the reaction mixture was diluted with CH3CN and filtered through celite and concentrated. The residue was diluted with CH2Cl2 and washed with water and dried over magnesium sulfate. Purification by preparation of a TLC plate or crystallization with CH 2 Cl 2 / MeOH yielded the desired product. Method C: A mixture of the hydroxyl intermediate (0.1 mmol), sodium hydroxide (1.5 eq.) And N-tetrabutylammonium bromide (0.1 eq.) In 0.5 mL of CH2CI2 and 0.5 mL of water was added the appropriate alkyl bromide under N2. After the reaction mixture was stirred at room temperature for 14-72 hours, the reaction mixture was concentrated and the residue was washed with water and dried over magnesium sulfate. Purification by preparation of a TLC plate with CH2Cl2 / MeOH or crystallization afforded the desired product. Example 167. A mixture of the XV intermediate of phenol (19.5 mg, 0.05 mmol), potassium carbonate (34.6 mg, 5 eq.) And potassium iodide (8.7 mg, 1.05 eq.) In 1.5 mL of acetone and 0.25 mL of DMF was added to the benzyl 2-bromoethylether (8.3 uL, 1.05 eq.) Under N2. After the mixture was stirred under reflux for 24 hours, the reaction mixture was diluted with EtOAc and washed with water, saturated NaCl solution and dried over magnesium sulfate. Purification by preparation of a TLC plate with 5% MeOH / CH 2 Cl 2 yielded the desired product (10 mg, 395). MS m / e 519 m / z (M + 1) +. Example 168. The product was obtained by first forming compound 1681 by Method A, using phenol XV and cyclopentyl bromide; 14 hours; Preparative TLC (10% MeOH) in CH2Cl2); 10% yield; MS: m / e 453 m / z (M + 1) +. A mixture of compound 1681-110 (5 mg, 0.01 mmol), 10% Pd (OH) 2 / C and 0.1 mL of concentrated HCl in 1.0 mL of EtOH was hydrogenated under 42 psi H2 in a Parr apparatus for 24 hours at room temperature. Filtration and concentration yielded 2.2 mg (27%) of the title compound. MS: m / e 451 m / z (M + 1) +. Example 169. Method C from phenol XV and epibromohydrin; 22 hours, preparative TLC (10% MeOH in CH 2 Cl 2), yield 30%; MS: m / e 463 m / z (M + Na) +. Example 170. Method C; phenol XV and 1-bromo-2- (2-methoxyethoxy) ethane; 14 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); 11% yield; MS: 509 m / z (M + Na) +. Example 171. Method B; phenol XV and 2- (2-bromoethyl) -1,3-dioxane; 14 hours of reflux; Preparative TLC (10% MeOH in CH 2 Cl 2); 54% yield; MS: 521 m / z (M + 1) +. Example 172. Method A; phenol XV and (bomomethyl) cyclopropane; 14 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); 17% yield; MS: m / e 439 m / z (M + 1) +. Example 173. Method A; phenol XV and 2-bromomethyl-1,3-dioxolane; 64 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); 15% yield; MS: 471 m / z (M + 1) +. Example 174. Method B; phenol XV and N- (3-bromopropyl) phthalimide; 48 hours; Preparative TLC (10% MeOH in CH 2 Cl 2); 17% yield; MS: m / e 494 m / z (M + Na) +. Example 175. Method B; phenol XV and ethyl 2-bromopropionate; 14 hours at 80 ° C; Preparative TLC (10% MeOH in CH 2 Cl 2); 9% yield; MS: m / e 507 m / z (M + Na) +. Example 176. Method A; phenol XV and methyl 4-chloro-3-methoxy- (E) -2-butenoate; 40 hours at 80 ° C; Preparative TLC (10% MeOH in CH 2 Cl 2); 21% yield; MS: m / e 535 m / z (M + Na) +. Example 177. Method A; phenol XV and 1-bromopinacolone; 14 hours at 60 ° C; Preparative TLC (10% MeOH in CH 2 Cl 2); 29% yield; MS: m / e 505 m / z (M + Na) +. Example 178. Method A; 20 hours at 50 ° C; Preparative TLC (10% MeOH in CH 2 Cl 2); yield of (5%); MS: 449 m / z (M + Na) +. Example 179. Method B; (38%) MS m / e 471 (M + 1); NMR 1H (DMSO-d6) 8.37 (s, 1H), 7.90 (d, 1H), 7.83 (d, 1H), 7.64 (d, 1H), 7.46 (t, 1H), 7.25 (t, 1H), 6.86 (s, 1H), 6.75 (d, 1H), 4.97 (t, 1H), 4.77 (d, 4H), 4.60 (t, 2H) ), 4.16 (m, 2H), 3.78 (m, 2H), 2. 45 (s, 2H), 1.21 (t, 3H). Example 180. Method B (19%). MS m / e 476 (M + 1); NMR 1H (DMSO-d6) 8.56 (s, 1H), 8.36 (s, 1H), 7.92 (d, 1H), 7.85 (m, 2H), 7.66 (d, 1H), 7.51 (d, 2H), 7.48 (t, 1H), 7.33 (m, 1H), 7.27 (t, 1H), 6.97 (s, 1H), 6.85 (d, 1H) ), 5.20 (s, 1H), 4.97 (m, 1H), 4.75 (s, 2H), 4.62 (m, 2H). Example 181. Method B (43%). MS m / e 443 (M + 1); NMR 1H (DMSO-d6) 8.36 (s, 1H), 7.90 (d, 1H), 7.83 (d, 1H), 7.64 (d, 1H), 7.45 (t, 1H), 7.24 (t, 1H), 6.87 (s, 1H), 6.77 (d, 1H), 4.97 (t, 1H), 4.75 (s, 2H), 4.61 (s, 2H) ), 4.11 (s, 2H), 3.77 (d, 2H), 3. 65 (s, 2H), 2.73 (s, 2H). Example 182. Method B (63%). MS m / e 452 (M + 1); NMR 1H (DMSO-de) 8.36 (s, 1H), 7.90 (d, 1H), 7.83 (d, 1H), 7.65 (d, 1H), 7.46 (t, 1H), 7.24 (t, 1H), 6.88 (s, 1H), 6.78 (d, 1H), 4.96 (t, 1H), 4.75 (s, 2H), 4.60 (m, 2H) ), 4.07 (t, 2H), 3.78 (m, 2H), 2. 74 (m, 2H), 2.64 (t, 2H), 2.02 (m, 2H). Example 183. Method B (72%). MS m / e 480 (M + 1); NMR 1H (DMSO-de) 8.35 (s, 1H), 7.91 (d, 1H), 7.82 (d, 1H), 7.64 (d, 1H), 6.85 (t, 1H), 6.76 (t, 1H), 4.96 (t, 1H), 4.75 (s, 2H), 4.60 (s, 2H), 4.00 (t, 2H), 3.77 (d, 2H) ), 2.73 (m, 2H), 1.73 (t, 3H), 1. 52 (m, 8H). Example 184. Method B (67%). MS m / e 456 (M + 1); NMR 1H (DMSO-de) 8.35 (s, 1H), 7.91 (d, 1H), 7.83 (d, 1H), 7.64 (d, 1H), 7.46 (t, 1H), 7.24 (t, 1H), 6.87 (s, 1H), 6.75 (d, 1H), 4.96 (t, 1H), 4.75 (s, 2H), 4.60 (t, 2H) ), 4.10 (s, 2H), 3.78 (m, 2H), 3. 70 (s, 2H), 3.00 (m, 2H), 2.70 (m, 2H), 1.11 (t, 3H). Example 185. Method B (88%). MS m / e 466 (M + 1); NMR 1H (DMSO-de) 8.35 (s, 1H), 7.91 (d, 1H), 7.83 (d, 1H), 7.64 (d, 1H), 7.46 (t, 1H), 7.24 (t, 1H), 6.86 (s, 1H), 6.77 (d, 1H), 4.96 (t, 1H), 4.75 (s, 2H), 4.61 (m, 2H) ), 4.03 (t, 2H), 3.78 (m, 2H), 2.74 (m, 2H), 2.54 (t, 2H), 1.73 (m, 6H). Example 186. Method B. MS m / e 516 (M + 1); 1 H NMR (DMSO-de) 8.35 (s, 1H), 7.90 (d, 1H), 7.81 (d, 1H), 7.64 (d, 1H), 7.46 (t, 1H), 7.24 (t, 1H), 6.85 (s, 1H), 6.76 (d, 1H), 4.96 (t, 1H), 4.75 (s, 2H), 4.60 (t, 2H) ), 3.99 (t, 2H), 3.78 (m, 2H), 2. 74 (m, 2H), 1.71 (m, 2H), 1.56 (t, 4H), 1.42 (m, 6H). Example 187. Method B. MS m / e 438 (M + 1). Example 188. This compound was formed from Example 185B, ethanol and gaseous hydrogen chloride (85%) MS m / e 512 (M + 1); 1H-NMR (DMSO-d6) 8.35 (s, 1H), 7.91 (s, 1H), 7.83 (d, 1H), 7.65 (d, 1H), 7.46 (t, 1H), 7.26 (t, 1H), 6.85 (s, 1H), 6.76 (d, 1H), 4.75 (s, 1H), 4.61 (m, 2H), 4.35 (m, 2H), 4.00 (m, 2H), 3.79 (m, 2H), 2.73 ( m, 2H), 2.66 (m, 2H), 1.77 (m, 6H), 1.33 (t, 3H). Example 189. Example 188 was refluxed in ethanol and concentrated hydrochloric acid for 18 hours. The solution was made basic with sodium hydroxide at pH 10 and refluxed for 4 hours. The solution was acidified until the product was precipitated. MS m / e 485 (M + 1); 1 H NMR (DMSO-d 6) 12.00 (s, 1H), 7.91 (d, 1H), 7.82 (d, 1H), 7.65 (d, 1H), 7.45 (t, 1H), 7.24 (m, 2H), 6.85 (s, 1H), 6.76 (d, 2H), 4.96 (t, 1H), 4.75 (s, 2H), 4.61 (m, 2H), 3.98 (t, 1H), 3.77 (m, 2H), 2.73 ( m, 2H), 2.23 (m, 4H), 1.71 (m, 8H). Example 190. The product was obtained from a reaction of Example 186 with ethanol and gaseous hydrogen chloride (45%) MS m / e 512 (M + 1); 1 H-NMR (DMSO-d 6) 8.37 (s, 1 H), 7.91 (d, 1 H), 7.82 (d, 1 H), 7.65 (d, 1 H), 7.47 (t, 1 H), 7.23 (m, 2 H), 6.86 (s, 1H), 6.77 (d, 2H), 6.67 (s, 1H), 4.99 (t, 1H), 4.76 (s, 2H), 4.61 (m, 2H), 3.98 (t, 1H), 3.80 ( m, 2H), 2.74 (m, 2H), 2.02 (t, 2H), 1.71 (m, 2H), 1.38 (m, 8H). Synthesis of phenol intermediate XVII CEP 5108: To aluminum trichloride (1.2 g, 9 mmol) in 12 mL of anhydrous dichloroethane was added 2 mL of ethanethiol followed by a methoxy derivative CEP 3371 (500 mg, 1.47 mmol). The mixture was stirred at 50 ° C for 48 hours. The reaction was concentrated and stirred with 10 mL of 1N hydrochloric acid for thirty minutes. The product was isolated by filtration and dried in vacuo to yield 483 mg (quantitative) of a gray solid., the phenol. 1 H-NMR (DMSO-de) 11-8 (s, 1H), 9.53 (s, 1H), 9.2 (d, 1H), 8.45 (s, 1H), 7.95 (s, 1H), 7.6 (d, 1H) , 7.45 (dd, 1H), 7.25 (dd, 1H), 7.08 (s, 1H), 6.8 (dd, 1H), 4.85 (s, 2H), 4.08 (s, 2H). MS (ES +): 327 (M + 1). Example 191 and Example 192. Phenol intermediate XVII (25 mg, 79 μmol), potassium carbonate (17 mg, 123 μmol), and ethyl bromoacetate (17 μL, 155 μmol) were combined in 10 mL dry acetone. A drop of N, N-dimethylformamide was added and the mixture was heated at 50 ° C for three days. The CLAR analysis revealed the presence of two products. The two products were separated using high performance reverse phase C8 liquid chromatography (1: 1 acetonitrile: water with 0.1% trifluoroacetic acid). The first eluate was identified as the mono-adduct of Example 191B. 2 mg. 1 H-NMR (DMSO-d 6) 11.7 (s, 1 H), 9.25 (d, 1 H), 8.5 (s, 1 H), 7.95 (d, 1 H), 7.60 (d, 1 H), 7.45 (dd, 1 H), 7.25 -7.3 (m, 2H), 7.0 (dd, 1H), 4.93 (s, 2H), 4.85 (s, 2H), 4.22 (q, 2H), 4.15 (s, 2H), 1.20 (t, 3H). MS (ES +): 435 (M + Na). Retention time: 13.03 minutes (gradient elution 10% -95% acetonitrile: water (0.1% trifluoroacetic acid) at 1.6 mL / minute on a Zorbax RX-C8 4.6 apparatus per 150 mm column). The second product eluted as the bis-adduct of Example 192B. 1H-NMR (DMSO-d6) 8.3 (d, 1H), 8.06 (s, 1H), 7.96 (d, 1H), 7.72 (d, 1H), 7.45 (dd, 1H), 7.27 (dd, 1H), 7.20 (br s, 1H), 6.95 (dd, 1H), 5.6 (s, 2H), 5.42 (s, 2H), 5.35 (s, 2H), 4.25 (s, 2H), 4.18 (q, 2H), 3.75 (q, 2H), 1.2 (m, 6H). 2 mg. MS (ES +): 521 (M + Na). Example 193. Prepared by the method described by Example 192 from bromoacetonitrile: 1H NMR (DMSO-d6) 11.85 (s, 1H), 9.3 (d, 1H), 8.48 (s, 1H), 7.95 (d, 1H ), 7.58 (d, 1H), 7.4 (m, 2H), 7.2 (dd, 1H), 7.1 (d, 1H), 5.2 (s, 2H), 4.85 (s, 2H), 4.18 (s, 2H) . MS (ES +): 366 (M + 1). Example 194. Example 192 (10 mg, 24 μmol) was treated in 10 mL of dry tetrahydrofuran with lithium borohydride (0.5 mL of a 2.0 M solution in tetrahydrofuran, 1.0 mmol) and heated at 40 ° C for 72 hours. Then 1 mL of water was added and the solution was concentrated. The crude solid was absorbed in 1 mL of DMF and concentrated in 600 mg of silica. The silica was applied to the top of a comma or silica bed and liquid chromatography of medium pressure was carried out eluting with 4% methane-dichloromethane to yield 3.0 mg of a tan solid. 1 H NMR (DMSO-d 6) 11.8 (s, 1 H), 9.2 (d, 1 H), 8.45 (s, 1 H), 7.92 (d, 1 H), 7.55 (d, 1 H), 7.41 (dd, 1 H), 7.25 (m, 2H), 6.95 (dd, 1H), 4.85 (s, 2H), 4.08 (s, 2H), 4.06 (m, 2H), 3.75 (m, 2H), 3.56 (t, 1H). MS (ES +): 371 (M + 1). Example 195. This compound was prepared by the method described for Example 194 from Example 193: 1H NMR (DMSO-de) 9.3 (d, 1H), 8.48 (s, 1H), 7.95 (d, 1H), 7.70 (d, 1H), 7.45 (dd, 1H), 7.28 (m, 1H), 7.22 (s, 1H), 6.95 (d, 2H), 4.9 (s, 2H), 4.7 (br s, 2H), 4.46 (s, 2H), 4.06 (br s, 2H), 3.80 (br s, 2H), 3.70 (br s, 2H), 3.52 (s overlap, 2H). MS (ES +): 415 (M + 1). Example 196. The O-allyl intermediate was prepared using allyl bromide as described for Example 194: 1H-NMR (DMSO-d6) 11.8 (s, 1H), 9.27 (d, 1H), 8.48 (s, 1H), 7.98 (d, 1H), 7.60 (d, 1H), 7.45 (dd, 1H), 7.30 (s, 2H), 7.25 (m, 1H), 7.05 (dd, 2H), 6.10 (m, 1H), 5.4 (dd, 1H), 5.3 (dd, 1H), 4.95 (s, 2H), 4.7 (d, 2H), 4.18 (s, 2H). MS (ES +): 367 (M + 1). The O-allyl intermediate (20 mg, 55 μmol), osmium tetroxide (0.1 mL of a solution of 25 mg / mL in carbon tetrachloride), N-methylmorpholine-N-oxide (50 mg) were combined in 10 mL of tetrahydrofuran to which 0.1 mL of water was added. The mixture was stirred in the dark for 48 hours. The mixture was concentrated on 0.6 g of silica and applied to a silica pad. Medium pressure liquid chromatography eluting with 5% methanokydloromethane yielded 23 mg of a yellow solid. 1 H NMR (DMSO-de) 11.8 (s, 1H), 9.23 (d, 1H), 8.43 (s, 1H), 7.92 (d, 1H), 7.55 (d, 1H), 7.40 (dd, 1H), 7.25 (s, 1H), 7.22 (m, 1H), 6.95 (d, 1H), 4.95 (d, 1H), 4.88 (s, 2H), 7.70 (dd, 1H), 4.10 (s, 2H), 4.05 (d, 1H), 3.7-3.95 (m, 4H ). MS (ES +): 401 (M + 1). Example 197. Example 194 (63 mg, 153 μmol), dimethylamine (3 mL of a 40% solution in water), and ammonium chloride (100 mg) were combined in N, N-dimethylformamide and stirred at room temperature in a sealed tube for 5 days. The solution was concentrated on 0.6 g of silica and applied to a silica pad. Medium pressure liquid chromatography using a 5-10% gradient of methanokydloromethane yielded 60 mg of an orange solid. 1 H NMR (DMSO-de) 11.80 (s, 1H), 9.20 (d, 1H), 8.45 (s, 1H), 7.95 (d, 1H), 7.55 (d, 1H), 7.40 (dd, 1H), 7.2 -7.28 (m, 2H), 6.93 (d, 1H), 4.90 (s, 2H), 4.82 (s, 2H), 4.05 (s, 2H), 3.0 (s, 3H), 2.83 (s, 3H). MS (ES +): m / e 434 (M + Na). Example 198. The epoxide (42 mg, 0.11 mmol), dimethylamine (3 mL of a 40% solution in water), and ammonium chloride (100 mg) were combined in 10 mL of N, N-dimethylformamide and stirred in a sealed tube for 16 hours. The mixture was concentrated to 700 mg of silica and applied to a silica pad. Medium pressure liquid chromatography using a 15-25% gradient of methanokydloromethane produced about 5 mg of the desired polar product. 1 H NMR (DMSO-de) 12.1 (br s, 1H), 9.55 (d, 1H), 8.45-8.52 (m, 2H), 7.72 (d, 1H), 7.65 (dd, 1H), 7.35-7.5 (m , 2H), 7.15 (d, 1H), 5.75 (s, 2H), 5.18 (s, 2H), 4.15-4.35 (m, 4H), 2.70 (m, 1H), 2.55 (s, 6H), 2.50 ( m, 1H). MS (ES +): m / e 428 (M + 1). Example 199. This compound was prepared by the same procedure as in Example 198 using morpholine: MS (ES +): m / e 470 (M + 1). Utility The compounds of the present invention are useful, inter alia, as therapeutic agents. Particularly, the compounds are useful for inhibition of the kinase, such as, for example, trk, VEGFR, PDGFR, PKC, MLK, DLK, Tie-2, FLT-3 and CDK1-6. Various compounds of the present invention show improved pharmaceutical properties over those described in the art and improved pharmacokinetic properties in mammals. The compounds of the present invention show improved pharmaceutical properties over those described in the art, including enhanced double MLK and DLK inhibition activity, or enhanced double-Tie-2 VEGFR inhibition activity, together with improved pharmacokinetic properties in mammals. . In one embodiment, the present invention provides a method for treating or preventing diseases and disorders, such as those described herein, which comprises administering to a subject in need of such treatment or prevention, a therapeutically effective amount of a compound of the invention. present invention. In a further embodiment, the present invention provides a method for inhibiting trk kinase activity comprising providing a compound of the present invention in a sufficient amount that results in effective inhibition. Particularly, the inhibition of trk involves utility in, for example, prostate diseases such as prostate cancer and benign prostatic hyperplasia, as well as for the treatment of inflammation, such as neurological inflammation and inflammation of chronic arthritis. In a preferred embodiment, the trk kinase receptor is trk A. Most cancers have an absolute requirement for angiogenesis, the process by which new blood vessels are formed. The most potent angiogenic cytokine is vascular endothelial growth factor (VEGF) and there is a substantial search for the development of VEGF / VEGF receptor antagonists (VEGFR). Tyrosine kinase receptor (RTK) inhibitors may have broad-spectrum antitumor activity in patients with pretreated, advanced breast and colorectal carcinoma and Kaposi's sarcoma. Potentially these agents may play a role in the treatment of both premature (adjuvant) and advanced cancer. The importance of angiogenesis for the progressive development and viability of solid tumors is well established. The data that emerge suggest an intricacy of angiogenesis in the pathophysiology of hematological malignancies as well. Recently, the authors have reported increased angiogenesis in the bone marrow of patients with acute myeloid leukemia (AML) and normalization of bone marrow microvessel density when complete remission (CR) is achieved in patients after induction chemotherapy. Tumor angiogenesis depends on the expression of specific mediators that initiate a cascade of events that lead to the formation of new microvessels. Among these, VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor) play a pivotal role in the induction of neovascularization in solid tumors. These cytokines stimulate the migration and proliferation of endothelial cells and induce angiogenesis in vivo. Recent data also suggest an important role for these mediators in hematological malignancies. Isolated AML blasts overexpress VEGF receptor 2 and VEGF. In this way, the trajectory of VEGF / VEGFR-2 can promote the development of leukemic blasts in an autocrine and paracrine fashion. Therefore, neovascularization and angiogenic mediators / receptors may be promising targets for anti-angiogenic and anti-leukemic treatment strategies. Thus, in other embodiments, the present invention provides a method for treating or preventing angiogenic disorders where the activity of VEGFR kinase contributes to pathological conditions, the method comprising providing a compound of the present invention in a sufficient amount resulting in the The vascular endothelial growth factor receptor is contacted with an effective inhibitory amount of the compound. Inhibition of VEGFR involves utility in, for example, angiogenic disorders such as cancer of solid tumors, endometriosis, macular degeneration, retinopathy, diabetic retinopathy, psoriasis, hemangioblastoma, as well as other ocular diseases and cancers. FLT3, a member of class III receptor tyrosine kinase (RTK), is preferentially expressed on the surface of a high proportion of acute myeloid leukemia (AML) and acute lymphocytic leukemia lineage B cells in addition to hematopoietic germ cells, brain , placenta and liver. An interaction of FLT3 and its ligand has been shown to play an important role in the survival, proliferation and differentiation of hematopoietic cells not only normal but also leukemia cells. FLT3 gene mutations were first reported as a duplication of the internal tandem (ITD) of the juxtamembrane domain (JM) coding sequence, subsequently as a missense mutation of D835 without a kinase domain. The ITD and D835 mutations are found essentially in the AML and their frequencies are approximately 20 and 6% of adults with AML, respectively. In this way, the mutation of the FLT3 gene is so far the most frequent genetic alteration reported to be involved in AML. Several large-scale studies in well-documented patients published to date have shown that the ITD mutation is strongly associated with leukocytosis and a poor prognosis. An FLT3 tyrosine kinase inhibitor compound has an application in the treatment of leukemia. The present invention provides a method for the treatment of disorders characterized by sensitivity to inhibition of FLT3, the method comprising providing a compound of the present invention in a sufficient amount that results in the inhibition of FLT3. Platelet-derived growth factor (PDGF) was one of the first growth factors of identified polypeptides that signal through a cell surface tyrosine kinase receptor (PDGF-R) to stimulate diverse cellular functions including growth, proliferation , and differentiation. Since later, several related genes have been identified that constitute a family of ligands (mainly PDGF A and B) and their related receptors (PDGF-R alpha and beta). Till the date, PDGF expression has been shown in a variety of different solid tumors, from glioblastomas to prostate carcinomas. In these various types of tumors, the biological role of PDGF signaling can vary from autocrine stimulation of cancer cell growth to more subtle paracrine interactions involving adjacent stroma and still angiogenesis. Thus, in additional embodiments, the present invention provides a method for the treatment or prevention of disorders where PDGFR activity contributes to pathological conditions, the method comprising providing a compound of the present invention in a sufficient amount resulting in the receptor of the platelet derived growth factor by contacting an effective inhibitory amount of the compound. Inhibition of PDGFR involves utility in, for example, various forms of neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, healing of abnormal wounds, diseases with cardiovascular endpoints, such as atherosclerosis, restenosis, post-angioplasty restenosis, and Similar. In other embodiments, the present invention provides a method for the treatment or prevention of disorders wherein the MLK activity contributes to pathological conditions, such as those listed above, wherein the method comprises providing a compound of the present invention in a sufficient amount that results from the MLK receptor by contacting an effective inhibitory amount of the compound. Inhibition of MLK implies utility in, for example, forms of cancer where MLKs play a pathological role as well as in neurological disorders. In yet other embodiments, the present invention provides a method for the treatment of disorders characterized by the aberrant activity of cells responsive to trophic factor, the method comprising providing a compound of the present invention in a sufficient amount resulting in the cellular factor receptor. trophic by contacting an effective activity that induces a quantity of the compound. In certain preferred embodiments, the activity of the cells responsive to the trophic factor is the activity of ChAT. Fibroblast growth factor receptors (FGFR) are members of a family of polypeptides synthesized by a variety of cell types during embryonic development processes and in adult tissues. FGFRs have been detected in normal and malignant cells and are implicated in biological events that include mitogenic and angiogenic activity with a consequent crucial role in cell differentiation and development. To activate signal transduction pathways, FGFRs are coupled to fibroblast growth factors (FGF) and heparan sulfate proteoglycans (HS) to form a biologically fundamental ternary complex. Based on these considerations, inhibitors capable of blocking the signaling cascade through a direct interaction with FGFR could have antiangiogenesis and subsequent antitumor activity. Accordingly, the present invention provides a method for the treatment of disorders characterized by the aberrant activity of FGF responsive cells, the method comprising providing a compound of the present invention in a sufficient amount which results in the FGFRs coming into contact with an activity effective that induces a quantity of the compound. The compounds of the present invention can also have positive effects on the function and survival of cells responsive to trophic factor by promoting the survival of neurons. With respect to the survival of a cholinergic neuron, for example, the compound can preserve the survival of a cholinergic neuronal population at risk of dying (due, for example, to injury, a disease condition)., a degenerative condition or a natural progression) when compared to a cholinergic neuronal population not presented with such a compound, if the treated population has a comparatively longer period of functionality than the untreated population. A variety of neurological disorders are characterized by neuronal cells that are dead, injured, functionally compromised, suffering from axonal degeneration, at risk of dying, etc. These neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease; disorders of the motor neuron (for example amyotrophic lateral sclerosis); Parkinson's disease; cerebrovascular disorders (for example, attack or fulminating crisis, ischemia); Huntington's disease; dementia due to AIDS; epilepsy; multiple sclerosis; peripheral neuropathies including diabetic neuropathy and peripheral neuropathy induced by chemotherapy, peripheral neuropathy related to AID; disorders induced by excitatory amino acids; and disorders associated with concussive or penetrating injuries of the brain or spinal cord. In other preferred embodiments, the compounds of the present invention are useful for the treatment or prevention of multiple myeloma and leukemias including, but not limited to, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, and chronic lymphocytic leukemia. In additional embodiments, the present compounds are also useful in the treatment of disorders associated with decreased ChAT activity or with death, injury to spinal cord motor neurons, and also have utility in, for example, diseases associated with cell death apoptotic of the central and peripheral nervous system, immune system and in inflammatory diseases. ChAT catalyzes the synthesis of the neurotransmitter acetylcholine, and is considered an enzymatic marker for a functional cholinergic neuron. A functional neuron is also capable of survival. Survival of the neuron is assayed by quantification of specific reabsorption and enzymatic conversion of a dye (eg calcein AM) by living neurons. The compounds described herein may find utility in the treatment of disease states that involve malignant cell proliferation, such as some cancers. Additional embodiments of the invention are directed to the use of any compound described herein, and stereoisomers or pharmaceutically acceptable salts thereof, in the treatment and / or prevention of any of the conditions, diseases and disorders described above. Other embodiments are directed to the use of the compounds described herein, and stereoisomers or pharmaceutically acceptable salts thereof, in the manufacture or manufacture of a medicament for treating and / or preventing conditions, disorders and diseases. The compounds of the present invention have important functional pharmacological activities that find utility in a variety of fixations, including experimentation and therapeutic arenas. For ease of presentation, and not to limit the range of utilities for which these compounds can be characterized, the activities of the compounds of the present invention can be described generally as follows: A. Inhibition of enzymatic activity B. Effect of the Function and / or survival of trophic factor responsive cells C. Inhibition of responses associated with inflammation D. Inhibition of cell growth associated with hyperproliferative states E. Inhibition of experimentally programmed motor neuron death Inhibition of enzyme activity can be determined using, for example, example, inhibition assays VEGFR (for example inhibition of VEGFR2), inhibition of MLK (for example, inhibition of MLK1, MLK2 or MLK3), inhibition of PDGFR kinase, phosphorylation of trk stimulated with NGF, inhibition of PKC, or inhibition of trk tyrosine kinase. The effect on the function and / or survival of cells responsive to the trophic factor, e.g., cells of a neuronal lineage, can be established using any of the following assays: (1) choline-acetyltransferase assay of cultured spinal cord ("ChAT "); trial of the extension of the neurite of the cultivated dorsal root ganglion ("DRG"); (3) assay of the ChAT activity of the cultured basal forebrain neuron ("BFN"). Inhibition of the response associated with inflammation can be established using an indoleamine 2,3-dioxygenase ("IDO") mRNA assay. The inhibition of cell growth associated with hyperproliferative states can be determined by measuring the growth of cell lines of interest, such as an AT2 line in the case of prostate cancer. The inhibition of experimentally programmed motoneuronal death can be tested in ovo using somatic motoneurons of embryonic chicken, whose cells suffer from death that occurs naturally between days 6 and 10 embryonic, and that analyze the inhibition of such cell death that occurs in natural form mediated by the compounds described herein. The invention of the enzymatic activity by the compounds of the present invention can be determined using, for example, the following tests: VEGFR Inhibition Assay MLK Inhibition Assay PKC Activity Inhibition Assay TrkA Tyrosine Kinase Activity Inhibition Assay Tie-2 Inhibition Assay CDK1-6 Inhibition Assay Inhibition of Stimulated Trk Phosphorylation with NGF in a complete cell preparation Growth Receptor Inhibition Assay Platelet Derivative (PDGFR) A description of assays that may be used in conjunction with the present invention is set forth below. They are not intended, nor are they to be constructed, as limiting the scope of the description. Inhibition of TrkA Tyrosine Kinase Activity Selected compounds of the present invention were tested for their ability to inhibit the kinase activity of the human cytoplasmic domain expressed with baculovirus using an ELISA-based assay as previously described (Angeles et al. , Anal., Biochem. 236: 49-55, 1996). Briefly, the 96-well microtiter plate was covered with a substrate solution (recombinant human fusion protein C-β1 phospholipase / glutathione S-transferase (Rotin et al., EMBO J., 11: 559-567, 1992). Inhibition studies were performed in 100 μl assay mixtures containing 50 mM Hepes, pH 7.4, 40 μM ATP, 10 mM MnCl 2, 0.1%) BSA, 2% DMSO, and various concentrations of inhibitor. The reaction was initiated by addition of trkA kinase and allowed to proceed for 15 minutes at 37 ° C. An antibody to the phosphotyrosine (UBI) was then added, followed by an antibody conjugated with the secondary enzyme, goat anti-mouse IgG labeled with alkaline phosphatase (Bio-Rad). The activity of the bound enzyme was measured via an amplified detection system (Gibco-BRL). The inhibition data were analyzed using the response equation with sigmoid dose (variable tilt) in GraphPad Prism. The concentration that resulted from 50% inhibition of kinase activity is referred to as "IC50". Inhibition of Vascular Endothelial Growth Factor Receptor Kinase Activity Selected compounds of the present invention were examined for their inhibitory effects on the kinase activity of the VEGF receptor kinase domain expressed with baculovirus (human flk-1, KDR, VEGFR2) using the procedure described for the trkA kinase ELISA assay described above. The kinase reaction mixture, consisting of 50 mM Hepes, pH 7.4, 40 μM ATP, 10 mM MnCl 2, 0.1%) of BSA, 2% DMSO, and various concentrations of inhibitor, was transferred to plates coated with PLC -? / GST. VEGFR kinase was added and the reaction was allowed to proceed for 15 minutes at 37 ° C. Detection of the phosphorylated product was performed by the addition of anti-phosphotyrosine antibody (UBI). A conjugated antibody was released with the secondary enzyme to capture the phosphorylated PLC-α / GST complex. The activity of the bound enzyme was measured via an amplified detection system (Gibco-BRL). Inhibition data were analyzed using the response equation with sigmoid dose (variable tilt) in GraphPad Prism. Inhibition of Mixed Kinase-1 Lineage Activity MLK1 kinase activity was assessed using the Millipore Multiscreen TCA "on-board" format as described for protein kinase C (Pitt & amp;; Lee, J. Biomol. Screening, 1_; 47-51, 1996). Briefly, each 50 μl assay mixture contained 20 mM Hepes, pH 7.0, 1 mM EGTA, 10 mM MgCl 2, 1 mM DTT, 25 mM β-glycerophosphate, 60 μM ATP, [α-32 P] ATP μCi 0.25, 0.1% ) of BSA, 500 μg / ml of myelin basic protein (UBI # 13-104), 2% of DMSO, 1 μM of test compound, and 1 μg / ml of baculoviral GST-MLK1KD. Samples were incubated for 15 minutes at 37 ° C. The reaction was stopped by adding 50% TCA cooled with ice and the proteins were allowed to precipitate for 30 minutes at 4 ° C. The plates were washed with 25% TCA cooled with ice. A super-blended scintillation cocktail was added, and the plates were allowed to equilibrate for 1-2 hours before counting using the Wallace MicroBeta 1450 PLUS scintillation counter. Kinase Assay Leucine Double-Rack Carrier Compounds were tested for their ability to inhibit the activity of recombinant baculoviral human DLK kinase activity, which contains the kinase and leucine zipper domain. Activity was measured in 384 cavity plates FluoroNunc (Cat # 460372) using a fluorescence reading of resolution in time (PerkinElmer Application Note 1234-968). The plates were coated with 30 μl of the MKK7 protein substrate (Merritt et al., 1999) at a concentration of 20 μg / ml in buffered saline solution Tris (TBS). Each 30 μl assay contained 20 mM MOPS (pH 7.2), 15 mM MgCl2, 0.1 mM Na3VO4, 1 mM DTT, 5 mM EGTA, 25 mM β-glycerophosphate, 0.1% BSA, 100 μM ATP and 2.5% DMSO. Reactions were initiated by the addition of 10 ng / ml of GST-hDLKKD / Lz- For IC50 determinations, a dot dose response curve 10 was generated for each compound. The plates were incubated at 37 ° C for 30 minutes, and the reactions were stopped by the addition of 100 mM EDTA. Product was detected using labeled anti-phosphothreonine Europium (Wallac # AD0093; diluted 1: 10000 in 3% BSA / T-TBS.) After capturing overnight at 4 ° C, 50 μl of reinforcing solution was added (Wallac # 1244 -105) and the plate was gently shaken for 5 minutes.The fluorescence of the resulting solution was then measured using a time-resolved fluorescence mode (TRF) in the Multi-Braille Reader (Model Victor2 # 1420-018 or Envision model # 2100) Inhibition data were analyzed using GraphPad PRISM See also Merritt, SE, Mata, M., Nihalani, D., Zhu, C, Hu, X., and Holzman, LB (1999). of the Mixed Kinase Lineage and not MKK4 as Substrate J. Biol. Chem. 274, 10195-10202. Tyrin Kinase Tie-2 Assay Compounds were tested for their ability to inhibit the kinase activity of the human cytoplasmic domain His6-Tie2. recombinant baculoviral using a modification of the ELISA described for trkA (Angel es et al., 1996). A 384-cavity plate format was used for single-tip protection while IC50 values were performed on 96-well plates. For single-tip projection, each Costar High Binding 384 cavity plate coded in bars (Cat # 3703) was coated with 50 μl / cavity of 10 μg / ml substrate solution (recombinant human GST-PLC-? Rotin et al. al., 1992) in saline buffered with Tris (TBS). Tie2 activity was measured in 50 μl assay mixtures containing 50 mM HEPES (pH 7.2), 40 μM ATP, 10 mM MnCl 2, 2.5% DMSO, 0.05% BSA, and 200 ng / ml His6-Tie2CD - For the IC50 determinations, the tests were run as described above but in 96-well Costar High Binding plates (Cat # 3703) and with the folded volumes. A point dose response curve 10 was generated for each compound. The kinase reaction was allowed to proceed at 37 ° C for 20 minutes. The detection antibody, the N1-Eu anti-phosphotyrosine antibody (PT66) (Wallac # AD0041), was added in 1: 2000 diluted in block buffer [3% BSA in TBS with 0.05% Tween-20 (TBST) ] After one hour of incubation at 37 ° C, 50 μl of reinforced solution (Wallac # 1244-105) was added and the plate was shaken gently. The fluorescence of the resulting solution was then measured using a time resolved fluorescence mode (TRF) in the Multi-Braille Reader (Model Victor2 # 1420-018 or Envision Model # 2100). The inhibition data were analyzed using an Activity Base and IC5o curves were generated "using XLFit. The cited references are as follows: 1. Angeles, T. S., Steffler, C, Bartlett, B.A., Hudkins, R.L., Stephens, R.M., Kaplan, D.R., and Dionne, C.A. (1996) Enzyme-linked immunosorbent assay for trkA tyrosine kinase activity. Anal. Biochem. 236, 49-55. 2. Rotin, D., Margolis, B., Mohammadi, M., Daly, RJ, Daum, G., Li, N., Fischer, EH, Burgess, WH, Ullrich, A., Schlessinger, J. (1992 ) The SH2 domains prevent tyrosine dephosphorylation of the EGF receptor: identification of Tyr992 as the high affinity binding site for the SH2 domains of phospholipase C- ?. EMBO J. 11, 559-567. Dosage and Formulation For therapeutic purposes, the compounds of the present invention can be administered by any means that results in contact of the active agent with the site of the agent of action in the body of the subject. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in combination with other therapeutic agents, such as, for example, analgesics. The compounds of the present invention are preferably administered in therapeutically effective amounts for the treatment of the diseases and disorders described herein to a subject in need thereof. A therapeutically effective amount can be easily determined by the skilled diagnostician serving the patient, as one skilled in the art, by the use of conventional techniques. The effective dose will vary depending on the number of factors, including the type and degree of progression of the disease or disorder, the general health status of the particular patient, the relative biological efficacy of the selected compound, the formulation of the active agent with appropriate excipients, and the route of administration.

Typically, the compounds are administered at lower dosage levels, with gradual increase until the desired effect is achieved. Typical dose ranges are from about 0.01 mg / kg to about 100 mg / kg of body weight per day, with a preferred dose of about 0.01 mg / kg to 10 mg / kg of body weight per day. A preferred daily dose for adult humans includes approximately 25, 50, 100 and 200 mg, and an equivalent dose in a human child. The compounds can be administered in one or more dosage unit forms. The unit dose ranges from about 1 to about 500 mg administered from one to four times a day, preferably from about 10 mg to about 300 mg, twice a day. In an alternate method for describing an effective dose, an oral unit dose is one that is necessary to achieve a blood serum level of about 0.05 to 20 μg / ml in a subject, and preferably about 1 to 20 μg / ml. . The compounds of the present invention can be formulated in pharmaceutical compositions in admixture with one or more pharmaceutically acceptable excipients. The excipients are selected on the basis of the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy, 20th ed .; Gennaro, A. R., Ed .; Lippincott Williams & Wiikins: Philadelphia, PA, 2000. The compositions can be formed to control and / or retard the release of the active agents, as in fat dissolution formulations, modified release, or prolonged release. Such controlled release compositions, or prolonged release may use, for example, biocompatible, biodegradable polymers, lactide / glycolide copolymers, polyoxyethylene-polyoxypropylene copolymers, or other solid or semi-solid polymer matrices known in the art. The compositions can be prepared for oral administration; parenteral means, including intravenous, intramuscular, and subcutaneous routes; topical or transdermal medium; transmucosal means, including the rectal, vaginal, sublingual and buccal routes; ophthalmic medium; or medium by inhalation. Preferably the compositions are prepared for oral administration, particularly in the form of tablets, capsules or syrups; for parenteral administration, particularly in the form of liquid solutions, suspensions or emulsions; for intranasal administration, particularly in the form of powders, nasal drops, or aerosols; or for topical administration, such as creams, ointments, solutions, suspensions, aerosols, powders and the like. For oral administration, tablets, pills, powders, capsules, troches and the like may contain one or more of the following: diluents or fillers such as starch, or cellulose; binders such as microcrystalline cellulose, gelatins or polyvinylpyrrolidones; disintegrants such as starch or cellulose derivatives; lubricants such as talc or magnesium stearate; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as mint or cherry flavor. The capsules may contain any of the excipients listed above, and may additionally contain a semi-solid or liquid carrier, such as a polyethylene glycol. Solid oral dosage forms may have coatings of sugar, shellac, or enteric agents. The liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as surfactants or surfactants, suspending agents, emulsifying agents, diluents, sweetening and flavoring agents, colorants and preservatives. The compositions can also be administered parenterally. Pharmaceutical forms acceptable for injectable use include, for example, sterile aqueous solutions, or suspensions. Aqueous carriers include mixtures of alcohols and water, buffered media, and the like. Non-aqueous solvents include alcohols and glycols, such as ethanol, and polyethylene glycols; oils, such as vegetable oils; fatty acids and fatty acid esters, and the like. Other components can be added including surfactants; as hydroxypropyl cellulose; isotonic agents, such as sodium chloride; electrolyte suppliers; agents that control the release of the active compounds, such as aluminum monostearate, and various copolymers; antibacterial agents such as chlorobutanol or phenol; shock absorbers, and the like. Parenteral preparations can be enclosed in ampoules, disposable syringes or small multi-dose vials. Other potentially useful parenteral delivery systems for the active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems and liposomes. Other possible modes of administration include formulations for inhalation, including such media as dry powder, aerosol, or drops. They may be aqueous solutions containing, for example, polyoxyethylene-9-Iauryl ether, glycolate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel that is applied intranasally. Formulations for topical use are in the form of an ointment, cream or gel. Typically these forms include a carrier, such as petrolatum, lanolin, stearyl alcohol, polyethylene glycols, or combinations thereof, and either an emulsifying agent, such as sodium lauryl sulfate, or a gelling agent, such as tragacanth. Suitable formulations for transdermal administration can be presented as discrete patches, as in a reservoir or micro-reservoir system, a controlled diffusion adhesive system or a dispersion-type matrix system. Formulations for buccal administration include, for example, tablets or lozenges and may also include a flavor base, such as sucrose or acacia, and other excipients such as glycolate. Formulations suitable for rectal administration are preferably present as unit dose suppositories, with a carrier with a solid base, such as cocoa butter, and may include a salicylate. As those skilled in the art will appreciate, numerous modifications and variations of the present invention are possible in the light of the foregoing teachings. It is therefore understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein, and the scope of the invention is intended to encompass all such variations.

Claims (44)

1. CLAIMS 1. A compound of Formula I: I characterized in that: the ring A together with the carbon atoms to which it is attached is selected from: (a) a phenylene ring in which 1 to 3 carbon atoms can be replaced by nitrogen atoms; and (b) a 5-membered aromatic ring in which 1 to 2 carbon atoms can be replaced by nitrogen atoms; A1 and A2 are independently selected from H, H; and a group wherein A1 and A2 together form a selected portion of = O; B1 and B2 are independently selected from H, H; and a group wherein B1 and B2 together form a selected portion of = O; with the proviso that at least one of the pairs A1 and A2, or B1 and B2 form = O; R1 is H or optionally substituted alkyl, wherein the optional substituents are groups of one to three R10; R2 is selected from H, C (= O) R2a, C (= O) NR2cR2d, SO2R2b, CO2R2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, wherein the optional substituents they are groups of one to three R10; R2a is selected from optionally substituted alkyl, optionally substituted aryl, OR2, NR2cR2d, (CH2) pNR2cR2d, and O (CH2) pNR2cR2d, wherein the optional substituents are groups of one to three R10; R2b is selected from H and optionally substituted alkyl, wherein the optional substituents are groups of one to three R10; R2c and R2d are each independently selected from H and optionally substituted alkyl, or together with the nitrogen to which they are attached form an optionally substituted heterocycloalkyl, wherein the optional substituents are groups of one to three R10; at least one of R3, R4, R5, and R6 is selected from OR14; C (= O) R22; CH = NR26; NR11C (= O) R20; NR11C (= O) OR15; OC (= O) R20; OC (= O) NR 11 R 20; O- (alkylene) -R24; Z - (alkylene) -R23), wherein Z1 is selected from CO2, O2C, C (= O), NR11, NR11C (= O), and NR11C (= O) O; and (alkylene) -Z2- (alkylene) -R23, wherein Z2 is selected from O, S (O) and, C (= O) NR11, NR11C (= O), NR11C (= O) NR11, OC (= O) NR11, NR11C (= O) O; wherein the alkylene groups are optionally substituted with one to three R10 groups; the other portions R3, R4, R5, or R6 may be independently selected from H, R10, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl, wherein the optional substituents are groups of one to three R10; Q is selected from an optionally substituted C-α-2 alkylene, wherein the optional substituents are groups of one to three R 10; R 10 is selected from alkyl, cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkoxy, F, Cl, Br, I, CN, CF 3, NR 27 AR 27 B, N 2? OR25, OCF3, = O, = NR25, = N-OR25, = NN (R25) 2, OC (= O) R25, OC (= O) NHR11, O-Si (R16) 4, O-tetrahydropyranyl, ethylene, NR16C (= O) R25, NR16CO2R25, NR16C (= O) NR27AR27B, NHC (= NH) NH2, NR16S (O) 2R25, S (O) and R25, CO2R25, C (= O) NR27AR27B, C (= O ) R25, CH2OR25, (CH2) pOR25, CH = NNR27AR27B, CH = NOR25, CH = NR25, CH = NNHCH (N = NH) NH2, S (= O) 2NR27AR27B, P (= O) (OR25) 2, OR13, and a monosaccharide wherein each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl, alkylcarbonyloxy, or alkoxy; R 11 is selected from H and optionally substituted alkyl, wherein the optional substituents are groups of one to three R 10; R 12 is selected from optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein the optional substituents are groups of one to three R 10; R 13 is the residue of an amino acid after removal of the hydroxyl portion of the carboxyl group thereof; R 14 is optionally substituted heteroaryl, wherein the optional substituents are groups of one to three R 10; R 15 is optionally substituted alkyl, wherein the optional substituents are groups of one to three R 10; R1ß is H or alkyl; R17 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, wherein the optional substituents are groups of one to three R10; R 18 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, wherein the optional substituents are groups of one to three R 10; R 19 is selected from optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl, wherein the optional substituents are groups of one to three R 0; R 2o is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, wherein the optional substituents are groups of one to three R 10; R 21 is selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, wherein the optional substituents are groups of one to three R10; R 22 is selected from optionally substituted aryl, and optionally substituted heteroaryl, wherein the optional substituents are groups of one to three R 10; R 23 is selected from optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, OR21, O (CH2) pOR21, (CH2) pOR21, SR18, SOR17, SO2R18, CN, N (R20) 2, CHOH (CH2) pN (R11) 2, C (= O) N (R18) 2, NR1ßC (= 0) R1 NR '° C (= O) N (Rpß) 2, C (= NR1B) OR1 C (R?) = NOR 18 NHOR20? 18 / - 18? NR1oC (= NR10) N (R1B) 2, NHCN, CONR ^ OR1 CO2R1B, OCOR 17 OC (= O) N (R, 1I8B>) 2, NR18C (= O) OR17, and C (= O) R18, wherein the optional substituents are groups of one to three R0; R 24 is selected from optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, CN, OR21, O (CH2) pOR2 \ (CH2) pOR21 SR19, SOR17, SO2R18, N (R18) 2 , CHOH (CH2) pN (R11) 2 NR18C (= O) R18, NR18C (= O) N (R18) 2, C (= NR18) OR18 NHOR21, NR18C (= NR18) N (R18) 2, NHCN, C (= O) N (R18) 2 C (= O) NR27AR27B, C (= O) NR11R28, C (= O) NR18OR18 C (= O) NR11N (R11) 2, C (= O) NR11 (alkylene) - NR27AR27B CO2R18, OCOR17, OC (= O) N (R8) 2, NR18C (= O) OR17 C (= O) NR11R18 and C (= O) R18, wherein the optional substituents are groups of one to three R10; R 25 is H, alkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; R is selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, wherein the optional substituents are groups of one to three R10; R 27A and R27B are each independently selected from H and alkyl, or together with the nitrogen to which they are attached form an optionally substituted heterocycloalkyl, wherein the optional substituents are selected from alkyl, aryl heteroaryl; R28 is optionally substituted arylalkyl, wherein the optional substituents are groups of one to three R10; p is independently selected from 1, 2, 3 and 4; and is independently selected from 0, 1 and 2; and with the proviso that: when A1, A2 is = O; B, B2 are independently H or OH, or B1, B2 combined form = O; rings A and B are each phenylene; Q is CH-Ra; and one of R2 or Ra is H and the other is optionally substituted wherein W is optionally substituted Ci alkyl, or NR27AR27B. in either any of R3, R4, R5 and R6 may not include OR14 or O- (alkyne) -R24; and a stereoisomer or a pharmaceutically acceptable salt form thereof.
2. 2. The compound according to claim 1, characterized in that A is a phenylene.
3. 3. The compound according to claim 1, characterized in that ring A is a 5-membered aromatic ring containing one or two nitrogen atoms.
4. 4. The compound according to claim 3, characterized in that ring A is pyrazolylene.
5. 5. The compound according to claim 1, characterized in that R1 is H or alkyl.
6. 6. The compound according to claim 1, characterized in that R2 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted cycloalkyl.
7. 7. The compound according to claim 6, characterized in that R2 is H or optionally substituted alkyl.
8. The compound according to claim 1, characterized in that at least one of R3, R4, R5, and R6 is OR14; C (= O) R, 2 ^ 2; NR, 11C (/ = - 0) R 2¿0ü .; NR 1111C (= IO) OR, 1155; OC (= O) R, 20 OR OC (= O) NR11R20.
9. 9. The compound according to claim 1, characterized in that R14 is benzoxazolyl, benzothiazolyl, pyrimidyl, pyrazinyl or triazinyl; R22 is a 5-membered heteroaryl group; R 20 is heterocycloalkyl or heteroaryl; R23 is heteroaryl or heterocycloalkyl; R24 is heteroaryl; and R26 is heterocycloalkyl, wherein each of the portions R14, R22, R23, R24 and R26 is optionally substituted with 1 to 3 R10 groups.
10. 10. The compound according to claim 1, characterized in that it has the structure of Formula II: p
11. 11. The compound according to claim 10, characterized in that R2 is H, C (= O) R2a, C (= O) NR2cR2d, SO2R2b, CO2R2b, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted cycloalkyl.
12. 12. The compound according to claim 10, characterized in that ring A is phenylene.
13. The compound according to claim 10, characterized in that the ring A is a pyrazolylene.
14. 14. The compound according to claim 13, characterized in that ring A is
15. 15. The compound according to claim 13, characterized in that ring A is
16. 16. The compound according to claim 10, characterized in that R1 is H or alkyl.
17. 17. The compound according to claim 10, characterized in that Q is CH2CH2.
18. 18. The compound according to claim 10, characterized in that at least one of R3, R4, R5, and R6 is OR14, wherein R14 is benzoxazole, benzothiazole, pyrimidine, pyrazine or triazine; C (= O) R22, wherein R22 is a 5-membered heteroaryl group; NR 11 C (= O) R 20, wherein R 20 is heteroaryl; NR11C (= O) OR15; OC (= O) R 20, wherein R 20 is heterocycloalkyl; or OC (= O) NR 11 R 20, wherein R 20 is cycloalkyl, wherein each of the portions R 14, R 22, and R 20 is optionally substituted with 1 to 3 R 10 groups.
19. 19. The compound according to claim 10, characterized in that it has a structure of Formula III: m wherein ring A is a phenylene or a pyrazolylene, and R1 is H or alkyl.
20. The compound according to claim 19, characterized in that it has a structure of Formula IV: rv
21. 21. The compound in accordance with the claim 19, characterized in that it has a structure of Formula V:
22. 22. The compound according to claim 19, characterized in that it has a structure of Formula VI: SAW
23. 23. The compound according to claim 20, 21 or 22, characterized in that R2 is H, C (= O) R2a, C (= O) NR2cR2d, SO2R2b, CO2R2b, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted cycloalkyl.
24. 24. The compound according to claim 23, characterized in that R2 is H or optionally substituted alkyl.
25. The compound according to claims 20, 21 or 22, characterized in that at least one of R3, R4, R5, and R6 is OR14, wherein R14 is benzoxazole, benzothiazole, pyrimidine, pyrazine or triazine; C (= O) R22, wherein R22 is a 5-membered heteroaryl group; NR 11 C (= O) R 20, wherein R 20 is heteroaryl; NR11C (= O) OR15; OC (= O) R 20, wherein R 20 is heterocycloalkyl; or OC (= O) NR 11 R 20, wherein R 20 is cycloalkyl, wherein each of the portions R 14, R 22, and R 20 is optionally substituted with 1 to 3 R 10 groups.
26. 26. The compound according to claim 25, characterized in that Q is CH2CH2 and R2 is H or optionally substituted alkyl.
27. 27. The compound according to claim 1, characterized in that the compounds are selected according to Table 1.
28. 28. The compound according to claim 1, characterized in that the compounds are selected according to Table 2.
29. 29. The compound according to claim 28, characterized in that the compounds are selected according to the following table:
30. 30. The compound according to claim 1, characterized in that the compounds are selected according to Table 3.
31. 31. The compound according to claim 1, characterized in that the compounds are selected according to Table 4.
32. 32. The compound according to claim 1, characterized in that the compounds are selected according to Table 5.
33. The compound according to claim 1, characterized in that the compound is:
34. 34. A pharmaceutical composition, characterized in that a compound according to claim 1 and at least one pharmaceutically acceptable excipient.
35. 35. A method for the treatment of a prostate disorder, characterized in that it comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 1.
36. 36. The method according to claim 35, characterized in that the prostate disorder is prostate cancer or benign prostatic hyperplasia.
37. 37. A method for the treatment of an angiogenic disorder, characterized in that it comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 1.
38. 38. The method according to claim 37, characterized in that the angiogenic disorder is selected from the group consisting of cancer of solid tumors, hematological tumors, macular degeneration, premature quality retinopathy, diabetic retinopathy, rheumatoid arthritis, psoriasis, endometriosis, and restenosis.
39. 39. A method for the treatment of a pathological disorder, characterized in that it comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 1.
40. 40. The method according to claim 39, characterized because the pathological disorder is selected from the group consisting of neoplasia, chronic arthritis, pulmonary fibrosis, myelofibrosis, healing of abnormal wounds, and atherosclerosis.
41. 41. A method for the treatment of a neurodegenerative disorder or disease, characterized in that it comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 1.
42. 42. The method according to claim 41 , characterized in that the neurodegenerative disorder or disease is Alzheimer's disease; amyotrophic lateral sclerosis, Parkinson's disease, fulminating attack or crisis, Huntington's disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, peripheral neuropathy induced by chemotherapy, peripheral neuropathy related to AIDS or injury of the brain or spinal cord.
43. 43. A method for the treatment of multiple myeloma or leukemia, characterized in that it comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 1.
44. 44. The method according to claim 43, characterized in that The leukemia is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.