MXPA06009245A - Pyrazolopyrimidine-derivatives as cyclin dependent kinase inhibitors - Google Patents

Abstract

In its many embodiments, the present invention provides pyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.

Description

DERIVATIVES OF PIRAZOLOPIR1MIDINAS AS CYCLIN-DEPENDENT KINASE INHIBITORS REFERENCE TO RELATED REQUESTS The present application is a Continuation in Part of the US Patent Application, Act No. 10 / 654,546 filed on September 3, 2003, which claims priority of the US provisional patent applications, Acts Nos. 60 / 408,027 filed on October 4, 2003. September 2002 and 60/421, 959 filed on October 29, 2002.

FIELD OF THE INVENTION The present invention relates to pyrazolo [1,5-a] pyrimidine compounds useful as protein kinase inhibitors (such as, for example, inhibitors of cyclin-dependent kinases, mitogen-activated protein kinase (MAPK ERK), kinase glycogen synthase 3 (GSK3beta) and the like), pharmaceutical compositions containing the compounds, and methods for the treatment using the compounds and compositions for treating diseases such as, for example, cancer, inflammation, arthritis, viral diseases, neurodegenerative diseases such as such as Alzheimer's disease, cardiovascular diseases and fungal diseases. The present application claims the priority benefit of the provisional US patent applications, Acts No. 60 / 408,027 filed on September 4, 2002, and Act No. 60 / 421,959 filed on October 29, 2002.

BACKGROUND OF THE INVENTION Protein kinase inhibitors include kinases such as, for example, inhibitors of cyclin-dependent kinases, cyclin-dependent kinases (CDKs), mitogen-active protein kinases (MAPK / ERK), glycogen synthase kinase 3 (GSK3beta), and the similar ones. Inhibitors of protein kinase are described, for example, in M. Hale et al in WO02 / 22610 A1 and by Y. Mettey et al in J. Med. Chem., (2003) 46 222-236. Cyclin-dependent kinases are serine / threonine protein kinases, which are the driving force behind the cell cycle and cell proliferation. Individual CDKs, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8 and the like, play different roles in cell cycle progress and can be classified as G1, S, or G2M phase enzymes. Uncontrolled proliferation is a hallmark of cancer cells and the lack of regulation of CDK function occurs very frequently in several important solid tumors. CDK2 and CDK4 are of special interest since their activities are frequently incorrectly regulated in a wide variety of human cancers. The activity of CDK2 is required for progress through the G1 phase to the S phase of the cell cycle, and CDK2 is one of the key components of the G1 checkpoint. Checkpoints serve to maintain the proper sequence of cell cycle events and allow the cell to respond to insults or proliferative signals, while loss of adequate control of the checkpoint in cancer cells contributes to tumorgenesis. The CDK2 pathway influences tumorgenesis at the level of tumor suppressor function (eg, p52, RB and p27) and oncogenic activation (cyclin E). Many reports showed that the activator, cyclin E, and the inhibitor, p27, of CDK2 will be over or under expressed, respectively, in breast cancer, colon, non-small cell lung, gastric, prostate, bladder, non-Hodgkin's lymphoma , ovaries and other cancers. It was shown that their altered expressions correlate with increased levels of CDK2 activity and poor overall survival. This observation makes that CDK2 and its regulatory routes are mandatory targets for the years of development, a number of competitive small organic molecules of adenosine 5'-triphosphate (ATP) were reported as well as peptides in the literature as CDK inhibitors for the potential treatment of cancer. U.S. Pat. 6,413,974, col. 1, line 23- col. 15, line 10 offers a good description of several CDKs and their relationship to various types of cancer. The CDK inhibitors are known. For example, flavopiridol (Formula I) is a non-selective inhibitor of CDK that is currently subject to human clinical trials, A. M. Sanderowicz et al., J. Clin. Oncol. (1998) 16, 2986-2999.

Formula I Other known inhibitors of CDKs include, for example, olomoucine (J. Vesely et al., Eur. J. Biochem., (1994) 224, 771-786) and roscovitine (I. Meijer et al, Eur. J. Biochem. , (1997) 243, 527-536). U.S. Patent 6,107,305 describes certain pyrazolo [3,4-b] pyridine compounds as CDK inhibitors. An illustrative compound of the '305 patent possesses Formula II: Formula II K. S. Kim et al, J. Med. Chem. 45 (2002) 3905-3927 and WO 2/10162 disclose certain aminothiazole compounds as CDK inhibitors. Pyrazolopyrimidines are known. For example, WO92 / 18504, WO02 / 50079, W095 / 35298, WO02 / 40485, EP94304104.6, EP0628559 (equivalent to U.S. Patents 5,602,136, 5,602,137 and 5,571,813), U.S. Patent 6,383,790, Chem. Pharm. Buli, (1999) 4_7_928, J. Med. Chem., (1977) 20, 296, J. Med. Chem., (1976) 19 517 and Chem. Pharm. Bull., (1962) 0 620 disclose several pyrazolopyrimidines. Other publications of interest are: WO 03/101993 (published on December 11, 2003), WO 03/091256 (published on November 6, 2003), and DE 10223917 (published on December 11, 2003). There is a need for new compounds, formulations, treatments and therapies to treat diseases and disorders associated with CDK. Accordingly, it is an object of the present invention to provide compounds useful for the treatment or prevention or alleviation of said diseases and disorders.

BRIEF DESCRIPTION OF THE INVENTION In its various embodiments, the present invention provides a novel class of pyrazolo [1,5-a] pyrimidine compounds as inhibitors of cyclin-dependent kinases, methods for preparing said compounds, pharmaceutical compositions comprising one or more such compounds , methods for preparing pharmaceutical formulations comprising comprising one or more such compounds, and methods of treating, preventing, inhibiting or alleviating one or more diseases associated with CDKs using said compounds or pharmaceutical compositions. In one aspect, the present application discloses a compound, or pharmaceutically acceptable salts or solvates of said compound, said compound possesses the general structure shown in Formula III: Formula III in which: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including the N-oxide of said heteroaryl), - (CHR °) n-aryl, - (CHRb) n-heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (O2) R5, - C (O) R5, -C (O) NR5R10, - SO3H, -SR10, -S (O2) R7, -S (O2) NR5R10, -N (R5) S (O2) R7, -N (R5) C (O) R7 and - N (R5) C (O) NR5R10; R2 is selected from the group consisting of R9, alkyl, alkenyl, alkynyl, CF3, heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R9 groups which may be the same or different and are independently selected from the list of R9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups, aryl fused to an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups, heteroaryl fused with an aryl or heteroaryl group, ^ - ^ YÍCH ^? TN ^ N- R8 wherein one or more of the aryl and / or one or more of the heteroaryl in the definitions set forth above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consists of halogen, -CN, -OR5, -SR5, -S (O2) R6, -S (O2) NR5R6, -NR5R6, - C (0) NR5R6, CF3, alkyl, aryl and OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, -OR6, -SR6, -C (O) N (R5R6), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 the heterocyclyl moieties whose structures are shown immediately above for R3 can be unsubstituted or optionally substituted independently with one or more portions that can be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) pOR5, -OR5, -NR5R6, - (CR4R5) PNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (O2) R6, -S (O2) NR5R6, -N (R5) S (O2) R7, -N ( R5) C (O) R7 and -N (R5) C (O) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring possesses an -OR5 portion; R 4 is H, halo or alkyl; R5 is H, alkyl, aryl or cycloalkyl; R6 is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R4Rd) pR9, -N (R5) Boc, - (CR4R5) pOR5, -C (O2) R5, -C (O) R5, -C (O) NR5R10, -SO3H, - SR10, -S (O2) R7, -S (O2) NR5R10, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5, - C (R4R5) P-R9, --N (R5) Boc, - (CR4R5) pOR5, -C (O2) R5, -C (O) NR4R5, -C (O) R5, -SO3H, -SR5, - S (02) R7, -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in -NR5R10, or (ii) R5 and R6 in the NR5R6 portion portion, can be joined to form a cycloalkyl or heterocyclyl portion, with each of said cycloalkyl or heterocyclyl portions being unsubstituted or being optionally substituted independently with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or substituted optionally independently with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (O2) R5, -C (O) NR5R10, -C (O) R5, -SR10, -S (O2) R10, -S (O2) NR5R10, ~ N (R5) S (O2) R10, -N ( R5) C (O) R10 and -N (R5) C (O) NR5R10; R8 is selected from the group consisting of R6, -OR6, -C (O) NR5R10, -S (O2) NR5R10, -C (O) R7, -C (= N-CN) -NH2, -C (= NH ) -NHR5, heterocyclyl, and -S (O2) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R10, -C (O2) R6, -C (O) NR5R10, -OR6, -SR6, -S (O2) R7, -S (O2) NR5R10, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R10; m is O to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R2 is phenyl, R3 is not alkyl, alkynyl or halogen, and that when R2 is aryl, R is not p (C R5) n NR5R8 j and with the additional proviso that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms. The compounds of Formula III may be useful as inhibitors of kinase proteins and may be useful in the treatment and prevention of proliferative diseases, for example, cancer, inflammation and arthritis. They may also be useful for the treatment of neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, viral and fungal diseases.

DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the present invention discloses pyrazolo [1,5-ajpyrimidine compounds which are represented by structural Formula III, or a pharmaceutically acceptable salt or solvate thereof, wherein the various portions are as described above. In another embodiment, R is - (CHR5) n-aryl, - (CHR5) n-heteroaryl, _ (CHR5) n-heteroaryl (with said heteroaryl being substituted with an additional heteroaryl, the same or different), - (CHR5) n -heterocyclyl (with said heterocyclyl being substituted with an additional heterocyclyl, the same or different), or (CH2 V N-Rc In another embodiment, R2 is halogen, CF3, CN, lower alkyl, alkyl substituted with -OR6, alkynyl, aryl, heteroaryl or heterocyclyl. In another embodiment, R3 is H, lower alkyl, aryl, heteroaryl, cycloalkyl, -NR5R6, Or wherein said alkyl, aryl, heteroaryl, cycloalkyl and the heterocyclyl structures shown immediately above for R3 are optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CF3, OCF3, lower alkyl, CN, -C (O) R5, -S (O2) R5, -C (= NH) -NH2, -C (= CN) -NH2, hydroxyalkyl, alkoxycarbonyl, -SR5, and OR5, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring possesses an -OR5 portion. In another embodiment, R 4 is H or lower alkyl. In another embodiment, R5 is H, lower alkyl or cycloalkyl. In another embodiment, n is 1 to 2. In a further embodiment, R is - (CHR5) n-aryl, - (CHR5) n-heteroaryl. In a further embodiment, R2 is halogen, CF3, CN, lower alkyl, alkynyl, or alkyl substituted with -OR6 '. In a further embodiment, R2 is lower alkyl, alkynyl or Br. In a further embodiment, R3 is H, lower alkyl , aril, wherein said alkyl, aryl and heterocyclyl moieties which are shown immediately above for R3 are optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CF3, lower alkyl, hydroxyalkyl, alkoxy , -S (O2) R5, and CN. In a further embodiment, R 4 is H. In a further embodiment, R 5 is H, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a further embodiment, R8 is alkyl or hydroxyalkyl. In a further embodiment, n is 1. In a further embodiment, p is 1 or 2. Another embodiment discloses the inventive compounds shown in Table 1, which exhibited CDK2 inhibitory activity of about 0.0001 μM at > around 5 μM. The test methods are described below (from page 333 onwards).

TABLE 1 Another embodiment of the invention reveals the following compounds, which exhibited CDK2 inhibitory activity of about 0.0001 μM to about 0.5 μM: Another embodiment of the invention reveals the following compounds, which exhibited CDK2 inhibitory activity of about O.OOOl μM to about 0.1 μM: As used above, and throughout the present disclosure, it will be understood that the following terms, unless otherwise indicated, have the following meanings: "Patient" includes both human beings and animals. "Mammal" means human beings and other mammalian animals. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. The term "substituted alkyl" means that the alkyl group may be substituted with one or more substituents which may be the same or different, each substituent being independently selected from! group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH (alkyl), -NH (cycloalkyl), -N (alkyl) 2, carboxy and -C (O) O- I rent. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably from about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means that the alkynyl group may be substituted with one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl. "Aryl" means a monocyclic or multicyclic aromatic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group may be optionally substituted with one or more "ring system substituents" which may be the same or different, and which are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Heteroaryl" means a monocyclic or multicyclic aromatic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element which is not carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" may be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or tia before the naming of the heteroaryl root means that at least one nitrogen, oxygen or sulfur atom respectively, is present as an annular atom. A nitrogen atom of a heteroaryl can optionally be oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryl include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,4- thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo [1,2-ajpyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. "Aralkyl" or "arylalkyl" means an aryl alkyl group in which the aryl and alkyl are as described above. Preferred aralkyl comprises a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The link to the progenitor portion is through the alkyl. "Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryl comprise a lower alkyl group. A non-limiting example of a suitable alkylaryl group is tolyl. The link to the progenitor portion is through the aril. "Cycloalkyl" means a mono or multicyclic nonaromatic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl may be optionally substituted with one or more "ring system substituents" which may be the same or different, and they are as defined above. Non-limiting examples of suitable monocyclic cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Non-limiting examples of suitable multicyclic cycloalkyl include 1-decalinyl, norbornyl, adamantyl and the like, as well as partially saturated species such as, for example, indanyl, tetrahydronaphthyl and the like. "Halogen" means fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are preferred. "Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system that, for example, replaces a hydrogen available in the ring system. The substituents of the ring system can be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C (= N-CN) -NH2, -C (= NH) -NH2, -C (= NH) -NH (alkyl), Y? Y2N-, Y? Y2N-alkyl-, Y1Y2NC (O) -, Y-, Y2NSO2- and -SO2NY1Y2 , in which Y1 and Y2 may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a simple portion that simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) in a ring system. Examples of said portion are methylene dioxy, ethylenedioxy, -C (CH3) 2- and the like forming portions such as, for example: "Heterocyclyl" means a monocyclic or multicyclic saturated non-aromatic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the system Ring is an element that is not carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and / or sulfur atoms present in the ring system. Preferred heterocycles contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the name of the heterocyclyl root means that at least one nitrogen, oxygen or sulfur atom, respectively, is present as an annular atom. Any-NH in a heterocyclyl ring may exist protected such as, for example, as a group -N (Boc), -N (CBz), -N (Tos) and the like; such protections are also considered as part of the present invention. The heterocyclyl may be optionally substituted with one or more "ring system substituents" which may be identical or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl may optionally be oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable monocyclic heterocyclic rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. It should be noted that in ring systems containing hetero atoms of the present invention, there are no hydroxyl groups on the carbon atoms adjacent to an N, O or S, just as there are no N or S groups on the carbon adjacent to another. heteroatom Therefore, for example, in the ring: H there is no -OH attached directly to the carbons marked 2 and 5. It should be noted that tautomeric forms such as, for example, the portions: they are considered equivalent in certain embodiments of the present invention. "Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as described above. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The link to the progenitor portion is through alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl. "Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as described above. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of aralkyl groups include pyridylmethyl, and quinoIin-3-ylmethyl. The link to the progenitor portion is through the alkyl. "Hydroxyalkyl" means an HO-alkyl-group in which alkyl is as defined above. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. "Acyl" means a group H-C (O) -, alkyl-C (O) - or cycloalkyl- C (O) -, group in which the various groups are as described above. The link to the progenitor portion is through the carbonyl. Preferred acyl contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl. "Aroyl" means an aryl-C (O) - group in which the aryl group is as described above. The link to the progenitor portion is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The link to the progenitor portion is through ether oxygen. "Aryloxy" means an aryl-O- group in which the aryl group is as described previously. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The link to the progenitor portion is through ether oxygen. "Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as described above. Non-limiting examples of suitable aralkyloxy include benzyloxy and 1- or 2-naphthalenemethoxy. The link to the progenitor portion is through ether oxygen. "Alkylthio" means an alkyl-S- group in which the alkyl group is as described above. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The link to the progenitor portion is through sulfur. "Arylthio" means an aryl-S- group in which the aryl group is as described above. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The link to the progenitor portion is through sulfur. "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as described above. A non-limiting example of a suitable aralkylthio group is benzylthio. The link to the progenitor portion is through sulfur. "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The link to the progenitor portion is through the carbonyl. "Aryloxycarbonyl" means an aryl-O-C (O) - group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The link to the progenitor portion is through the carbonyl. "Aralkoxycarbonyl" means an aralkyl-O-C (O) - group. A non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The link to the progenitor portion is through the carbonyl. "Alkylsulfonyl" means an alkyl-S (O2) - group. Preferred groups are those in which the alkyl group is lower alkyl. The link to the progenitor portion is through the sulfonyl.

"Arylsulfonyl" means an aryl-S (O 2) - group. The link to the progenitor portion is through the sulfonyl. The term "substituted" means that one or more hydrogens in the designated atom is replaced with a selection of the indicated group, provided that the normal valence of the designated atom is not exceeded in the existing circumstances, and that the results of the substitution have a compound stable. Combinations of substituents and / or variables are allowed only if such combinations produce stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive the isolation to a useful degree of purity of a reaction mixture, and the formulation into an effective therapeutic agent. The term "optionally substituted" means optional substitution with the groups, radicals or specified portions. The term "isolated" or "in isolation" for a compound, refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. The term "purified" or "in purified form" for a compound refers to the physical state of said compound after it is obtained from a purification process or processes described herein or known to an expert, in a sufficient purity so that it can be characterized by standard analytical techniques described herein or known to the expert. It should be noted that it is assumed that any heteroatom with valences not covered in the text, schemas, examples and tables in the present possesses the hydrogen atom (s) to cover the valences. When a functional group in a compound is called "protected", this means that the group is in modified form to avoid unwanted side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those of ordinary skill in the art, as well as in reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York. When any variable (eg, aryl, heterocycle, R2, etc.) is present more than once in any constituent or in Formula III, its definition in each occurrence is independent of its definition in any other occurrence. In accordance with its use herein, the term "composition" is intended to encompass a product comprising the specified components in the specified amounts, as well as any product that results, directly or indirectly, from the combination of the components specified in the amounts specified. The pro-drugs and solvates of the compounds of the invention are also contemplated herein. The term "pro-drug", as used herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to give a compound of Formula III or a salt and / or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Dehigadoy Systems (1987) 14 of A.C.S. Symposium Series, and in Bioreversible Carries in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference. "Solvate" means a physical association of a compound of the present invention with one or more molecules of the solvent. This physical association comprises varying degrees of ionic and covalent binding, including hydrogen bonding. In certain instances, the solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" encompasses both the phase of the solution and insulable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate in which the solvent molecule is H2O. "Effective amount" or "therapeutically effective amount" is used to describe an amount of compound ou a composition of the present invention effective in inhibiting the CDK (s) and thus producing the desired therapeutic, relieving, inhibiting or preventive desired. The compounds of Formula III can form salts that are also within the scope of the present invention. It is understood that reference to a compound of Formula III herein includes reference to salts thereof, unless otherwise indicated. The term "salt (s)", as used herein, denotes acid salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. In addition, when a compound of Formula III contains a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, can form zwitterions ( "inner salts") and are included in the term "salt (s)" in accordance with its use herein. Salts acceptable for pharmaceutical use are preferred (ie, non-toxic, physiologically acceptable), although other salts are also useful. Salts of the compounds of Formula III can be formed, for example, by reacting a compound of Formula III with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt it is precipitated or in an aqueous medium followed by lyophilization. Sales acid addition example include acetates, ascorbates, benzoates, benzensulfonatos, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, yodohidratos, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates , salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally suitable for the formation of salts useful for pharmaceutical use of basic pharmaceutical compounds are treated, for example, by S. Berge er al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson went to, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food &Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by way of reference thereto. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases, (e.g., organic amines) , such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. The basic groups containing nitrogen can be quatemized with agents such as lower alkyl halides (for example methyl, ethyl, and butyl, bromide, and iodide chlorides), dialkyl sulfate (for example dimethyl, diethyl, and dibutyl sulfates, chain halides extensive (for example decylol, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (for example benzyl and phenethyl bromides), and others, all said acid salts and base salts are intended to be acceptable salts for pharmaceutical use within the scope of the invention and all the acid and base salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention The compounds of Formula III, and salts, solvates and prodrugs thereof, may exist in their tautomeric form (e.g., as an amide or amino ether) All of such tautomeric forms are contemplated herein as part of the present invention. esteroisomers (e.g., geometric isomers, optical isomers and the like) of the present compounds (including those of salts, solvates and prodrugs of compounds as well as the salts and solvates of the prodrugs), such as those that may exist due to Asymmetric carbons in various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotamate forms, atropisomers and diastereomeric forms, are contemplated within the scope of the present invention, with positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). The individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be mixed, for example, as racemates or with all other stereoisomers, or other selected ones. The chiral centers of the present invention may possess the S or R configuration as defined by the IUPAC Recommendations 1974. It is intended that the use of the terms "salt", "solvate", "prodrug" and the like, be applied in an equivalent manner. to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds. The compounds according to the invention possess pharmacological properties; in particular, the compounds of Formula III can be inhibitors of protein kinases such as, for example, inhibitors of cyclin-dependent kinases, mitogen-activated protein kinase (MAPK / ERK), glycogen synthase kinase 3 (GSK3beta) and Similar. Cyclin-dependent kinases (CDKs) include, for example, CDC2 (CDK1), CDK2, CDK4, CDK5, CDK6, CDK7 and CDK8. It is expected that novel compounds of Formula III will be useful in the therapy of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological / neurodegenerative disorders, arthritis, inflammation, anti-proliferative (eg, retinopathy), neuronal disease, alopecia and cardiovascular. Many of these diseases and disorders are listed in U.S. 6,413,974 cited above, the disclosure of which is incorporated herein. More specifically, the compounds of Formula III may be useful in the treatment of a variety of cancers, including (but not limited to) the following: carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including cancer cellular lung, esophagus, vesicle, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of the lymphoid lines, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, and Burkett's lymphoma; hematopoietic tumors of the myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctantoma, follicular thyroid cancer, and Kaposi sarcoma. Due to the key role of CDKs in the regulation of cell proliferation in general, inhibitors could act as reversible cytostatic agents that may be useful in the treatment of any disease process that characterizes abnormal cell proliferation, for example, benign hyperplasia of prostate, polyposis familial adenomatosis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, formation of hypertrophic scars, inflammation of the intestine disease, rejection of transplants, endotoxic attack and fungal infections . Compounds of Formula III may also be useful in the treatment of Alzheimer's disease, as suggested by the recent discovery that CDK5 is related to the phosphorylation of tau protein (J. Biochem, (1995) 117, 741-749 ). The compounds of Formula III can induce or inhibit apoptosis. The apoptic response is aberrant in a variety of human diseases. Compounds of Formula III, as modulators of apoptosis, will be useful in the treatment of cancer (including, but not limited to those types mentioned hereinabove), viral infections (including but not limited to herpeviruses, poxviruses, Epstein-Barr viruses). , Sindbis virus and adenovirus), prevention of the development of AIDS in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer's disease, AIDS-related dementia, Parkinson's disease1, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarction , infarction and injury reperfusion, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis) sensitive rhinosinusitis Aspirin, cysts, multiple sclerosis, kidney diseases and pain due to cancer. The compounds of Formula III, as inhibitors of CDKs, can modulate the cellular level of RNA and DNA synthesis. These agents, therefore, will be useful in the treatment of viral infections (including but not limited to HIV, human papillomavirus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus). The compounds of Formula ill may also be useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer either by blocking the mutagenic event that is initiated or by blocking the progress of pre-malignant cells that have already suffered an aggression or by inhibiting the return of the tumor. The compounds of Formula III may also be useful in the inhibition of angiogenesis and tumor metastasis. The compounds of Formula III can also act as inhibitors of other protein kinases, for example, protein kinase C, her2, raf 1, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, weel kinase, Src, Abl and therefore may be effective in the treatment of diseases associated with other protein kinases. Another aspect of the present invention is a method for the treatment of a mammal (e.g., a human) having a disease or condition associated with CDK by administering a therapeutically effective amount of at least one compound of Formula III, or an acceptable salt for pharmaceutical use or solvate of said compound to the mammal. A preferred dosage is around 0.001 to 500 mg / kg of body weight / day of the compound of Formula III. A particularly preferred dosage is about 0.01 to 25 mg / kg body weight / day of a compound of Formula III, or a pharmaceutically acceptable salt or solvate of said compound. The compounds of this invention may also be useful in combination (administered together or in sequence) with one or more anti-cancer treatments such as radiation therapy, and / or one or more anticancer agents selected from the group consisting of cytostatic agents, agents cytotoxic (such as, for example, but not limited to, interactive DNA agents (such as cisplatin or doxorubicin)); taxanes (for example taxotere, taxol); topoisomerase II inhibitors (such as etoposide); topoisomerase I inhibitors (such as irinotecan (or CPT-11), camptostar, or topotecan); interactive tubulin agents (such as paclitaxel, docetaxel or the epothilones); hormonal agents (such as tamoxifen); thymidylate synthase inhibitors (such as 5-fluorouracil); anti-metabolites (such as methotrexate); alkylating agents (such as temozolomide (TEMODAR ™ from Schering-Plow Corporation, Kenilworth, New Jersey), cyclophosphamide); Farnesyl protein transferase inhibitors (such as, SARASAR ™ (4- [2- [4 - [(11 R) -3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo [5,6] ] cyclohepta [1,2- b] pyridin-11-yl] - 1 -piperidinyl] -2-oxoethyl] -1-piperidinecarboxamide, or SCH 66336 from Schering-Plow Corporation, Kenilworth, New Jersey), tipifarnib ( Zamestra® or R115777 from Janssen Pharmaceuticals), L778.123 (a farnesyl protein transferase inhibitor from Merck &Company, Whitehouse Station, New Jersey), BMS 214662 (a farnesyl protein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, New Jersey), signal transduction inhibitors (such as, Iressa (from Astra Zeneca Pharmaceuticals, England), Tarceva (EGFR kinase inhibitors), antibodies to EGFR (eg, C225), GLEEVEC ™ (C-inhibitor) abl kinase from Novartis Pharmaceuticals, East Hanover, New Jersey), interferons such as, for example, intron (from Schering-Plow Corporation), Peg-lntron (from Schering-Plow Corporation) ), combinations of hormonal therapies; aromatase combinations; ara-C, adriamycin, cytoxan, and gemcitabine. Other anti-carcinogenic agents (also known as antineoplastics) include, but are not limited to, uracil mustard, chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Tritylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin (ELOXATIN ™ from Sanofi-Synthelabo Pharmaeuticals, France), Pentostatin, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin , Deoxicoformycin, Mitomycin-C, L-Asparaginase, 17D-Ethinylestradiol, Diethystilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesterone acetate, Leuprolide , Flutam gone, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafina, Droloxafina, or Hexamethylmelamine. If formulated as a fixed dose, such combination products employ the compounds of the present invention within the dosage scale described herein and the other pharmaceutically active agent or treatment within their dosage range. For example, it was discovered that the olomucine of the inhibitor CDC2 acts synergistically with known cytotoxic agents in the induction of apoptosis (J. Cell Sci., (1995) 108, 2897. The compounds of Formula III can also be administered in sequences with anticancer agents. or known cytotoxics when a combination formulation is not appropriate The invention is not limited in the sequence of administration; the compounds of Formula III can be administered either before or after administration of the known anticancer or cytotoxic agent. For example, the cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is affected by the sequence of administration with anticancer agents. Cancer Research, (1997) 57, 3375. Such techniques are within the capabilities of persons with experience in the art as well as of attending physicians. Accordingly, in one aspect, the present invention includes combinations comprising an amount of at least one compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof, and an amount of one or more anticancer treatments listed and anticancer agents. previous in which the amounts of compounds / treatments produce the desired therapeutic effect. The pharmacological properties of the compounds of the present invention can be confirmed by a number of pharmacological assays. The exemplified pharmacological assays described further were carried out without the compounds according to the invention and their salts. The present invention is also directed to pharmaceutical compositions comprising at least one compound of Formula III, or a pharmaceutically acceptable salt or solvate of said compound and at least one vehicle acceptable for pharmaceutical use. To prepare pharmaceutical compositions from the compounds described by the present invention, inert, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, chewable tablets and suppositories. The powders and tablets may be composed of about 5 to about 95 percent active component. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, chewable tablets and capsules can be used as solid dosage forms suitable for oral administration. Examples of acceptable vehicles for pharmaceutical use and methods of making various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania. Liquid form preparations include solutions, suspensions and emulsions. As an example, there may be mentioned water or water-glycol propylene solutions for parenteral injection or addition of sweeteners or opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be found in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, for example nitrogen. Also included are solid form preparations which are intended to be converted, immediately after use, into liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be delivered transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and / or emulsions and can be included in a transdermal patch of the matrix or reservoir type, as are conventional in the art for this purpose. The compounds of the present invention can also be administered subcutaneously. Preferably, the compound is administered orally or intravenously. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into unit doses of suitable size containing appropriate quantities of the active component, for example, an effective amount to achieve the desired effect. The amount of active compound in a unit dose of preparation can be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application. The actual dose used may vary depending on the requirements of the patient and the severity of the condition being treated. The determination of the appropriate dosing regimen for a particular situation is within the knowledge of the art. For added convenience, the total daily dosage can be divided and administered in portions during the day as required. The amount and frequency of administration of the compounds of the invention and / or pharmaceutically acceptable salts thereof will be regulated according to the criteria of the attending physician considering factors such as the age, condition and size of the patient, as well as How serious are the symptoms that undergo treatment. A typical dosage regimen recommended for oral administration may range from about 1 mg / day to about 500 mg / day, preferably 1 mg / day to 200 mg / day, in divided doses in two to four. Another aspect of the present invention is a kit comprising a therapeutically effective amount of at least one compound of Formula III, or a pharmaceutically acceptable salt or solvate of said compound a carrier, vehicle or diluent acceptable for pharmaceutical use. Yet another aspect of the present invention is a kit comprising an amount of at least one compound of Formula III, or a pharmaceutically acceptable salt or solvate of said compound and an amount of at least one anti-cancer therapy and / or anti-cancer agent listed. above, in which the amounts of the two or more components produce the desired therapeutic effect. The invention disclosed herein is exemplified by means of the following preparations and examples which are not to be construed as limiting the scope of the invention. Mechanistic routes and alternative analogous structures will be evident to those with experience in the art. When the NMR data were presented, the 1 H spectra were obtained in either a Varian VXR-200 (200 MHz, 1 H), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz) and reported as ppm in descending field of Me4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenterally. When the LC / MS data were presented, the analyzes were performed using an Applied Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC column: Altech platinum C18, 3 microns, 33mm x 7mm ID; gradient flow: 0 min - 10% CH3CN, 5 min - 95% CH3CN, 7 min - 95% CH3CN, 7.5 min - 10% CH3CN, 9 min - high. The retention time and the observed parent ion are given. The following solvents and reagents can be referred to by their abbreviations in parentheses: Thin layer chromatography: TLC dichloromethane: CH2Cl2 ethyl acetate: AcOEt or EtOAc methanol: MeOH trifluoroacetate: TFA triethylamine: Et3N or TEA butoxycarbonyl: n-Boc or Boc Nuclear magnetic resonance spectroscopy: NMR liquid chromatography mass spectrometry: LCMS high definition mass spectrometry: HRMS milliliters: mL millimoles: mmol microliters: μl grams: g milligrams: mg ambient temperature or ta (ambient): about 25 ° C. dimethoxyethane: DME EXAMPLES In general, the compounds described in the present invention can be prepared through the general routes described below in Scheme 1.

SCHEME 1 2 3 The treatment of the starting nitrile with potassium t-butoxide and the ethyl formate produces the enol 2 intermediate which, when treated with hydrazine, gives the desired substituted 3-aminopyrazole. Condensation of type 3 compounds with the keto ester with appropriately functional groups of type 5 gives rise to the pyridones 6 as shown in Scheme 3. The keto esters used in this general route are commercially available or can be prepared as illustrated in Scheme 2.

SCHEME 2 Type 9 chlorides can be prepared by treating pyridones 8 with POCI3, When R2 equals H, substitution at this position is possible in type 9 compounds by electrophilic halogenation, acylation, and various other aromatic substitutions. electrophilic The introduction of the N7-amino functional groups can be achieved by displacement of the chloride of the compounds of type 9 by reaction with the appropriate amine as shown in Scheme 3.

SCHEME 3 Condensation of type 7 compounds with the malonate ester with appropriate functional groups of type 11 results in the pyridones 13 as shown in Scheme 4. Chlorides of type 14 can be prepared by treating the 13 with POCI3 ? When R2 is H, substitution in this position is possible in compounds of type 9 by electrophilic halogenation, acylation, and various other electrophilic aromatic substitutions. The incorporation of the N7-amino functional groups can be achieved through the regioselective displacement of the chloride of the type 14 compounds. Incorporation of the N5-amino functional groups by the addition of an appropriate amine at a higher temperature.

SCHEME 4 Alternatively, condensations of type 7 aminopyrazoles with a keto ester with functional groups in an appropriate manner as prepared in Scheme 5, generates the compounds of type 13 as shown in Scheme 4.

SCHEME 5 Type 14 chlorides can be prepared by treatment with pyridones 13 with POCI3, When R2 equals H, substitution in this position is possible in type 14 compounds by electrophilic halogenation, acylation, and various other electrophilic aromatic substitutions. . The incorporation of the N7-amino functional groups can be achieved through the displacement of the chloride of the compounds of type 15.

I PREPARED EXAMPLES PREPARED EXAMPLE 1 Step A: A procedure was followed in the German Patent DE 19834047 A1, p 19. To a solution of KOtBu (6.17 g, 0.055 mol) in THF anhydride (40 ml) was added, dropwise, a solution of cyclopropylacetonitrile (2.0 g, 0.025 mol) and ethyl formate (4.07 g, 0.055 mol) in THF anhydride (4 ml). Immediately a precipitate formed. This mixture was stirred for 12 hr. It was concentrated in vacuo and the residue was stirred with Et2O (50 ml). The resulting residue was decanted and washed with Et2O (2? 50 ml) and Et2O was removed from the residue in vacuo. The residue was dissolved in cold H2O (20 ml) and the pH was adjusted to 4-5 with 12 N HCl. The mixture was extracted with CH2Cl2 (2 x 50 ml). The organic layers were combined, dried over MgSO and concentrated in vacuo to give the aldehyde as a tan liquid.

Step B: The product of Preparative Example 1, Step A (2.12 g, 0.0195 mol), NH2NH2 • H2O (1.95 g, 0.039 mol) and 1.8 g (0.029 mol) of CH3CO2H glacial (1.8 g, 0.029 mol) in EtOH (10 g) were dissolved. ml). It was refluxed for 6 hr. and concentrated in vacuum. The residue was suspended in CH2Cl2 (150 ml) and the pH was adjusted to 9 with 1 N NaOH. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the product as an orange waxy solid. .

PREPARED EXAMPLES 2-4 Essentially by the same procedure set forth in Preparative Example 1, substituting only the nitrile shown in Column 2 of Table 2, the compounds in column 3 of Table 2 were prepared: TABLE 2 PREPARED EXAMPLE 4 2-carbomethoxycyclopentanone (6.6 ml, 0.05 mol) was added in THF (15 ml) dropwise to a vigorously stirred suspension of NaH (60% in mineral oil, 4 g, 0.1 mol) in THF (100 ml) at O - 10 ° C. When the bubbling ceased, the reaction mixture was treated at the same temperature with CICOOMe (7.8 ml, 0.1 mol) in THF (15 ml). The resulting whitish suspension was stirred for 30 minutes at room temperature and 30 minutes under reflux. The reaction was monitored by TLC for the disappearance of the starting material. The reaction mixture was carefully quenched with water and partitioned between ethyl acetate and saturated ammonium chloride solution in a funnel. Agitated and separated, the organic layer was washed with brine and dried over sodium anhydride sulfate. The solvents were removed, and the residue was purified by flash chromatography, eluted with 5% and then 10% ethyl acetate in hexane. 9.4 g of colorless oil was obtained with 94% yield. 1 H NMR (CDCl 3) d 3.90 (s, 3 H), 3.73 (s, 3 H), 2.65 (m, 4 H), 1.98 (m, 2H).

PREPARED EXAMPLE 5 To a solution of lithium diisopropylamide in THF (2.0 N, 0.04 mol) at -65 ° C, 2,2-dicarbomethoxycyclopentanone (4 g, 0.02 mol) was added dropwise in THF (60 ml). The resulting reaction mixture was stirred at the same temperature before adding methyl chloroformate (1.54 ml, 0.02 mol). The reaction mixture was stirred for one hour and poured into saturated ammonium chloride solution with a little ice. This solution was extracted three times with ether, and the combined ether layers were dried over sodium sulfate. The solvents were removed in vacuo, and the residue was purified by flash chromatography, eluted with ethyl acetate increased from 30% to 50% in hexane. 2.3 g of yellowish oil was obtained with 58% yield. 1 H NMR (CDCl 3) d 3.77 (s, 6H), 3.32 (t, 1 H), 3.60-3.10 (m, 4H).

PREPARED EXAMPLE 6 The reactions were carried out as described in (K. O.

Olsen, J. Org. Chem., (1987) 52, 4531-4536). Accordingly, freshly distilled ethyl acetate was added dropwise to a stirred solution of lithium diisopropylamide in THF at -65 to -70 ° C. The resulting solution was stirred for 30 min and the chloroquid was added as a solution in the solution. THF The reaction mixture was stirred at -65 to -70 ° C for 30 min and then terminated by the addition of 1 N HCl solution. The resulting two-phase mixture was allowed to warm to room temperature. The resulting mixture was diluted with EtOAc (100 mL) and the organic layer was collected. The aqueous layer was extracted with EtOAc (100 mL). The organic layers were combined, washed with brine, dried (Na 2 SO 4), and concentrated in vacuo to give the β-keto esters, which were used in the subsequent condensations.

PREPARED EXAMPLES 7-19 Essentially by the same procedure set forth in Preparative Example 6, replacing only the acid chlorides shown in Column 2 of Table 3, prepared the β-keto esters shown in Column 3 of Table 3: TABLE 3 PRE-PARATIVE EXAMPLE 20 O O o O OH R A Y OEt To a solution of the acid in THF was added Et3N, followed by isobutyl chloroformate at -20 s -30 ° C. Subsequently, the mixture was stirred for 30 min at -20 to -30 ° C, triethylamine hydrochloride was filtered under Argon, and the filtrate was added to the reaction mixture of LDA-EtOAc (prepared as described in Method A) -65 to -70 ° C. After the addition of 1 N HCl, followed by the processing of the reaction mixture and the evaporation of the solvents, the crude ß-keto-esters were isolated and isolated. The raw material was used in the subsequent condensations.

PREPARED EXAMPLES 21 - 28 Essentially by the same conditions set forth in Preparative Example 20 by substituting only the carboxylic acid shown in Column 2 of Table 4, the compounds shown in Column 3 of Table 4 were prepared: PREPARED EXAMPLE 29 A solution of 3-aminopyrazole (2.0 g, 24.07 mmol) and ethyl benzoylacetate (4.58 ml, 1.1 eq.) In AcOH (15 ml) was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting solid was diluted with EtOAc and filtered to give a white solid (2.04 g, 40% yield).

PREPARED EXAMPLES 30-73 Essentially by the same procedure set forth in Preparative Example 29, substituting only the aminopyrazole shown in Column 2 of Table 5 and the ester shown in Column 3 of Table 5, the compounds shown in the Column 4 of table 5: TABLE 5 PREPARED EXAMPLE 74 Ethyl benzoylacetate (1.76 ml, 1.1 eq.) And 3-amino-4-cyanopyrazole (1.0 g, 9.25 mmol) in AcOH (5.0 ml) and H2O (10 ml) were heated at reflux for 72 hours. The resulting solution was cooled to room temperature, concentrated in vacuo, and diluted with EtOAc. The resulting precipitate was filtered, washed with EtOAc, and dried in vacuo (0.47 g, 21% yield).

PREPARED EXAMPLE 75 The procedure was followed in U.S. Patent 3,907,799. Sodium (2.3 g, 2 eq.) Was added to EtOH (150 ml) in portions. When the sodium was completely dissolved, 3-aminopyrazole (4.2 g, 0.05 mol) and diethyl malonate (8.7 g, 1.1 eq.) Were added and the resulting solution was heated to reflux for 3 hours. The resulting suspension was cooled to room temperature and filtered. The filter cake was washed with EtOH (100 ml) and dissolved in water (250 ml). The resulting solution was cooled in an ice bath and the pH was adjusted to 1-2 with concentrated HCl. The resulting suspension was filtered, washed with water (100 ml) and dried in vacuo to give a white solid (4.75 g, 63% yield).

PREPARED EXAMPLES 76-78 Essentially by the same procedure set forth in Preparative Example 75, substituting only the compound shown in Column 2 of Table 6, the compounds shown in Column 3 of Table 6 were prepared: TABLE 6 PREPARED EXAMPLE 79: A solution of the compound prepared in Preparative Example 29 (1.0 g, 4.73 mmol) in POCI3 (5 ml) and pyridine (0.25 ml) was stirred at room temperature for 3 days. The resulting suspension was diluted with Et2O, filtered, and the solid residue was washed with Et2O. The combined Et 2 O washes were cooled to 0 ° C and treated with ice. When the vigorous reaction was stopped, the resulting mixture was diluted with H2O, separated, and the aqueous layer was extracted with Et2O. The combined organics were washed with H2O and saturated NaCl, dried over Na2SO4, filtered, and concentrated to give a pale yellow solid (0.86 g, 79% yield). LCMS: MH + = 230.

PREPARED EXAMPLE 80-122: Essentially by the same procedure set forth in Preparative Example 79, substituting only the compound shown in Column 2 of Table 7, the compounds shown in Column 3 of Table 7 were prepared: TABLE 7 PREPARED EXAMPLE 123 POCI3 (62 ml) was cooled to 5 ° C under nitrogen and dimethylaniline (11.4 g, 2.8 eq.) And the compound prepared in Preparative Example 75 (4.75 g, 0.032 mol). The reaction mixture was heated to 60 ° C and stirred until the next day. The reaction mixture was cooled to 30 ° C and the POCI was distilled under reduced pressure. The residue was dissolved in CH2Cl2 (300 ml) and poured into ice. After stirring for 15 minutes, the pH of the mixture was adjusted to 7-8 with solid NaHCO3. The layers were separated and the organic layer was washed with H2O (3 x 200 ml), dried over MgSO, filtered and concentrated. The crude product was purified by flash chromatography using a 50:50 CH2Cl2: hexanes solution as eluent to elute the dimethyl aniline. Then, the eluent was changed to 75: 25 CH2Cl2: hexanes to elute the desired product (4.58 g, 77% yield). MS: MH + = 188.

PREPARED EXAMPLES 124-126 Essentially by the same procedure set forth in Preparative Example 123, substituting only the compound in Column 2 of Table 8, the compounds shown in Column 3 of Table 8 were prepared: TABLE 8 PREPARED EXAMPLE 127 A solution of the compound prepared in Preparative Example 79 (0.10 g, 0.435 mmol) in CH3CN (3 mL) was treated with NBS (0.085 g, 1.1 eq.). The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 20% EtOAc-en-hexanes solution as eluent (0.13 g, 100% yield). LCMS: MH + = 308.

PREPARED EXAMPLES 128-164 Essentially by the same procedure set forth in Preparative Example 127 substituting only the compounds shown in Column 2 of Table 9, the compounds shown in Column 3 of Table 9 were prepared: TABLE 9 PREPARED EXAMPLE 165 A solution of the compound prepared in Preparative Example 80 (0.3 g, 1.2 mmol) in CH 3 CN (15 ml) was treated with NCS (0.18 g, 1.1 eq.) And the resulting solution was heated to reflux 4 hours. NCS (0.032 g, 0. 2 eq.) And the resulting solution was stirred at reflux until the next day. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue was purified by flash chromatography using a 20% EtOAc in hexanes solution as eluent (0.28 g, 83% yield). LCMS: MH + = 282.

PREPARED EXAMPLE 166-167 Essentially by the same procedure set forth in Preparative Example 165, substituting only the compound shown in Column 2 of Table 10, the compound shown in Column 3 of Table 10 was prepared: TABLE 10 PREPARED EXAMPLE 167.10 Essentially by the same procedure set forth in Preparative Example 165, substituting only N-iodosuccinimide, the above compound was prepared.

PREPARED EXAMPLE 168 To a solution of the compound of Preparative Example 79 (1.0 g, 4. 35 mmol) in DMF (6 ml) was added POCI3 (1.24 ml, 3.05 eq.) And the resulting mixture was stirred at room temperature until the next day. The reaction mixture was cooled to 0 ° C and the excess POCI3 was deactivated by the addition of ice. The resulting solution was neutralized with 1N NaOH, diluted with H2O, and extracted with CH2Cl2. The combined organics were dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using a 5% MeOH solution in CH2Cl2 as eluent (0.95 g, 85% yield). LCMS: MH + = 258.

PREPARED EXAMPLE 169 Essentially by the same procedure set forth in Preparative Example 168, substituting only the compound prepared in Preparative Example 80, the above compound was prepared (0.45 g, 40% yield).

PREPARED EXAMPLE 170 To a solution of the product of Preparative Example 169 (0.25 g, 0. 97 mmol) in THF was added NaBH 4 (0.041 g, 1.1 eq.) And the resulting solution was stirred at room temperature until the next day. The reaction mixture was quenched by the addition of H2O and extracted with CH2Cl2. The combined organics were dried over Na2SO, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using a mixture of 60: 40 hexanes: EtOAc as eluent (0.17 g, 69% yield). MS: MH + = 260.

PREPARED EXAMPLE 171 A solution of the compound prepared in Preparative Example 170 (0.12 g, 0.462 mmol), dimethyl sulfate (0.088 mL, 2.0 eq), 50% NaOH (0.26 mL) and catalytic NBr Bu in CH2Cl2 (4 mL) was stirred at room temperature overnight. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using a solution of 30% EtOAc-en-hexanes as eluent (0.062 g, 48% yield).

PREPARED EXAMPLE 172 To a solution of PPh3 (4.07 g, 4.0 eq.) And CBr4 (2.57 g, 2.0 eq.) In CH2Cl2 (75 ml) at 0 ° C was added the compound prepared in Preparative Example 168 (1.0 g, 3.88 mmol) . The resulting solution was stirred at 0 ° C for 1 hour and concentrated under reduced pressure. The residue was purified by flash chromatography using a solution of 20% EtOAc in hexanes as eluent (1.07 g, 67% yield).

PREPARED EXAMPLE 173 Essentially by the same procedure set forth in Preparative Example 172, substituting only the compound prepared in Preparative Example 169, the above compound was prepared (0.5 g, 70% yield). PREPARED EXAMPLE 174 The compound prepared in Preparative Example 127 (3.08 g, 10.0 mmol), NH32.0 M in 2-propanol (50 mL, 100.0 mmol), and 37% aqueous NH3 (10.0 mL) in a closed pressure vessel was stirred. 50 ° C for 1 day. The solvent was evaporated and the crude product was purified by flash chromatography using 3: 1 CH2Cl2: EtOAc as eluent. A pale yellow solid was obtained (2.30 g, 80%). LCMS: M + = 289.

PREPARED EXAMPLES 175-180 Essentially by the same procedure set forth in Preparative Example 174, substituting only the compound shown in Column 2 of Table 11, the compounds shown in Column 3 of Table 11 were prepared.

TABLE 11 PREPARED EXAMPLE 181 The compound prepared in Preparative Example 80 (0.3 g, 1.2 mmol), K2CO3 (0.33 g, 2 eq.), And 4-aminomethylpyridine (0.13 mL, 1.1 eq.) Was heated to reflux until the next day. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with H2O and extracted with CH2Cl2. The combined organics were dried over Na 2 SO 1, filtered and concentrated. The crude product was purified by flash chromatography using a 5% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent (0.051 g, 40% yield). LCMS: MH + = 320.

PREPARED EXAMPLE 182 Essentially by the same procedure set forth in Preparative Example 181, substituting only the compound described in Preparative Example 92, the above compound was prepared. LCMS: MH + = 370.

PREPARED EXAMPLE 183 IPr2NEt (0.47 ml, 2.0 eq.) And 3-aminomethylpyridine (0.15 ml, 1.1 eq.) Were added to a solution of the compound prepared in Preparative Example 123 (0.25 g, 1.3 mmol) in dioxane (5 ml). The resulting solution was stirred at room temperature for 72 hours. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organics were washed with H2O and saturated NaCl, dried over Na2SO, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography using a 5% MeOH solution in CH2Cl2 as eluent (0.29 g, 83% yield). MS: MH + = 260.

PREPARED EXAMPLES 184-187 Essentially by the same procedure set forth in Preparative Example 183, substituting only the compound shown in Column 2 of Table 12, the compounds shown in Column 3 of Table 12 were prepared. TABLE 12 PREPARED EXAMPLE 188 and PREPARED EXAMPLE 189 LAH (4.78 mL, 1 M in Et 2 O, 1.0 eq.) Was added dropwise to a solution of the compound prepared in Preparative Example 185 (1.18 g, 3.98 mmol) in THF (35 mL) at -78 ° C. The reaction mixture was stirred at -78 ° C for 3 hours at which time additional LAH (2.0 ml, 1 M in Et2O, 0.42 eq.) Was added dropwise. The reaction mixture was stirred an additional 1.25 hours and deactivated by the addition of saturated Na 2 SO 4 (8.5 ml).

The reaction mixture was diluted with EtOAC (23 ml), H2O (2 ml), and CH3OH (50 ml). The resulting suspension was filtered through a plug of Celite. The Celite was washed with CH3OH and the filtrate was dried with Na2SO4, filtered, and concentrated. The product was purified by flash chromatography using a solution of CH CI2: CH3OH (93: 7) as eluent to give aldehyde as the first eluent and alcohol as the second eluent. Preparative Example 188: (aldehyde): 0.4 g, 39% yield. MS: MH + = 254. Preparative Example 189: (alcohol): 0.25 g, 24% yield. MS: MH + = 256.

PREPARATORY EXAMPLE 190 To a solution of the compound prepared in Preparative Example 188 (0.075 g, 0.30 mmol) in THF (2.0 ml) at 0 ° C was added CH3MgBr (0.3 ml solution, 3.0 M in Et2O, 3.0 eq.) Dropwise. The resulting solution was stirred at 0 ° C for an additional 1.5 hours, warmed to room temperature, and stirred until the next day. Additional CH3MgBr (0.15 mL, 3.0M in Et2O, 1, eq.) Was added and the resulting solution was stirred an additional 1.5 hours. The reaction mixture was cooled to 0 ° C and deactivated by the addition of saturated NH CI. The resulting solution was diluted with CH2CI and H2O and extracted with CH2Cl2. The combined organics were washed with saturated NaCl and dried over Na2SO, filtered and concentrated. The crude product was purified by flash chromatography using a solution of CH2Cl2: CH3OH (90:10) as eluent (0.048 g, 60% yield). MS: MH + = 270.

PREPARED EXAMPLE 191 Essentially by the same procedure set forth in Preparative Example 190, substituting only the compound prepared in Preparative Example 185 and using excess MeMgBr (5 eq.), The above compound was prepared.

PREPARED EXAMPLE 192 The compound prepared in Preparative Example 181 (0.29 g, 0. 91 mmol), BOC2O (0.22 g, 1.1 eq), and DMAP (0.13 g, 1.1 eq.) In dioxane (10 ml) was stirred at room temperature for 3 days. Additional BOC2O (0.1 Og, 0.5 eq.) Was added and the reaction mixture was stirred 4 hours. The reaction mixture was concentrated in vacuo, diluted with saturated NaHCO3 (15 mL), and extracted with CH2Cl2 (2 x 100 mL). The combined organics were dried over Na SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 5% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent (0.35 g, 91% yield). LCMS: MH + = 420.

PREPARED EXAMPLE 193 Essentially by the same procedure set forth in Preparative Example 192, substituting only the compound prepared in Preparative Example 183, the above compound was prepared. MS: MH + = 360.

PREPARED EXAMPLE 193.10 Essentially by the same procedure set forth in Preparative Example 192, substituting only the compound prepared in Preparative Example 184.1, the above compound was prepared. MS: MH + = 454.

PREPARED EXAMPLE 194 Essentially by the same procedure set forth in Preparative Example 192, substituting only the above compound prepared in Preparative Example 187.11, the above compound was prepared (0.223 g, 88% yield). MS: MH + = 528.

PREPARED EXAMPLE 195 Essentially by the same procedure set forth in Preparative Example 127, substituting only the compound prepared in Preparative Example 192, the above compound was prepared (0.38 g, 95% yield). LCMS: MH + = 498.

PREPARED EXAMPLE 196 Essentially by the same procedure set forth in Preparative Example 195, substituting only the compound prepared in Preparative Example 193, the above compound was prepared (0.3 g, 83% yield). MS: MH + = 438.

PREPARED EXAMPLE 197 A solution of the compound prepared in Preparative Example 195 (0.15 g, 0.3 mmol), phenylboronic acid (0.073 g, 2.0 eq.), K3PO4 (0.19 g, 3.0 eq.), And Pd (PPh3) (0.017 g, 5 mol%) at reflux in DME (16 ml) and H2O (4 ml) 7 hours. The resulting solution was cooled to room temperature, diluted with H2O (10 mL), and extracted with CH2Cl2 (3 x 50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography using a 2.5% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent (0.16 g, 100% yield).

PREPARED EXAMPLE 198 To a solution of 4-aminomethylpyridine (1.41 ml, 13.87 mmol) in CH2Cl2 (50 ml) was added BOC2O (3.3 g, 1.1 eq.) And TEA and the resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with H2O (50 ml) and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 5% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent to give a yellow solid (2.62 g, 91% yield). LCMS: MH + = 209.

PREPARED EXAMPLE 199 Essentially by the same procedure set forth in Preparative Example 198, substituting only 3-aminomethylpyridine, the above compound was prepared as a yellow oil (2.66 g, 92% yield). LCMS: MH + = 209.

EXAMPLE PREPARATION 200 To a solution of the compound prepared in Preparative Example 198 (0.20 g, 0.96 mmol) in CH 2 Cl 2 (5 ml) at 0 ° C was added m-CPBA (0.17 g, 1.0 eq) and the resulting solution stirred at 0 ° C 2. hours and stored at 4 ° C until the next day, at that time, the reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The combined organics were dried over Na2SO, filtered and concentrated. The crude product was purified by flash chromatography using a 10% solution (10% NH 4 OH in MeOH) as eluent: LCMS: MH + = 255.

PREPARED EXAMPLE 201 A solution of oxone (58.6 g) in H 2 O (250 ml) was added dropwise to the compound prepared in Preparative Example 199 (27 g, 0.13 mol) and NaHCO 3 (21.8 g, 2.0 eq.) In MeOH (200 ml) and H2O (250 ml). The resulting solution was stirred at room temperature until the next day. The reaction mixture was diluted with CH2Cl2 (500 mL) and filtered. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a white solid (21.0 g, 72% yield). MS: MH + = 255.

PREPARED EXAMPLE 202 The compound prepared in Preparative Example 200 (0.29 g, 1.29 mmol) was stirred at room temperature in 4M HCl in dioxane (0.97 ml) for 2 hours. The reaction mixture was concentrated in vacuo and used without further purification. LCMS: MH + = 125.

PREPARED EXAMPLE 203 Essentially by the same procedure set forth in Preparative Example 202, substituting only the compound prepared in Preparative Example 201, the compound shown above was prepared. LCMS: MH + = 125.

PREPARED EXAMPLE 204 TEA (1.40 mL, 2.5 eq.) And 3-trifluoromethyl benzoyl chloride (1.05 g, 1.25 eq.) Were added to 4-N-t-Butoxycarbonylaminopiperidine (0.8 g, 4.0 mmol) in CH2Cl2 (10 mL) at 0 ° C. The resulting solution was stirred 15 minutes and warmed to room temperature and stirred 3 hours. The reaction mixture was diluted with CH2Cl2 and washed with 3.5% Na2C (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a pale yellow solid (crude quantitative yield).

PREPARED EXAMPLE 205 TFA (8 ml) was added to a solution of the compound prepared in Preparative Example 204 (1.0 g, 2.76 mmol) in CH 2 Cl 2 (15 ml) at 0 ° C and the resulting solution was stirred at 0 ° C for 30 minutes and temperature 1 hour environment. The reaction mixture was poured into Na 2 CO 3 (40 g) and H 2 O (400 ml) was added and the resulting mixture was extracted with CH 2 Cl 2. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 20% solution (7N NH 3 in MeOH) in CH 2 Cl 2 as eluent (0.6 g, 82% yield).

PREPARED EXAMPLES 206 STEP A: Na 2 CO 3 (0.81 g, 7.67 mmol) was added to a solution of 6-chloronicotinamide (1 g, 6.39 mmol) in isoamyl alcohol (15 ml) at room temperature followed by methoxyethylamine (0.67 ml, 7.67 mmol). The mixture was heated at 130 ° C for 16 h, cooled to rt, and filtered through a medium glass filter, the resulting filtrate was concentrated under reduced pressure and the resulting solid was triturated with Et 2 O (2 x 10 ml) . the crude solid was placed under high vacuum to give 1.2 g (96%) of a light yellow solid. M + H = 196.

STEP B: To a solution of amide (1.2 g, 6.12 mmol) of Preparative Example 206, Step A in THF (5 mL) at 0 ° C was added a solution of BH3-THF (43 mL, 43 mmol) dropwise for 10 min. The resulting solution was heated to rt and stirred for 14 h. The mixture was cooled to 0 ° C and sequenced with 6M HCl (35 ml), water (30 ml), and MeOH (150 ml). The mixture was stirred for 8 h and concentrated under reduced pressure. The crude residue was triturated with MeOH, concentrated under reduced pressure, and placed under high vacuum to give 1.6 g (82%) of a white solid as the dihydrochloride salt. M + H (free base) = 182.0. This material was used crude in the coupling with adducts 7-CI.

EXAMPLES PREPARATION 207-211 Essentially by the same procedure set forth in Preparative Example 206, using only the amines shown in Column 2 of Table 13, the amines shown in Column 3 of Table 13 were prepared: TABLE 13 PREPARED EXAMPLE, 212: The above compound was prepared according to the methods described in WO 91/18904.

PREPARED EXAMPLE 213 The above compound was prepared according to the methods described in US 6,180,627 B1.

PREPARED EXAMPLE 214 The known amine was prepared as described in J. Med.

Chem. (2001), 44, 4505-4508.

PREPARED EXAMPLE 215 The known amine was prepared as described in J. Med. Chem. (1997), 40, 3726-3733.

PREPARED EXAMPLE 216 STEP A: A solution of aldehyde (50 g, 0.41 mol) [WO 0232893] in MeOH (300 ml) was cooled to 0 ° C and carefully treated with NaBH 4 (20 g, 0.53 mol in 6 batches) for 20 minutes. The reaction was then allowed to warm to 20 ° C and stirred for 4 hours. The mixture was again cooled to 0 ° C, carefully deactivated with saturated aqueous NH 4 Cl, and concentrated. Flash chromatography (5-10% 7N NH 3 -MeOH / CH 2 Cl 2) gave the primary alcohol (31 g, 62%) as a light yellow solid.

STEP B: A suspension of alcohol (31 g, 0.25 mol) of Preparative Example 216, Step A in CH2Cl2 (500 mL) was cooled to 0 ° C and slowly treated with SOCI2 (55 mL, 0.74 mol for 30 minutes). Then, the reaction was stirred overnight at 20 ° C. The material was concentrated, suspended in acetone, and then filtered. The resulting beige solid was dried overnight in vacuo (38.4 g, 52%, HCl salt).

STEP C: To a 15 ml pressure tube loaded with a stir bar was added chloride (150 mg, 0.83 mmol) of Preparative Example 216, Step B followed by 7 M NH 3 / MeOH (10 ml). The resulting solution was stirred for 48 h at room temperature at which time the mixture was concentrated under reduced pressure to give a pale yellow solid (0.146 g, 83%). M + H (free base) = 140.

PREPARED EXAMPLE 217 The above compound was prepared according to the methods described in WO 00/26210.

PREPARED EXAMPLE 218 The above compound was prepared according to the methods described in WO 99/10325.

PREPARED EXAMPLE 219 The known amine dihydrochloride was prepared according to methods described in WO 02/64211.

PREPARED EXAMPLE 220 The above compound was prepared according to methods described in WO 02/64211.

PREPARED EXAMPLE 221 The known primary alcohol was prepared according to WO 00/37473 and converted into the desired amine dihydrochloride in analogous design to Preparative Example 220 according to WO 02/064211.

PREPARED EXAMPLE 222 STEP A: To a solution of aldehyde (WO 02/32893) (0.46 g, 2.07 mmol) in MeOH / THF (2 mL / 2 mL) at 0 ° C was added NaBH 4 (94 mg, 2.48 mmol) in one portion. The resulting mixture was stirred for 12 h at room temperature and diluted with aqueous sat. NH CI (STEP) The mixture was concentrated under reduced pressure and the resulting aqueous layer was extracted with CH 2 Cl 2 (3 x 5 mL) The organic layers were combined, washed with brine (1 x 5 mL), dried (Na 2 SO 4), and filtered The organic layer was concentrated under reduced pressure to give 417 mg (90% yield) of a white solid M + H = 225.

STEP B: To the crude alcohol of Preparative Example 222, step A (0.4 g, 1.78 mmol) in CH 2 Cl 2 (4 mL) was added SOCI2 (0.65 mL, 8.91 mmol) and the mixture was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure to give 407 mg (94%) of a light yellow solid. M + H = 243. The crude product was captured without further purification.

STEP C: To a crude chloride solution of Preparative Example 222, Step B (0.33 g, 1.36 mmol) in a pressure tube charged with 7M NH3 MeOH (35 ml) and the mixture was stirred for 72 h. The mixture was concentrated under reduced pressure to give 257 mg (85%) of a yellow semi-solid. M + H (free base) = 224.

PREPARED EXAMPLE 223 To a flask charged with amine hydrochloride (0.24 g, 1.1 mmol) of Preparative Example 222 and a bar for stirring was added HCI4N / dioxane (10 mL). The resulting solution was stirred for 12 h at room temperature, concentrated under reduced pressure, and triturated with CH 2 Cl 2 (3 x 5 mL). The crude product was filtered, washed with Et 2 O (2 x 5ml), and dried under high vacuum to give 0.19g (91%) as the dihydrochloride salt. M + H (free base) = 124.

PREPARED EXAMPLE 224 Pd (PPh3) 4 (0.404 gm, 0.35 mmol) was added to a solution of 4-cyanobenzene boronic acid (1.029 g, 7 mmol) and 2-bromopyridine (1.11 g, 7 mmol) in 75 ml acetonitrile. 0.4M sodium carbonate solution (35 ml) was added to the reaction mixture and the resulting solution was refluxed at 90 ° C under Ar for 24 hours (progress of the reaction was monitored by TLC). The reaction mixture was cooled and the aqueous layer was separated. The organic layer containing the spent product and catalyst was mixed with silica gel (15 g) and concentrated until dried. The 4- (2-pyridyl) -benzonitrile was isolated by chromatography on the Column (0.850 g, 68%). LCMS: MH + = 181; 1 H NMR (CDCl 3) d 8.85 (d, 1 H), 8.7 (dd, 1 H), 7.9 (dd, 1 H), 7.75 (d, 2 H), 7.7 (d, 2 H), 7.4 (dd, 1 H ).

PREPARED EXAMPLES 225-228 By following essentially the same procedure described in Preparative Example 224, replacing only the bromides in Column 2 of Quad 4, the compounds were prepared in column 3 of Table 14. TABLE 14 PREPARED EXAMPLE 229 The BH3-THF solution (1 M, 24 mL, 5 eq) was slowly added to a stirred solution of 4- (2-pyridyl) -benzonitrile (0.85 g, 4.72 mmol) in THF anhydride (25 mL). ) under Ar, and the resulting solution was refluxed for about 12 hr. The solution was cooled to 0 ° C using frozen water. Methanol (15 ml) was added dropwise to the cold reaction mixture and stirred for 1 h to destroy the excess BH3. HCl-methanol (1M, 10 ml) was slowly added to the reaction mixture and refluxed for 5 h. The solution was concentrated until it was dried and the residue was dissolved in 25 ml of water and extracted with ether to remove any material that was not reacted. The aqueous solution was neutralized with solid potassium carbonate at pH 10-11. The free amine, which was formed in this manner, was extracted with ether, dried over potassium carbonate (0.45 g, 50%). LCMS: MH + = 185; 1 H NMR (CDCl 3) d 8.85 (d, 1 H), 8.7 (dd, 1 H), 7.9 (dd, 1 H), 7.75 (d, 2 H), 7.7 (d, 2 H), 7.4 (dd, 1 H), 3.7 (t, 2H), 1.7 (t, 2H).

PREPARED EXAMPLES 230-233 By essentially following the same procedure set forth in Preparative Example 229, the compounds were prepared in column 3 of Table 15.

TABLE 15 PREPARED EXAMPLE 234 Step A: A mixture of 4-fluorobenzonitrile (3 g, 25 mmol) and sodium imidazolyl (2.48 g, 27.5 mmol) in DMF (50 mL) was stirred at 80 ° C under Ar for 12 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated in vacuo and the residue was diluted with 50 ml water and stirred. The aqueous mixture was extracted with EtOAc (2 x 50 ml). The combined EtOAc extracts were dried over anhydrous MgSO 4, concentrated, and the 4- (1-imidazolyl) -benzonitrile was isolated by column chromatography (3.6 g, 78%). LCMS: MH + = 170; 1 H NMR (CDCl 3) d 8.0 (s, 1 H), 7.5 (d, 2 H), 7.4 (m, 3 H), 7.3 (d, 1 H).

Step B: 4- (1-imidazole) -benzontrotyl (1g, 5.92 mmol) was dissolved in anhydrous THF (10 mL) and added dropwise to a stirred solution of LAH -THF (1 M in THF, 18 ml) at room temperature. The reaction mixture was refluxed under Ar for 2 h and progress was monitored by TLC. The mixture was cooled to 0 ° C and deactivated by the dropwise addition of a saturated Na 2 SO 4 -H 2 O solution. The mixture was stirred for 1 h and filtered to remove the lithium salts. The filtrate was dried over anhydrous MgSO 4 and concentrated to obtain 4- (1-imidazolyl) -benzylamine (0.8 g, 80%). LCMS: MH + = 174.

PREPARED EXAMPLE 235 A mixture of 4- (5-oxazolyl) benzoic acid (1.0 g, 5.46 mmol) and Et3N (552 mg, 5.46 mmol) in 25 mL of THF was cooled to 0 ° C and CICOO / '- Bu (745 mg. , 5.46 mmol) dropwise. After the addition was complete, the reaction mixture was stirred for additional 5 min and then NH4OH aq. (0.63 ml of 28% solution, 10.46 mmol). After stirring until the next day, the solvent was evaporated, the residue was taken up in water and basified to pH 9. The precipitated solid was filtered, washed with water and dried over P2O5 in a vacuum desiccator to give 500 mg (48%) of 4- (5-oxazolyl) -benzamide: 1 H NMR (DMSO-d 6) d 8.50 (s, 1 H), 8.20-7.80 (m, 5H).

PREPARED EXAMPLE 236 A suspension of 4- (5-oxazolyl) benzamide (500 mg, 2657 mmol) in 10 mL of dry THF was cooled to 0 ° C and 10 mL of 1 M BH3. THF (10.00 mmol) was added. The contents were refluxed until the next day and the excess boron was destroyed by the dropwise addition of methanol. The solvent was evaporated and the residue was treated with methanolic HCl to decompose the amine-boron complex. After evaporation of methanol, the residue was taken up in water, basified to pH 10 and the product extracted for DCM. The DCM layer was dried (K2CO3) and the solvent was removed to give 150 mg (32%) of 4- (5-oxazolyl) benzylamine: 1 H NMR (CDCl 3) d 7.90 (s, 1 H), 7.60 (d, 2H), 7.40 (d, 2H), 7.30 (s, 1 H), 3.90 (s, 2H).

PREPARED EXAMPLES 237-239 Essentially, by the same procedures set forth above, the compounds in column 2 of Table 16 were reduced using the method indicated in Column 3 of Table 16 to give the amine indicated in Column 4 of Table 16.

TABLE 16 PREPARED EXAMPLE 240 Prepared by the literature procedure (PCT Int. Appl, WO 0105783): H NMR (CDCl 3) d 7.35 (d, 1H), 7.24-7.10 (m, 2 H), 7.02 (d, 1H), 3.95 (t , 1H), 3.70 (d, 1H), 3.37 (d, 1H), 2.65 (m, 2H), 2.45 (s, 3H), 1.90 (bs, 2H).

PREPARATIVE EXAMPLE 241 3- (aminomethypiperidine-1-carboxamide to. 3- (fer-butoxycarbonylaminomethyl) pperiod-1 -carboxamide 3 (R / S) - (fer-Butoxycarbonyllaminomethyl) piperidine (3g, 14.0 mmol) was dissolved in dichloromethane anhydride (50ml) and trimethylsilylisocyanate (9.68g, 11.4ml, 84.0mmol) was added. The mixture was stirred under Argon at 25 ° C for 68 h. Additional trimethylsilylisocyanate (4.84g, 5.7ml, 42.0 mmol) was added and the mixture was stirred at 25 ° C for a total of 90h. The mixture was evaporated until dried and subjected to silica gel column chromatography (30x5cm) using 2% (10% conc. Ammonium hydroxide in methanol) -dichloromethane as the eluent to give 3- (tert-butoxycarbonylaminomethyl) ) piperidin-1 -carboxamide (3.05g, 85%): FABMS: m / z 258.1 (MH +); HRFABMS: m / z 258.1816 (MH +). Calculated for C 12 H 24 O 3 N 3: m / z 258.1818; d H (CDCl 3) 1.22 91 H, m, CH 2), 1.42 (9 H, s, -COOC (CH 3) 3), 1.48 (1 H, m, CH 2), 1.67 (2 H, m, CH 2), 1.78 (1 H, m, CH), 2.80 (1 H, m, CH2), 2.99, 3H, m, CH2), 3.59 (1 H, m, CH20 3.69 (1 H, m, CH2), 4.76 (2H, bm, CONH2) and 4.98ppm (1H, bm, NH), dc (CDCl3) CH3: 28.5, 28.5, 28.5, CH2: 24.0, 28.3, 43.2, 45.1, 47.8, CH: 36.5, C: 79.4, 156.3, 158.5.

B. 3- (aminomethyl) piperidin-1 -carboxamide 3- (tert-Butoxycarbonylaminomethyl) piperidine-1-carboxamide (150 mg, 0.583 mmol) (prepared as described in Preparative Example 241, Step A above) was dissolved in methanol (3 ml). Sulfuric acid conc. 10% in 1, 4-dioxane (7.9 ml) and the mixture was stirred at 25 ° C for 1 h. The mixture was diluted with methanol and BioRad AG1-X8 resin (OH form ") was added until the pH was made basic.The resin was filtered, washed with methanol, evaporated to dryness and subjected to gel column chromatography. silica (15x2cm) using dichloromethane followed by 15% (10% conc. ammonium hydroxide in methanol) -dichloromethane as the eluent to give 3- (aminomethyl) piperidin-1 -carboxamide (80mg, 87%): FABMS: m / z 158.1 (MH +); HRFABMS: m / z 158.1294 (MH +).

Calculated for C7H16N3O: m / z 158.1293; d H (CDCl 3 + drop of CD 3 OD) 1.20 (1 H, m, CH 2), 1.48 (1 H, m, CH 2), 1.60 (1 H, m, CH), 1.68 (1 H, m, CH 2), 1.83 (1 H , m, CH2), 2.64 (bm, 2H, -CH2NH2), 2.82 (1 H, m, CH2), 3.02 (1 H, m, CH2), 2.98 (2H, m, CH2), 3.70 (1H, m , -C? 2NH2), 3.78 (1 H, m, -CH2NH2) and 5.24 ppm (1 H, bs, NH); d c (CDCl 3 + drop CD 3 OD) CH 2: 24.1, 28.6, 44.0, 44.8, 47.9; CH: 38.3; C: 159.0.

PREPARATIVE EXAMPLE 242 3- (2-aminoethyl) piperidine-1-carboxamide A. 3- (2-tert-butoxycarbonylaminoethyl) piperidin-1 -carboxamide 3- (2-te? -Butoxycarbonylaminoethyl) piperidine (500 mg, 2. 19 mmol) in dichloromethane anhydride (10 ml) and trimethylsilylisocyanate (2.96 ml, 21.9 mmol) was added. The mixture was stirred under Argon at 25 ° C for 3.35 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO), filtered, evaporated to dryness and subjected to silica gel column chromatography (15x5cm) using 5% (conc. 10% ammonium hydroxide in methanol) -dichloromethane as the eluent to give 3- (2-fer-butoxycarbonyllaminoetyl) piperidin-1 -carboxamide (417.7mg, 70%): FABMS: m / z 272.0 (MH +); HRFABMS: m / z 272.1979 (MH +). Calculated for C 13 H 26 O 3: m / z 272.1974; d H (CDCl 3) 1.16 (1 H, m, CH 2), 1-30- 1.60 (5 H, m, CH / CH 2), 1.46 (9 H, s, -COOC (CH 3) 3), 1.68 (1 H, m , CH2), 1 84 (1 H,, CH2), 2.54 (1 H, dd, CH2), 2.73 (1 H, m, CH2), 3.08 (1 H, m, CH2), 3.42 (1H, m, CH2), 4.02 (1H, m, CH2), 4.10 (1 H, m, CH2), 4.84 (1 H, m, NH) and 4.96 ppm (2H, bm, CONH2); d c (CDCl 3) CH 3: 28.5, 28.5, 28.5; CH2: 25.2, 31.7, 34.9, 37.3, 44.6, 50.3; CH: 32.9; C: 79.5, 156.4, 158.2.

B. 3- (2-aminoethyl) piperidin-1 -carboxamide BocHN 3- (2-Fer-Butoxycarbonylaminoethyl) piperidine-1-carboxamide (392.7mg, 1.45mmol) (prepared as described in Preparative Example 242, Step A above) was dissolved in methanol (7.5ml) and conc. Sulfuric acid was added. . 10% in 1, 4-dioxane (19.5ml). The mixture was stirred at 25 ° C for 1.25h. The mixture was diluted with methanol and BioRad AG1-X8 resin (OH form ") was added until the pH was basic.The resin was filtered, washed with methanol, evaporated to dryness and subjected to gel column chromatography. of silica (30x2.5cm) using 15% (10% conc. ammonium hydroxide in methanol) -dichloromethane as the eluent to give 3- (2-aminoethyl) piperidin-1 -carboxamide (233mg, 94%): FABMS: m / z 172.1 (MH +); HRFABMS: m / z 172.1444 (MH +).

Calculated for C8H? 8N3O requires: m / z 172.1450; d H (CDCl 3 + 3% CD 3 OD) 1.14 (1 H, m, CH 2), 1.40 (2 H, m, CH 2), 1.49 (1 H, m, CH), 1.58 (1 H, m, CH 2), 1.69 ( 1 H, m, CH 2), 1.85 (1 H, m, CH 2), 2.55 (1 H, m, CH 2), 2.67 (5 H, m, CH 2 / NH 2), 2.76 (1 H, bm, CH 2), 2.84 (1 H, m, CH2) and 3.82 ppm (2H, m, CONH2); d c (CDCl 3 + 3% CD 3 OD) CH 2: 24.8, 30.9, 36.6, 38.9, 44.9, 50.0; CH: 33.4.

PREPARATIVE EXAMPLE 243 4- (2-aminoethyl) piperidine-1-carboxamide A. 4- (2-tert-butoxycarbonylaminoethyl) piperidin-1 -carboxamide 4- (2- / er-Butoxycarbonylaminoethyl) piperidine (500 mg, 2.19 mmol) was dissolved in dichloromethane anhydride (10 ml) and trimethylsilylisocyanate (2.96 ml, 21.9 mmol) was added. The mixture was stirred under Argon at 25 ° C for 3.25 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO), filtered, evaporated to dryness and subjected to silica gel column chromatography (15x5cm) using 5% (10% conc. Ammonium hydroxide in methanol) -dichloromethane as the eluent to give? - (2-tert-butoxycarbonylaminoethyl) piperidin-1 -carboxamide (308.2 mg, 52%): FABMS: m / z 272.0 (MH +); HRFABMS: m / z 272.1965 (MH +). Calculated for C-13H26O3N3: m / z 272.1974; d H (CDCl 3) 1.20 (2 H, m, CH 2), 1.47 (9 H, s, -COOC (CH 3) 3), 1.45-1.55 (3 H, m, CH / CH 2), 1.75 (2 H, m, CH 2), 2.82 (2H, m, CH2), 3.19 (2H, m, CH2), 3.96 (2H, m, CH2), 4.64 (2H, m, CH2) and 4.70 ppm (1 H, bm, NH); d c (CDCl 3) CH 3: 28.5, 28.5, 28.5; CH2: 31.8, 31.8, 36.7, 38.0, 44.5, 44.5; CH: 33.4; C: 79.2, 156.7, 158.1.

A. 3- (2-aminoethyl) piperidin-1 -carboxamide 4- (2-tert-Butoxycarbonylaminoethyl) piperidine-1-carboxamide (283.3 mg, 1.04 mmol) (prepared as described in Preparative Example 243, Step A above) was dissolved in methanol (5.4 ml) and added sulfuric acid conc. 10% in 1,4-dioxane (14.2ml) and the mixture was stirred at 25 ° C for 1.25h. The mixture was diluted with methanol and BioRad AG1-X8 resin (OH form ") was added until the pH was basic.The resin was filtered, washed with methanol, evaporated to dryness and subjected to gel column chromatography. of silica (30x2.5 cm) using 15% (ammonium hydroxide conc. % in methanol) -dichloromethane as the eluent to give the 3- (2-aminoetyl) piperidin-1 -carboxamide (170 mg, 95%): FABMS: m / z 172.1 (MH +); HRFABMS: m / z 172.1442. Calculated for C8H18N3O requires: m / z 172.1450; d H (CDCl 3 + 3% CD 3 OD) 1.16 (2 H, m, CH 2), 1.43 (2 H, m, CH 2), 1.52 (1 H, m, CH), 1.70 (2 H, m, CH 2), 2.70-2.85 ( 8H, m, CH2) and 3.92 ppm (2H, m, CONH2); d c (CDCl 3 + 3% CD 3 OD) CH 2: 31.9, 31.9, 39.0, 39.7, 44.4, 44.4; CH: 33.5; C: 158.7.

PREPARATIVE EXAMPLE 244: 3- (aminomethyl) -1-methylpiperidine A. 3- (bromomethyl) -1-methylpiperidine 3- (Hydroxymethyl) -1-methylpiperidine (2g, 15.5mmol) was dissolved in acetonitrile anhydride (32ml) and pyridine anhydride (2.02ml, 24.8mmol) was added and the solution was cooled to 0 ° C. Dibromotriphenylphosphorane (8.49 g, 20.2 mmol) was added at 0 ° C and the mixture was allowed to warm to 25 ° C and was stirred for 94 h. The mixture was evaporated to dryness and the residue was chromatographed on a column of silica gel (30x5cm) using gradient elution with dichloromethane, 35% diethyl ether in dichloromethane and 5-10% methanol in dichloromethane as the eluent to give 3. - (bromomethyl) -1- methylpiperidine (3.13g, 100%): FABMS: m / z 192.1 (MH +); d H (CDCl 3) 1.52 (1 H, m, CH 2), 1.99 (2 H, m, CH 2), 2.43 (1 H, m, CH 2), 2.75 (2 H, m, CH 2), 2.82 (1 H, m, CH ), 2.86 / 2.88 (3H, s, NCH3), 3.42 / 3.49 (2H, dd, -CH2Br) and 3.56 ppm (2H, m, CH2); d c (CDCl 3) CH 3: 44.3; CH2: 22.1, 26.6, 35.4, 54.8, 58.2; CH: 34.6.

A. 3- (di-tert-butoxycarbonylaminomethyl) -1-methylpiperidine 3- (Bromomethyl) -1-methylpiperidine (1.5g, 7.81 mmol) (from Preparative Example 244, Step A above) and di-fer-butyliminodicarboxylate (1697g, 7.81 mmol) were dissolved in acetonitrile anhydride (25ml). Cesium carbonate (5.1 g, 15.6 mmol) and lithium iodide (52 mg, 0.391 mmol) were added and the mixture was stirred at 70 ° C for 20 h. The mixture was evaporated until it was dried and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO), filtered and evaporated until dried, the residue was chromatographed on a column of silica gel (30x5cm) using 3% methanol in dichloromethane as the eluent to give 3- (dihydro). -er-butoxycarbonylamino) -1-methylpiperidine (1.331g, 52%): FABMS: m / z 329.2 (MH +); HRFABMS: m / z 329.2438 (MH +). Calculated for C 17 H 33 N 2 O 4: m / z 329.2440; dH (CDCl 3) 1.10 (1 H, m, CH 2), 1.54 (18 H, s, -COOC (CH 3) 3), 1-86 (2 H, m, CH 2), 2.01 (1 H, m, CH 2), 2.19 (1 H m, CH), 2.34 (2 H, bm, CH 2), 2.59 (3 H, -NCH 3), 3.19 (2 H, m, CH 2) and 3.52 / 3.52 ppm (2 H, -CH 2 N-); d c (CDCl 3) CH 3: 28.5, 28.5, 28.5, 28.5, 28.5, 28.5, 47.2; CH2: 25.4, 28.3, 50.4, 56.8, 60.8; CH: 37.2; C: 83.0, 83.0,153.5, 153.5, A. 3- (aminomethyl) -1-methylpiperidine 3- (Di-1-butoxycarbonylamino) -1-methylpiperidine (500 mg, 1.52 mmol) (from Preparative Example 244, Step B above) was dissolved in methanol (7.5 ml) and 10% (v / v) conc. Sulfuric acid was added. . in 1, 4-dioxane (19.75ml). The solution was stirred at 25 ° C for 0.5h. Methanol (300ml) was added, followed by BioRad AG1-X8 resin (OH form ") until the pH was -10 The resin was filtered and washed with methanol (2x200ml) The combined eluates were evaporated until dried and the residue was subjected to chromatography on a silica gel column (30x2.5cm) using 10% (10% conc. ammonium hydroxide in methanol) -dichloromethane as the eluent to give 3- (aminomethyl) -1-methylpiperidine (69.2 mg, 35%): FABMS: m / z 129.1 (MH +); HRFABMS: m / z 129.1392 (MH +). Calculated for C7H17N2: m / z 129.1392; d H (CDCl3) 0.90 (2H, m, CH2), 1.65 (2H, m, CH2), 1.72 (1 H, m, CH), 1.79 (1 H, m, CH2), 1.91 (1 H, m, CH2), 2.30 (3H, s, -NCH3), 2.64 ( 2H, m, CH2), 2.82 (1 H, m, -CH2NH2) and 2.92 ppm (1 H, m, - CH2NH2), dc (CDCl3) CH3: 46.7, CH2: 25.2, 28.0, 46.3, 56.4, 60.3; CH: 39.9.

PREPARATIVE EXAMPLE 245 4- (amomethyl) -1-methylpiperidine A. 1-methylisipecotamide Isonipecotamide (10g, 78.0 mmol) was dissolved in distilled water (100ml) and 37% aqueous formaldehyde was added (7.6ml, equivalent to 2.81g HCHO, 93.6mmol). 10% wet Pd-C (8 spoon spatulas) was added under Argon and the mixture was hydrogenated at 25 ° C and 50 psi for 43h. The catalyst was filtered through Celite and the latter was washed with water and methanol. The combined filtrates were evaporated until they were dried and the residue was subjected to chromatography on a silica gel column (60x5cm) using 8% -10% -20% (10% conc. Ammonium hydroxide in methanol) -dichloromethane as the eluent to give 1-methylisipecotamide (7.15g, 64%): FABMS: m / z 143.1 (MH +); HRFABMS: m / z 143.1184 (MH +).

Calculated for C7H15N2O: m / z 143.1184; dH (d6-DMSO) 1.50 / 1.57 (4H, m, CH2), 1.76 / 1.94 (4H, m, CH2), 2.10 (3H, s, -NCH3), 2.72 (1 H, m, CH) and 6. 68 / 7.18 ppm (2H, m, CONH2); dc (d6-DMSO) CH3: 41.2; CH2: 28.5, 28.5, 54. 9, 54.9; CH: 46.2; C: 176.7. B. 4- (aminomethyl) -1-methylpiperidine 1-Methylisonipecotamide (6.75g, 47.5mmol) (prepared as described in Preparative Example 245, Step A above) was dissolved in anhydrous THF (350ml) and the resulting mixture was added in portions to a stirred suspension of lithium aluminum hydroxide. (1.8g, 47.5mmol) in THF anhydride (100ml) at 0 ° C under nitrogen. The mixture was stirred at 0 ° C for 30 min and then heated at 66 ° C for 25 h under nitrogen. Distilled water (1.88ml) was added dropwise to the stirred mixture at 0 ° C, followed by 20% aqueous sodium hydroxide (1.42ml) and then distilled water (6.75ml) and the mixture was stirred for 15 min. The mixture was filtered and the solids were washed with THF and dichloromethane. The combined filtrates were evaporated until dried and subjected to chromatography on a silica gel column (30x5cm) using 15% -20% (conc. 10% ammonium hydroxide in methanol) -dichloromethane as the eluent to give 4- (aminomethyl) -l-methylpiperidine (0.678g, 11%): FABMS: m / z 129.1 (MH +); HRFABMS: m / z 129.1389 (MH +). Calculated for C7H17N2: m / z 129.1392; d H (d6-DMSO): 2.08ppm (3H, s, -NCH3); d c (de-DMSO): CH3: low DMSO peaks; CH2: 29.6, 29.6, 46.7, 55.2, 55.2; CH: 46.2.

PREPARATIVE EXAMPLE 246 3- (ammonium) benzonitrile A. 3- (di-fer-butoxycarbonylamino) benzonitrile 3- (Bromomethyl) benzonitrile (5g, 25.5mmol) and di-tert-butyliminodicarboxylate (5.54g, 25.5mmol) were dissolved in anhydrous THF (50ml) and cesium carbonate (16.62g, 25.5mmol) and lithium iodide were added. (170.5mg, 1,275mmol). The mixture was stirred at 70 ° C for 22 h and the reaction was processed as described in Preparative Example 89, Step B above. The residue was chromatographed on a column of silica gel (60x5cm) using 5% ethyl acetate in hexane as the eluent to give 3- (di-ert-butoxycarbonylamino) benzonitrile (7.39g, 87%): FABMS: m / z 333.2 (MH +); HRFABMS: m / z 333.1815 (MH +); Calculated for C 8 H 25 N 2 O 4: m / z 333.1814; d H (CDCl 3) 1.52 (18 H, s, - COOC (CH 3) 3), 4.84 (2 H, s, CH 2), 7.48 (1 H, m, Ar-H), 7.60 (2 H, m, Ar-H) and 7.65 ppm (1 H, m, Ar-H); dc (CDCl 3) CH 3: 28.1, 28.1, 28.1, 28.1, 28.1, 28.1; CH2: 48.4; CH: 129.2, 131.0, 131.0, 131.9; C: 83.2, 83.2, 112.5, 118.8, 140.1, 152.5, 152.5.

B. 3- (aminomethyl) benzonitrile 3- (Di-tert-butoxycarbonyllamino) benzonitrile (2g, 6. 0 mmol) (prepared as described in Preparative Example 246, Step A above) in methanol (30 ml) and added 10% (v / v) (10% conc. Sulfuric acid in 1,4-dioxane) (79 ml). The solution was stirred at 25 ° C for 0.25h and processed as described in Preparative Example 89, Step C above). The residue was subjected to chromatography on a column of silica gel (15x5cm) using 3% (10% conc. Ammonium hydroxide in methanol) -dichloromethane as the eluent to give the title compound (651.4 mg, 82%): FABMS : m / z 133.1 (MH +); HRFABMS: m / z 133.0762 (MH +). Calculated for C8H9N2: m / z 133.0766; dH (CDCl3) 2.57 (2H, s, -CHsNFb), 3.92 (2H, s, -CH2NH2), 7.46 (1 H, m, Ar-H), 7.57 (2H, m, Ar-H) and 7.64 ppm ( 1 H, m, Ar-H); dc (CDCl 3) CH 2: 45.2; CH: 129.4, 130.7, 130.7, 131.8; C: 112.4, 118.8, 143.8.

PREPARATIVE EXAMPLE 247 4- (aminomethyl) benzonitrile A. 3- (di-fer-butoxycarbonylaminomethyl) benzonitrile 4- (Bromomethyl) benzonitrile (5g, 25.5mmol) and di-tert-butyliminodicarboxylate (5.54g, 25.5mmol) were dissolved in anhydrous THF (50ml) and cesium carbonate (16.62g, 25.5mmol) and lithium iodide were added. (170.5mg, 1,275mmol). The mixture was stirred at 70 ° C for 23 h and the reaction was processed as described in Preparative Example 244, Step B above. The residue was chromatographed on a column of silica gel (50x5cm) using 5% ethyl acetate in hexane as the eluent to give 4- (di-te / '-butoxycarbonylaminomethyl) benzonitrile (7.07g, 83%): FABMS : m / z 333.2 (MH +); HRFABMS: m / z 333.1816 (MH +).

Calculated for C18H25N2O4: m / z 333.1814; dH (CDCl 3) 1.45 (18H, s, -COOC (CH 3) 3), 4.81 (2H, s, CH 2), 7.37 (2H, d, Ar-H) and 7.62 ppm (2H, d, Ar-H); dc (CDCl 3) CH 3: 28.1, 28.1, 28.1, 28.1, 28.1, 28.1; CH2: 49.2; CH: 127.8, 127.8, 132.3, 132.3; C: 83.2, 83.2, 111.1, 118.9, 144.1, 152.4, 152.4.

B. 4- (aminomethyl) benzonitrile 4- (Di-tert-butoxycarbonylaminomethyl) benzonitrile (2g, 6.0 mmol) (prepared as described in Preparative Example 247, Step A above) was dissolved in TFA (4ml) and the solution was stirred at 25 ° C for 0.25h . The reaction mixture was diluted with dichloromethane and extracted with 1 N sodium hydroxide. The organic layer was dried (MgSO4), filtered and evaporated until dried. The residue was subjected to chromatography on a column of silica gel (15x5cm) using 3% (10% conc. Ammonium hydroxide in methanol) -dichloromethane as the eluent to give 4- (aminomethyl) benzonitrile (108mg, 68%): FABMS: m / z 133.1 (MH +); HRFABMS: m / z133.0764 (MH +). Calculated for C8H9N2: m / z 133.0766; dH (CDCl3) 2.04 (2H, s, -CH2NH2), 3.89 (2H, s, -CH2NH2), 7.40 (2H, d, Ar-H) and 7.59 ppm (2H, d, Ar-H); dc (CDCl 3) CH 2: 45.7; CH: 127.8, 127.8, 132.4, 132.4; C: 110.6, 118.9, 148.0.

PREPARED EXAMPLE 248 To a solution of (1 S, 2 S) -2-benzyloxycyclopentyl amine (1.5 g, 7. 84 mmol) in MeOH (50 ml) at room temperature was added 10% Pd / C (50% wet, 1.0 g) followed by the dropwise addition of conc. HCl. (0.7 ml). The mixture was stirred under a balloon of H2 for 14 h and the catalyst was filtered through a pad of Celite. The Celite bed was washed with MeOH (2 x 10 mL) and the resulting filtrate was concentrated under reduced pressure to give 0.97 g (90%) of a yellow semi-solid; M + H (free base) = 102.

PREPARED EXAMPLES 249-251 In a manner analogous to Preparative Example 248, the benzyl protected cycloalkyl amines (Column 2) were converted to the desired aminocycloalkanol hydrochloride derivatives (Column 3) as listed in Table 17.

TABLE 17 PREPARED EXAMPLE 252 To an ester solution (which was prepared according to J. Org. Chem. (1999), 64, 330) (0.5 g, 2.43 mmol) in THF (8 ml) at 0 ° C was added L¡AIH4 (0.37. g, 9.74 mmol) in one portion. The resulting mixture was refluxed for 12 h and cooled to 0 ° C. The mixture was treated in sequences with H 2 O (1 ml), 1 M NaOH (1 ml), and H 2 O (3 ml). CH2Cl2 (10 mL) was added to the mixture which was stirred vigorously for 30 min. The mixture was filtered through a pad of Celite which was washed generously with CH 2 Cl 2 (3 x 5 ml). The resulting filtrate was concentrated under reduced pressure to give 0.41 g (85%) of a yellow / orange solid. M + H = 142.

PREPARED EXAMPLE 253 STEP B 0 H TFA HCI STEP A: To a solution of L-proline methyl ester hydrochloride (0.50 g, 3.0 mmol) in CH2Cl2 (15 mL) at 0 ° C was added Et N (1.1 mL, 7.55 mmol) followed by TFAA (0.56 mL, 3.92 mmol). The mixture was stirred for 12 h at room temperature and 1 N HCl (25 mL) was added. The layers were separated and the organic layer was washed sequentially with aqueous sat. NaHCO3. (1 x 25 ml), and brine (1 x 25 ml). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to give 0.72 g (100%) of a yellow oil. M + H = 226. The crude material was taken over Step B without further purification.

STEP B: To a solution of the compound prepared in Preparative Example 253, Step A (0.68 g, 3.0 mmol) in THF (20 mL) at 0 ° C was added MeMgl (5.1 mL, 3.0 M in Et 2 O) dropwise during 10 minutes. The resulting solution was stirred for 16 h at room temperature at which time the mixture was quenched by the addition of aqueous sat. NH 4 Cl. The mixture was concentrated until it was dried and the resulting residue was stirred with EtOAc (100 ml) for 45 min. it leaked The filtrate was concentrated under reduced pressure to give 0.68 g (100%) of a yellow / orange oil. M + H = 226. The crude material was taken over Step C without further purification.

STEP C: To a solution of the compound prepared in Preparative Example 253Step B (0.68 g, 3.0 mmol) in MeOH (5 mL) was added a solution of KOH (0.68 g, 12.1 mmol) in MeOH (5 mL). The mixture was stirred at reflux for 12 h and at room temperature for 72 h at which time the mixture was concentrated until it was dried. The crude residue was suspended in EtOAc (50 ml) and stirred vigorously for 30 min and filtered. This procedure was repeated two more times and the resulting filtrate was concentrated under reduced pressure to give 128 mg (33%) of a brown / orange oil. M + H = 130. This material was used without further purification in the next coupling step.

PREPARED EXAMPLE 254 The aldehyde was prepared according to the Gupton method (J. Heterocyclic Chem. (1991), 28, 1281).

PREPARATORY EXAMPLE 255 Using the aldehyde from Preparative Example 254, the Gupton method (J. Heterocyclic Chem. (1991), 28, 1281) was used to prepare the title aldehyde.

PREPARED EXAMPLE 256 The title aldehyde was prepared according to the procedure of Ragan et. to Synlett (2000), 8, 1172-1174.

PREPARED EXAMPLE 257 The reaction of cyclopentyl guanidine hydrochloride (Org Lett. (2003), 5, 1369-1372) under the conditions of Ragan (Synlett (2000), 8, 1172-1174) gave the title aldehyde.

PREPARED EXAMPLE 258 The title compound was prepared according to the known literature Monatshefte fur Chemie (1973), 104, 1372-1382.

EXAMPLES EXAMPLE 1 A solution of the product of Preparative Example 127 (0.27 g, 0.875 mmol), 4-aminomethylpyridine (0.12 g, 1.3 eq.), And K2CO3 (0.24 g, 2 eq.) In CH3CN (5 ml) at room temperature was stirred. 48 hours. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The combined organics were dried over Na2SO, filtered and concentrated. The crude product was purified by flash chromatography using a 4% MeOH solution in CH2Cl2 as eluent (0.28 g, 93% yield). LCMS: MH + = 380; mp = > 205 ° C (dec).

EXAMPLES 2-210 By essentially following the same procedure set forth in Example 1, substituting only the chlorides shown in Column 2 of Table 18 and the amines shown in Column 3 of square 8, the compounds were prepared in column 4 of table 18: TABLE 18 Additional data for selected examples given below.

EXAMPLE 23 1 H NMR (CD3OD) d 8.63 (d, J = 5.7 Hz, 2H), 8.18 (s, 1H), 7.81 (dd, J = 8.1 Hz, 2.1 Hz, 1H), 7.58 (d, J = 6.0 Hz, 2H), 7.48 (m, 1H), 7.15-7.10 (m, 2H), 6.50 (s, 1H), 4.86 (s, 2H), 3.70 (s, 3H) EXAMPLE 24 1 H NMR (CDCl 3) d 8.82 (s, 1 H), 8.73 (d, J = 4.2 Hz, 1 H), 8.11 (s, 1 H), 8.06 (dd, J = 7.8 Hz, 1.8 Hz, 1 H), 7.91 (d , J = 8.1 Hz, 1H), 7.53-7.47 (m, 2H), 7.20 (m, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.75 (s, 1H), 4.81 (d, J = 4.5 Hz, 2H), 3.86 (s, 3H) EXAMPLE 25 1 H NMR (CDCl 3) d 8.75 (d, J = 5.7 Hz, 2 H), 8.12 (s, 1 H), 7.81 (d, J = 2.1 Hz, 1 H), 7.53 (dd, J = 8.4, 2.1 Hz, 1 H) , 7.45 (d, J = 6.0 Hz, 2H), 6.96 (t, J = 6.0 Hz, 2H), 6.33 (s, 1H), 4.85 (d, J = 6.0 Hz, 2H), 4.09 (s, 3H) , 4.03 (s, 3H) EXAMPLE 26 1 H NMR (CDCl 3) d 8.82 (s, 1 H), 8.72 (s, 1 H), 8.09 (m, 1 H), 7.87- 7.83 (m, 2 H), 7.60 (m, 1 H), 7.45 (m, 1 H), 7.03 (d, J = 8.4 Hz, 1H), 6.87 (s, 1H), 6.43 (s, 1 H), 4.83 (d, J = 4.5 Hz, 2H), 4.11 (s, 3H), 4.04 (s, 3H) EXAMPLE 27 1 H NMR (CDCl 3) d 8.75 (d, J = 4.5 Hz, 2 H), 8.19 (s, 1 H), 7.63 (d, J = 7.8 Hz, 2 H), 7.44-7.40 (m, 3 H), 7.07 (m, 1H), 6.26 (s, 1H), 4.83 (d, J = 5.1 Hz, 2H) EXAMPLE 28 1 H NMR (CDCl 3) d 8.86 (s, 1 H), 8.74 (m, 1 H), 8.17 (s, 1 H), 7.97. (m, 1H), 7.66-7.63 (m, 2H), 7.62 (m, 1H), 7.41 (m, 1H), 7.07 (m, 1H), 6.35 (s, 1H), 4.87 (d, J = 6.0 Hz, 2H) EXAMPLE 30 1 H NMR (CDCl 3) d 8.16 (s, 1 H), 7.66-7.62 (m, 2 H), 7.41 (m, 1 H), 7.33-7.22 (m, 3 H), 6.96 (t, J = 6.0 Hz, 1 H), 6.33 (s, 1H), 4.73 (d, J = 6.0 Hz, 2H) EXAMPLE 31 1 H NMR (CDCl 3) d 8.13 (s, 1 H), 7.66 (d, J = 7.8 Hz, 2 H), 7.45- 7.40 (m, 2 H), 7.10-7.04 (m, 2 H), 6.93 (t, J = 6.6 Hz, 1 H), 6.60 (s, 1 H), 4.84 (d, J = 6.6 Hz, 2H) EXAMPLE 32 1 H NMR (CDCl 3) d 8.16 (s, 1 H), 7.66-7.62 (m, 2 H), 7.57-7.55 (m, 2 H), 7.41 (t, J = 7.8 Hz, 1 H), 7.31 (d, J = 7.8, 1.8 Hz, 1 H), 6.99 (t, J = 6.0 Hz, 1 H), 6.32 (s, 1 H), 4.73 (d, J = 6.0 Hz, 2H) EXAMPLE 40 1 H NMR (CDCl 3) d 8.01 (s, 1 H), 7.31 - 7.24 (d, J = 8.2 Hz, 1 H), 6. 72 - 6.64 (br t, J = 5.4 Hz, 1 H), 6.62 - 6.52 (m, 2 H), 6.05 - 6.01 (s, 1 H), 5.56 - 4.64 (d, J = 6.0 Hz, 2 H), 4.03 - 3.93 (s, 3H), 3.94 - 3.86 (s, 3H), 2.79 - 2.70 (d, J = 8.1 Hz, 2H), 2.02 - 1.66 (m, 6H), 1.43-1.22 (m, 3H), 1.20 - 1.02 (m, 2H) EXAMPLE 45 1 H NMR (CDCl 3) d 8.73 (d, 2 H), 8.54 (s, 1 H), 7.41 (d, 2 H), 7.02 (br, 1 H), 5.90 (s, 1 H), 4.80 (s, 2 H) , 4.48 (q, 2H), 2.75 (s, 2H), 1.50 (t, 2H), 1.06 (s, 9H); EXAMPLE 46 1 H NMR (CDCl 3) d 8.79 (s, 1 H), 8.72 (d, 1 H), 8.14 (s, 1 H), 7.84 (d, 1 H), 7.54-7.33 (m, 4 H), 6.97 (t, 1 H), 6.18 (s, 1 H), 4.79 (d, 2H), 2.47 (s, 3H) EXAMPLE 108 1 H NMR (CDCl 3) d 8.79 (s, 1 H), 8.72 (d, J = 3.0 Hz, 1 H), 8.16 (s, 1 H), 7.84 (d, J = 7.8 Hz, 1 H), 7.74 (d, J = 7.5 Hz, 2H), 7.55-7.35 (m, 3H), 6.92 (t, J = 6.3 Hz, 1 H), 6.42 (s, 1 H), 4.81 (d, J = 6.3 Hz, 2H) EXAMPLE 110 1 H NMR (CDCl 3) d 8.18 (t, 1 H), 8.03 (s, 1 H), 7.44 (m, 1 H), 7.30 (t, 1 H), 7.17 (q, 1 H), 6.66 (s, 1 H), 6.56 (br, 1 H), 4.28 (d, 2H), 2.38 (s, 1 H) EXAMPLE 111 1 H NMR (CDCl 3) d 8.72 (br, 1 H), 8.59 (d, 1 H), 8.11 (t, 1 H), 8.06 (s, 1 H), 7.73 (d, 1 H), 7.44 (d, 1 H), 7.42- 7.21 (m, 3H), 7.07 (q, 1H), 6.39 (d, 1H), 5.21 (q, 1H), 4.16 (q, 2H), 3.08 (d, 2H), 1.22 (t, 3H) EXAMPLE 112 1 H NMR (CDCl 3) d 8.22 (t, 1 H), 8.15 (s, 1 H), 7.51-7.33 (m, 7 H), 7.21 (q, 1 H), 6.82 (d, 1 H), 6.51 (s, 1 H), 4.68 (q, 1H), 2.18 (m, 2H), 1.17 (t, 3H) EXAMPLE 113 1 H NMR (CDCl 3) d 8.22 (t, 1 H), 8.14 (s, 1 H), 7.51-7.33 (m, 7 H), 7.21 (q, 1 H), 6.82 (d, 1 H), 6.51 (s, 1 H), 4.68 (q, 1H), 2.18 (m, 2H), 1.17 (t, 3H) EXAMPLE 114 1 H NMR (CDCl 3) d 8.81 (s, 1 H), 8.75 (d, 1 H), 8.21 (s, 1 H), 7.84 (d, 1 H), 7.47 (q, 1 H), 6.96 (s, 1 H) , 6.94 (t, 1 H), 4.85 (d, 2H), 4.60 (q, 2H), 1.58 (t, 3H) EXAMPLE 115 1 H NMR (CDCl 3) d 8.77 (s, 1 H), 8.72 (d, 1 H), 8.14 (s, 1 H), 7.83 (d, 1 H), 7.65 (d, 1 H), 7.44 (q, 1 H), 7.80 ( t, 1H), 7.6 (d, 1H), 6.18 (s, 1H), 4.75 (d, 2H), 3.91 (s, 3H), 3.81 (s, 3H) EXAMPLE 116 1 H NMR (CDCl 3) d 8.67 (s, 1 H), 8.55 (d, 1 H), 8.50 (s, 1 H), 7.92 (d, 1 H), 7.90 (d, 1 H), 7.78 (t, 1 H), 7.10 ( d, 1H), 6.97 (s, 1H), 5.11 (s, 2H), 3.77 (s, 6H) EXAMPLE 117 1 H NMR (CDCl 3) d 8.38 (s, 1 H), 8.30 (d, 1 H), 8.17 (s, 1 H), 7.52-7.37 (m, 6 H), 6.97 (t, 1 H), 6.13 (s, 1 H), 4.77 (d, 2H), 2.50 (s, 3H) EXAMPLE 118 1 H NMR (CDCl 3) d 8.18 (t, 1 H), 8.03 (s, 1 H), 7.44 (m, 1 H), 7.30 (t, 1 H), 7.17 (q, 1 H), 6.66 (s, 1 H) , 6.56 (br, 1 H), 4.28 (d, 2H), 2.38 (s, 1 H); EXAMPLE 121 1 H NMR (CDCl 3) d 8.6 (S, 1H), 8.15 (dt, 1H), 8.1 (s, 1H), 8.0 (d, 2H), 7.5 (d, 2H), 7.4 (dd, 1H), 7.2 ( d, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.6 (s, 1H), 4.75 (d, 2H).

EXAMPLE 126 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.5 (d, 1 H), 7.42 - 7.35 (m, 2 H), 7.3 -7.2 (m, 2 H), 7.15 (dd, 1 H ), 7.1 (dd, 1H), 7.0 (t, 1H), 6.6 (s, 1H), 4.8 (d, 2H).

EXAMPLE 127 1 H NMR (CDCl 3) d 8.2 (dt, 1 H), 8.0 (s, 1 H), 7.4 (dd, 1 H), 7.3- 7.25 (m, 3H), 7.1 (dd, 1H), 6.9-6.85 (m, 2H), 6.7 (t, 1H), 6.6 (s, 1H), 4.6 (d, 2H), 3.2 (m, 4H), 2.6 (m, 4H), 2.3 (s, 3H) EXAMPLE 128 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.1 (s, 1 H), 8.0 (d, 2 H), 7.5 (d, 2 H), 7.4 (m, 2 H), 7.25 (d, 1 H), 7.2 ( s, 1H), 7.15 (dd, 1H), 7.0 (s, 1H), 6.8 (t, 1H), 6.6 (s, 1H), 4.75 (d, 2H).

EXAMPLE 129 1 H NMR (CDCl 3) d 8.15 (dt, 1H), 8.05 (s, 1H), 8.0 (d, 2H), 7.5 (d, 2H), 7.4 (m, 1H), 7.3 (dd, 1H), 7.15 ( dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H), 4.75 (d, 2H), 3.85 (s, 3H) EXAMPLE 130 1 H NMR (CDCl 3) d 8.2 (dt, 1 H), 8.0 (s, 1 H), 7.4 (dd, 1 H), 7.3 (dd, 1 H), 7.15 (dd, 1 H), 6.8 (t, 1 H), 6.4 ( s, 1H), 4.2 (d, 2H), 3.8 (s, 3H).

EXAMPLE 131 1 H NMR (CDCl 3) d 8.2 (dt, 1H), 8.0 (s, 1H), 7.4-7.15 (m, 3H), 6.7 (t, 1H), 4.2 (q, 2H), 3.8 (dt, 2H), 2.8 (t, 2H), 1.2 (t, 3H) EXAMPLE 132 1 H NMR (CDCl 3) d 8.2 (dt, 1H), 8.0 (s, 1H), 7.4-7.15 (m, 3H), 6.7 (t, 1H), 4.2 (q, 2H), 3.8 (dt, 2H), 2.8 (t, 2H), 2.05 (m, 2H) 1.2 (t, 3H) EXAMPLE 133 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.4 (m, 1 H), 7.3 (dd 1 H), 7.2 (dd, 1 H), 6.5 (s, 1 H), 6.4 (t , 1H), 3.7 (s, 3H), 3.5 (dd, 2H), 2.4 (t, 2H), 1.8 (m, 4H) EXAMPLE 134 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.95 (d, 2 H), 7.6 (d, 2 H), 7.4 (m, 1 H), 7.25 (dd, 1 H), 7.1 ( dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H), 4.8 (d, 2H), 3.0 (s, 3H) EXAMPLE 135 1 H NMR (DMSO d6) d 9.1 (bs, 2H), 8.4 (s, 1H), 8.0 (t, 1H), 7.85 (d, '2H), 7.7 (d, 2H), 7.6 (m, 1H), 7.4 (m, 2H), 6.6 (s, 1H), 4.8 (bs, 2H) EXAMPLE 136 1 H NMR (CDCl 3) d 8.2 (dt, 1 H), 8.0 (s, 1 H), 7.4 (m, 1 H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.9 (m, 3H), 6.7 (t, 1H), 6.5 (s, 1H), 4.5 (d, 2H), 4.2 (s, 4H) EXAMPLE 137 1 H NMR (CDCU) d 8.2 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.3 (dd, 1H), 7.2 (dd, 1H), 6.9 (dd, 1H), 6.8 ( t, 1H), 6.7 (m, 1H), 6.6 (s, 1H), 5.3 (s, 2H), 4.85 (s, 2H), 4.6 (d, 2H).

EXAMPLE 138 1 H NMR (CDCl 3) d 8.2 (dt, 1 H), 8.0 (s, 1 H), 7.9 (d, 1 H), 7.8 (d, 1 H), 7.4 (m, 2 H), 7.3 (dd, 1 H), 7.1 ( dd, 1H), 6.9 (t, 1H), 6.6 (s, 1H), 4.8 (d, 2H) EXAMPLE 139 1 H NMR (CDCl 3) d 8.2 (dt, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.3 (m, 2H), 7.2 (dd, 1H), 7.1 (dd, 1H), 6.8 ( d, 1H), 6.7 (t, 1H), 6.6 (s, 1H), 4.6 (m, 4H), 3.2 (t, 2H) EXAMPLE 140 H NMR (CDCl 3) d 8.45 (s, 1H), 8.2 (dt, 1H), 8.0 (s, 1H), 7.7 (dd, 1 H), 7.4-7.3 (m, 3H), 7.15 (dd, 1 H), 6.8 (t, 1 H), 6.6 (s, 1 H), 4.7 (d, 2H) EXAMPLE 141 1 H NMR (CDCl 3) d 8.2 (dt, 1 H), 8.0 (s, 1 H), 7.45 - 7.1 (m, 7 H), 6.6 (s, 1 H), 4.4 (dt, 2 H), 2.6 (t, 2 H), 1.8 (m, 2H), 1.4 (m, 2H) EXAMPLE 171 1 H NMR (CD 3 OD) d 8.41 (s, 1 H), 8.25 (d, J = 6.3 Hz, 1 H), 8.15 (s, 1 H), 7.67 (d, J = 7.8 Hz, 2 H), 7.55-7.48 (m, 2H), 7.45 (dd, J = 7.5, 1.2 Hz, 1H), 7.34 (dd, J = 7.5, 1.8 Hz, 1 H), 6.28 (s, 1 H), 4.79 (s, 2H).

EXAMPLE 172 1 H NMR (CDCl 3) d 8.64 (s, 1 H), 7.68-7.64 (m, 2 H), 7.52 (m, 1 H), 7.43 (t, J = 7.8 Hz, 1 H), 6.89 (t, J = 6.0 Hz, 1H), 6.51 (s, 1H), 6.48 (m, 2H), 4.74 (d, J = 6.0 Hz, 2H).

EXAMPLE 173 1 H NMR (DMSO-d 6) d 8.86 (s, 1 H), 8.46 (s, 1 H), 8.32-8.28 (m, 2H), 7.97 (m, 1H), 7.87 (m, 1H), 7.52 (m, 1H), 7.35-7.24 (m, 2H), 6.57 (s, 1H), 6.46 (m, 1H), 3.65 (m , 4H).

EXAMPLE 174 1 H NMR (CDCl 3) d 8.37 (s, 1 H), 8.16 (t, J = 7.5 Hz, 1H), 7.45-7.35 (m, 1H), 7.32-7.20 (m, 3H), 7.17-7.07 (m, 1H ), 6.92 (t, J = 6 Hz, 1H), 6.48 (s, 1 H), 4.65 (d, 2H), 2.50 (s, 3H). EXAMPLE 175 1 H NMR (CDCl 3) d 8.16 (t, J = 9 Hz, 1 H), 8.00 (s, 1 H), 7.49 (d, J = 9 Hz, 1 H), 7.46-7.36 (m, 1 H), 7.18-7.08 ( m, 1H), 7.00 (d, J = 9 Hz, 1H), 6.62-6.50 (m, 2H), 2.60 (s, 3H), 2.55 (s, 3H).

EXAMPLE 176 1 H NMR (CDCl 3) d 8.15 (t, J = 9 Hz, 1H), 8.00 (s, 1H), 7.45-7.35 (m, 1H), 7.32-7.20 (m, 1H), 7.20-7.05 (m, 3H ), 6.80 (t, 1H), 6.50 (s, 1H), 4.65 (d, 2H), 2.65 (s, 3H), 2.50 (s, 3H).

EXAMPLE 177 1 H NMR (CDCl 3) d 8.20 (t, 1H), 7.90 (s, 1H), 7.50-7.05 (m, 8H), 6. 80 (s, 1H), 5.05-4.90 (m, 2H), 3.80 (d, 1H), 3.45 (d, 1H), 3.00 (dd, 1H), 2.90 (dd, 1H), 2.50 (s, 3H) .

EXAMPLE 181 H NMR (300MHz, CDCl 3) d 8.41 (s, 1H), 8.28 - 8.23 (d, 1H), 8.15 (s, 1H), 7.69 -7.60 (d, 1H), 7.62 - 7.50 (m, 3H), 7.50 - 7.47 (dd, 1H), 6.35 (s, 1 H), 5.36 (s, 1 H), 4.80 (s, 2H). EXAMPLE 184 1 H NMR (300 MHz, CDCl 3) d 8.96 - 8.90 (s, 1 H), 8.08 (s, 1 H), 8.04 (d, 1 H), 7.72 (d, 1 H), 7.70 - 7.61 (dd, 1 H), 7.24 - 7.20 (dd, 1 H), 6.92 - 6.84 (t, 1 H), 6.36 (s, 1 H), 4.96 - 4.89 (d, 2H).

EXAMPLE 186 1 H NMR (300MHz, CDCl 3) d 8.96 - 8.90 (s, 1H), 8.08 (s, 1H), 8.44 (s, 1H), 8.27 - 8.24 (d, 1H), 8.02 (s, 1H), 7.78 - 7.76 (d, 1H), 7.73-7.70 (d, 1H), 7.58-7.51 (m, 2H), 7.13-7.08 (dd, 1H), 5.51 (s, 2H).

EXAMPLE 195 1 H NMR (CD 3 OD) d 8.40 (s, 1 H), 8.27 (d, 1 H), 8.03 (s, 1 H), 7.75- 7.50 (m, 2 H), 6.10 (s, 1 H), 4.76 (s, 2 H), 4.05 (m, 2H), 3.88 (m, 2H), 3.52 (m, 1H), 2.33 (m, 1H), 2.20 (m, 1H).

EXAMPLE 196 1 H NMR (CD 3 OD) d 8.73 (d, 1 H), 8.58 (q, 1 H), 8.12 (s, 1 H), 8.00 (d, 1 H), 7.54 (q, 1 H), 6.19 (s, 1 H) ), 4.86 (s, 2H), 4.22-4.08 (m, 2H), 4.03-3.93 (m, 2H), 3.63 (m, 1 H), 2.50-2.39 (m, 1 H), 2.32-2.21 (m , 1 HOUR).

EXAMPLE 197 1 H NMR (CD 3 OD) d 8.73 (d, 1 H), 8.58 (q, 1 H), 8.12 (s, 1 H), 8.00 (d, 1 H), 7.54 (q, 1 H), 6.19 (s, 1 H), 4.86 (s, 2H), 4.22-4.08 (m, 2H), 4.03-3.93 (m, 2H), 3.63 (m, 1 H), 2.50-2.39 (m, 1 H), 2.32-2.21 (m, 1 H).

EXAMPLE 199 1 H NMR (300MHz, CDCl 3) d 8.29 (s, 1 H), 8.15 (br s, 1 H), 7.95 (s, 1 H), 7.28 (d, 1 H), 7.05 - 6.95 (appt t, 1 H), 5.70 (s, 1 H), 4.62 (d, 2 H), 2.90 (m, 1 H), 2.30 (m, 1 H), 1.9-1.2 (m, 8H), 0.65 (d, 3H).

EXAMPLE 200 1 H NMR (300 MHz, CDCl 3) d 8.71 (s, 2 H), 8.00 (s, 1 H), 6.13 (s, 1 H), 3.59 (s, 2 H), 3.01 - 2.58 (m, 1 H), 2.51 - 2.45 (m, 1 H), 2.44 -2.30 (m, 1 H), 2.20 (s, 3 H), 2.09 - 1.95 (m, 2 H), 1.85 -1.70 (m, 2 H), 0.80 - 0.76 (d, 3 H) ).

EXAMPLE 203 1 H NMR (300MHz, CDCl 3) d 8.10 (s, 1 H), 8.08 (s, 1 H), 6.27 (s, 2H), 4.95 (s, 2H), 3.00 - 2.90 (dd, 2H), 2.60 (m , 2H), 2.48 (br s, 1H), 2.39 (s, 3h), 2.25 m, 1 H), 1.95 - 1.70 (m, 3H).

EXAMPLE 211 To a solution of the compound prepared in Example 156 (100 mg, 0.23 mmol) in dry THF (4 mL) was added LiAIH4 (1.0 M in THF, 0.110 mL, 0.110 mmol) at ° C under N2. The mixture was stirred at 0 ° C for 1hr, heated to 25 ° C, then additional LiAIH4 (1.0 M in THF, 0.400 ml) was added, the mixture was stirred for 20 min and then deactivated with MeOH (2.0 ml). . The solvent was evaporated and the crude product was purified by flash chromatography using 10: 1 CH2Cl2: MeOH as eluent. White solid was obtained (46 mg, 49%). LCMS: M + = 416, Mp = 71-72 ° C.

EXAMPLE 212 To a solution of the compound prepared in Example 156 (70 mg, 0.16 mmol) in dry THF (3 mL) was added MeMgBr (3.0 M in Et 2 O, 1.10 mL, 3.20 mmol) under N 2. The mixture was stirred at 25 ° C for 45 min and then quenched with saturated aqueous NH 4 Cl (5.0 mL). The mixture was poured into saturated aqueous NH4CI (30 ml) and extracted with CH2Cl2 (3x20 ml). The extracts were dried over Na2SO4 and filtered. The solvent was evaporated and the crude product was purified by flash chromatography using 20: 1 CH2Cl2: MeOH as eluent. White solid was obtained (25 mg, 36%). LCMS: M + = 444. Mp = 76-80 ° C.

EXAMPLE 213 DMF anhydride (40 ml) under N2 was added to the compound prepared in Preparative Example 174 (2.50 g, 8.65 mmol) and 60% NaH in mineral oil (346 mg, 8.65 mmol). The mixture was stirred at 25 ° C for 1 hr, then 2-chloro-5-chloromethylpyridine N-oxide (1.54 g, 8.65 mmol) in anhydrous DMF (20 ml) was slowly added. The mixture was stirred at 25 ° C for 18 hr, the solvent was evaporated and the crude product was purified by flash chromatography using 30: 1 CH2Cl2: MeOH as eluent. The solid obtained in this way was triturated by 50 ml of 1: 1 EtOAc: hexane. A pale yellow solid (1.25 g, 34%) was obtained. LCMS: MH + = 432. Mp = 224-226 ° C.

EXAMPLES 214-217 By essentially the same procedure set forth in Example 213, by combining the compounds shown in Column 2 of Table 19 with the compounds in Column 3 of Table 19, the compounds shown in Column 3 of Table 19 were prepared.

TABLE 19 EXAMPLE 218 CF3CH2OH (3.0 ml) under N2 was added to 60% NaH in mineral oil (40 mg, 1.0 mmol), the mixture was stirred for 20 min, then the product prepared in Example 213 (50 mg, 0.12 mmol) was added. The mixture was refluxed for 20 hr, the solvent was evaporated, and the residue was purified by flash chromatography using 20: 1 CH2Cl2: MeOH as eluent to give a pale yellow solid (35 mg, 61%). LCMS: M2H + = 496, Mp = 208-210 ° C. EXAMPLES 219-225 Essentially by the same procedure set forth in Example 218, by combining the compounds shown in Column 1 of Table 20 with the appropriate alcohol, the compounds shown in Column 2 of Table 20 were prepared.

TABLE 20 EXAMPLE 226 A mixture of the product prepared in Example 213 (100 mg, 0.23 mmol) and KOH (95 mg, 1.70 mmol) in 1,2-dimethoxyethane (3 ml) and H2O (1.5 ml) was refluxed under N2 for 20 hr, deactivated with (0.30 ml), and the solvent was evaporated. The residue was suspended in H2O (15 ml), filtered and the solid was washed with H2O (15 ml) and Et2O (10 ml). It was then mixed with CH2Cl2 (2 ml) and Et2O (2 ml) and filtered. Et2O (5 ml) was added to the filtrate and the mixture was allowed to settle until the next day. The solid was removed by filtration, washed with Et2O and then dissolved in MeOH (5 ml). The solution was filtered and the solvent in the filtrate was evaporated. Whitish solid was obtained (5 mg, 5%). LCMS: M + = 412. Mp = 206-208 ° C.

EXAMPLE 227 A mixture of the product prepared in Example 213 (129 mg, 0.30 mmol), N, N-dimethylethylenediamine (0.165 ml, 1.50 mmol), and diisopropylethylamine (0.10 ml) in anhydrous N-methylpyrrolidinone (1.0 ml) at 100 ° was stirred. C for 24 hr. The solvent was evaporated, and the residue was purified by flash chromatography using 20: 1 CH2Cl2: 7N NH3 in MeOH as eluent to give pale yellow solid (110 mg, 76%). LCMS: M + = 482. Mp = 76-78 ° C.

EXAMPLES 228-233 Essentially by the same procedure set forth in Example 227, by combining the compounds shown in Column 1 of Table 21 with the appropriate amine, the compounds shown in Column 2 of Table 21 were prepared.

TABLE 21 EXAMPLE 234 A mixture of the product prepared in Example 213 (80 mg, 0.19 mrnol) and 2.0 M methylamine in THF was stirred in a closed pressure vessel at 50 ° C for 72 hr. The solvent was evaporated, and the residue was purified by flash chromatography using 10: 1 CH2Cl2: MeOH as eluent to give pale yellow solid (40 mg, 51%). LCMS: M2H + = 427, Mp = 217-219 ° C.

EXAMPLE 235 Essentially by the same procedure set forth in Example 234, the compound shown above was prepared. LCMS: M2H + = 441. Mp = 98-101 ° C.

EXAMPLE 236 The compound prepared in Preparative Example 174 (140 mg, 0.48 mmol) and the aldehyde (71 mg, 0.58 mmol) in THF anhydride (4 ml) were stirred at 50 ° C under N2. Ti (OiPr) 4 (0.574 ml, 1.92 mmol) was added, the mixture was stirred at 50 ° C 3 hr, and cooled to 25 ° C. NaBH 3 CN (181 mg, 2.88 mmol) was added, the mixture was stirred for a further 2 hours, then poured into 10% aqueous Na 2 CO 3 (100 mL), and extracted with CH 2 Cl 2 (3 x 50 mL). The combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by flash chromatography using 15: 1 CH2Cl2: MeOH as eluent to give pale yellow solid (40 mg, 21%). LCMS: MH + = 398. Mp > 230 ° C.

EXAMPLES 237-256 Essentially by the same procedure set forth in Example 236, by combining the compounds shown in Column 2 and 3 of Table 22, the compounds shown in Column 4 of Table 22 were prepared.

TABLE 22 EXAMPLE 257 A mixture of the compound prepared in Example 242 (100 mg, 0.24 mmol), conc. Aqueous HCl was stirred. (1.0 ml) and acetic acid (2.0 ml) a 100 ° C under N 2 for 2 hr, then poured into Na 2 CO 3 (15 g), and extracted with 1: 1 acetone: CH 2 Cl 2 (3 x 30 ml). The combined extracts were filtered, and the solvent was evaporated. The residue was purified by flash chromatography using 10: 1 CH2Cl2: MeOH as eluent to give pale yellow solid (36 mg, 37%). LCMS: M2H + = 398, EXAMPLES 258-260 Essentially by the same procedure set forth in Example 257, from the compounds shown in Column 1 of Table 23, the compounds shown in Column 2 of Table 23 were prepared.

TABLE 23 EXAMPLE 261 To a stirred solution of the compound prepared in Example 239 (41 mg, 0.10 mmol) in CH 2 Cl 2 was added 1.0 M BBr 3 (0.30 mL, 0.30 mmol) in CH 2 Cl 2 at -78 ° C. The mixture was stirred at -78 ° C for 5 min, then at 24 ° C for 3 hr, then MeOH (2.0 ml) was added and the mixture was stirred for 10 min. The solvent was evaporated and the residue was purified by flash chromatography using 5: 1: 0.1 CH2Cl2: MeOH: conc. NH 4 OH as eluent to give white solid (39 mg, 99%). LCMS: M + = 397, Mp > 230 ° C.

EXAMPLE 262 A mixture of the product prepared in Example 217 (40 mg, 0.077 mmol) and 5.0 M aqueous NaOH (0.8 mL) in MeOH (3.0 mL) was refluxed under N2 for 1 hr. NaHCO3 (700 mg) was added, the solvent was evaporated, and the residue was purified by flash chromatography using 10: 1: 0.1 CH2Cl2: MeOH: NH4OH conc. as eluent to give white solid (10 mg, 35%). LCMS: M2H + = 371. Mp = 237-239 ° C.

EXAMPLES 263-264 Essentially by the same procedure set forth in Example 262, from the compounds shown in Column 1 of Table 24, the compounds shown in Column 2 of Table 24 were prepared.

TABLE 24 EXAMPLE 265 TFA (0.5 ml) was added to a solution of the compound prepared in Preparative Example 197 (0.08 g, 0.16 mmol) in CH 2 Cl 2 (2.0 ml) at 0 ° C and the resulting solution was stirred 2.5 hours and stored at 4 ° C. until the following day at that time TFA (0.5 ml) was added. The resulting solution was stirred 4 hours and concentrated in vacuo. The residue was neutralized with 1N NaOH and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 2.5% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent (0.009 g, 15% yield). LCMS: MH + = 396; mp = 53-54 ° C.

EXAMPLE 266 A solution of the compound prepared in Preparative Example 182 (26 mg, 0.070 mmol) and potassium thiocyanate (13 mg, 0.14 mmol) in MeOH (1 mL) was cooled in a cold water bath. To it, a solution of bromine (22 mg, 0.14 mmol) in MeOH (0.7 ml) was added dropwise. The resulting reaction mixture was stirred for 4 h at room temperature and the volatiles were removed under reduced pressure. The residue obtained was suspended in a small amount of CH 2 Cl 2, the potassium bromide was filtered and the pH of the filtrate was adjusted to about 7 by the addition of aqueous ammonia. This was concentrated under reduced pressure and the residual oil was purified by preparative thin layer chromatography using 15% MeOH in CH2Cl2 as eluent (26 mg, 87% yield). 1 H NMR (CDCl 3) d 8.75 (d, J = 4.2 Hz, 2 H), 8.38 (s, 1 H), 7.68- 7.64 (m, 2 H), 7.46-7.39 (m, 3 H), 7.22 (t, J = 6.3 Hz, 1 H), 6.43 (s, 1 H), 4.84 (d, J = 6.3 Hz, 2H); LCMS: MH + = 427.

EXAMPLE 267 Boron tribromide (1 M in CH 2 Cl 2, 0.60 ml, 0.60 mmol) was added dropwise to a stirred frozen solution of the compound prepared in Example 24 (50 mg, 0.12 mmol) in CH 2 Cl 2 (1.5 ml) under an argon atmosphere . The resulting reaction mixture was stirred at 0 ° C for 30 minutes, allowed to warm to room temperature, and stirred until the next day. The mixture was quenched by the addition of a small amount of water and extracted with CH2CI2. The organic layer was dried over magnesium sulfate and concentrated in vacuo (45 mg, 94% yield). 1 H NMR (CD3OD) d 9.16 (s, 1 H), 8.95 (s, 1 H), 8.88 (d, J = 8.1 Hz, H), 8.24 (t, J = 6.9 Hz, 1 H), 8.18 (s) , 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 7.40 (t, J = 7.8 Hz, 1 H), 7.00-6.96 (m, 2H), 6.86 (s, 1 H), 5.28 ( s, 2H); LCMS: MH + = 396.

EXAMPLE 268 A solution of the compound of Preparative Example 184 (0.05 g, 0.15 mmol), N-methylpiperazine (20 μL, 1.2 eq.) And iPr2Et (52 μL, 2.0 eq.) In dioxane (1 mL) at 70 ° C was heated up the next day. The reaction mixture was cooled to room temperature and diluted with H2O and saturated NaHCO3. The resulting mixture was extracted with CH2Cl2, the combined organics were dried over Na2SO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC using a 5% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent (0.028 g, 47% yield). MS: MH + = 402, mp = 210 ° C (dec.) EXAMPLES 269-275 Essentially by the same procedure set forth in Example 268, replacing only the amine in Column 2 of Table 25 and the chlorides in Column 3 of the table 25, the compounds shown in Column 4 of Table 25 were prepared: TABLE 25 EXAMPLE 276 Step A 4-Fluorophenyl magnesium bromide (0.68 ml, 1.2 eq.) Was added to the compound prepared in Preparative Example 193 (0.20 g, 0.55 mmol) and PdCI2 (dppf) 2 (0.037 g, 10 mol%) in THF and the solution The resulting mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with saturated NH 4 Cl and extracted with EtOAc. The combined organics were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using pure EtOAc as eluent (0.15 g, 65% yield). MS: MH + = 420.

Step B Essentially by the same procedure set forth in Preparative Example 127, substituting only the compound prepared in Example 276, Step A, the above compound was prepared (0.17 g, 94% yield).

Step C Essentially by the same procedure set forth in Preparative Example 200 substituting only the compound prepared in Example 276, Step B, the above compound was prepared (0.1 g, 100% yield).

Step D put in the Example 265, substituting only the compound prepared in Example 276, Step C, the above compound was prepared (0.049 g, 62% yield). MS: MH + = 414; mp = 110-115 ° C.

EXAMPLE 277 Step A Pd (PPh3) (0.065 g, 10 mol%) was added to 3-cyanophenyl zinc iodide (2.2 ml, 0.5 M solution in THF, 2 eq.) And the compound prepared in Preparative Example 193 (0.2 g, 0.56 mmol ) in DMF (2.0 ml) and the resulting solution was heated at 80 ° C for 144 hours. The reaction mixture was cooled to room temperature, diluted with saturated NH 4 Cl and extracted with EtOAc. The combined organics were washed with H2O and brine, dried over Na2SO, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a pure EtOAC solution as eluent (0.07 g, 29% yield). MS: MH + = 427.

Step B to Step D Essentially by the same procedures set forth in Example 276, Step B to Step D, the above compound was prepared (0.023 g, 53% yield). MS: MH + = 421; mp = 230 ° C (dec.) EXAMPLE 278 Essentially by the same procedure set forth in Example 276, replacing only the suitable cyclopropylmagnesium bromide in Step A, the compound was prepared. MS: MH + = 372; m. p. = 96-98 ° C.

EXAMPLE 279 The cross-coupling reaction of palladium-catalyzed zinc was carried out in a similar manner to the procedure described in J. Org. Chem. (1999), 453. A solution of chloropyrazolopyrimidine (200 mg, 0.458 mmol), Pd (PPh3) 4 (53 mg, 0.046 mmol), and exo-2-norbonylzinc bromide (0.5 M in THF, 0.95) was refluxed. ml, 0.47 mmol) in DMF (2 ml) at 100 ° C (oil bath temperature) until the next day. The reaction mixture was quenched with half-saturated NH CI and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography using a 50% EtOAc solution in hexanes as eluent. A solution of the product obtained protected by N-Boc (121 mg, 53% yield, LCMS: MH + = 498) and TFA (1 mL) in CH2Cl2 (2 mL) was stirred at room temperature for 2 hr. The volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2, neutralized with saturated NaHCO3, and extracted with CH2Cl2? The organic phase was dried over MgSO and concentrated in vacuo (96 mg, 99% yield).

LCMS: MH + = 398; 1 H NMR (CDCl 3) d 8.78 (s, 1 H), 8.71 (d, J = 4.2 Hz, 1 H), 8.04 (d, J = 3.9 Hz, 1 H), 7.80 (d, J = 7.8 Hz, 1 H ), 7.44 (m, 1 H), 6.73 (m, 1 H), 5.98 (d, J = 7.5 Hz, 1 H), 4.74 (d, J = 5.4 Hz, 2 H), 3.40-1.00 (m, 11) H).

EXAMPLES 280-294 By essentially following the same procedure set forth in Example 279, substituting only the chlorides shown in Column 2 of Table 26 and the zinc organ reagents shown in Column 3 of Table 26, the compounds were prepared column 4 of table 26: TABLE 26 Below are additional data for selected compounds.

EXAMPLE 280 1 H NMR (CDCl 3) d 8.65 (s, 1 H), 8.57 (d, J = 4.2 Hz, 1 H), 8.50 (d, J = 4.5 Hz, 1 H), 8.01 (s, 1 H), 7.69 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.31-7.22 (m, 2H), 6.77 (m, 2H), 4.71 (d, J = 5.4 Hz, 2H), 2.68 (s, 3H).

EXAMPLE 281 1 H NMR (CDCl 3) d 8.80 (s, 1 H), 8.72 (d, J = 4.8 Hz, 1 H), 8.08 (s, H), 7.85-7.40 (m, 3 H), 7.02 (d, J = 5.1 Hz, 1H), 6.90 (t, J = 6.0 Hz, 1H), 6.29 s, 1 H), 4.79 (d, J = 6.0 Hz, 2H), 2.61 (s, 3H).

EXAMPLE 282 1 H NMR (CDCl 3) d 8.67 (s, 1 H), 8.61 (d, J = 3.9 Hz, 1 H), 8.03 (s, 1 H), 7.72-7.31 (m, 3 H), 7.22-7.00 (m, 2 H), 6.81 (t, J = 6.0 Hz, 1H), 6.03 (s, 1 H), 4.68 (d, J = 6.0 Hz, 2H), 2.28 (s, 3H).

EXAMPLE 283 1 H NMR (CDCl 3) d 8.68 (s, 1 H), 8.63 (d, J = 4.0 Hz, 1 H), 8.00 (s, 1 H), 7.80-7.72 (m, 2 H), 7.54-7.47 (m, 3 H), 7.35 (m, 1H), 6.74 (t, J = 6.0 Hz, 1H), 6.19 (s, 1H), 4.67 (d, J = 6.0 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 1.13 (t, J = 7.2 Hz, 3H).

EXAMPLE 284 1 H NMR (CDCl 3) d 7.97 (s, 1 H), 7.65 (d, J = 7.2 Hz, 1 H), 7.33-7.15 (m, 5 H), 6.73 (t, J = 5.4 Hz, 1 H), 5.99 (s, 1H), 4.61 (d, J = 5.4 Hz, 2H), 3.09 (sept, J = 6.9 Hz, 1H), 1.11 (d, J = 6.9 Hz, 6H).

EXAMPLE 285 1 H NMR (CDCl 3) d 8.56-8.55 (m, 2 H), 7.94 (s, 1 H), 7.54 (m, 1 H), 7.30-7.22 (m, 6 H), 6.59 (t, J = 5.7 Hz, 1 H), 5.66 (s, 1H), 4.47 (d, J = 5.7 Hz, 2H), 4.26 (q, J = 7.2 Hz, 1H), 1.68 (d, J = 7.2 Hz, 3H).

EXAMPLE 286 1 H NMR (CDCl 3) d 8.67 (m, 2 H), 7.94 (s, 1 H), 7.69 (d, J = 7.8 Hz, 1H), 7.34 (m, 1H), 6.63 (t, J = 5.7 Hz, 1H), 5.87 (s, 1H), 4.62 (d, J = 5.7 Hz, 2H), 3.64 (s, 3H), 3.13 ( m, 2H), 2.82 (m, 1H), 1.22 (m, 3H).

EXAMPLE 287 1 H NMR (CDCl 3) d 8.66 (m, 2 H), 7.94 (s, 1 H), 7.68 (d, J = 7.8 Hz, 1 H), 7.34 (m, 1 H), 6.62 (t, J = 6.0 Hz, 1 H) , 5.87 (s, 1H), 4.62 (d, J = 6.0 Hz, 2H), 3.64 (s, 3H), 3.13 (m, 2H), 2.81 (m, 1H), 1.22 (m, 3H).

EXAMPLE 288 1 H NMR (CDCl 3) d 8.64 (s, 1 H), 8.60 (d, J = 3.6 Hz, 1 H), 8.04 (s, 1 H), 7.68 (m, 1 H), 7.31 (m, 1 H), 7.16 (m, 1H), 7.07-7.05 (m, 2H), 6.80 (t, J = 6.3 Hz, 1H), 5.93 (s, 1H), 4.64 (d, J = 6.3 Hz, 2H), 2.08 (s, 6H).

EXAMPLE 289 1 H NMR (CDC b) d 8.72 (s, 1 H), 8.62 (d, J = 4.8 Hz, 1 H), 7.99- 7.97 (m, 2 H), 7.73-7.69 (m, 2 H), 7.40-7.33 (m, 2 H) ), 6.67 (t, J = 6.0 Hz, 1H), 6.29 (s, 1 H), 4.71 (d, J = 6.0 Hz, 2H). EXAMPLE 290 1 H NMR (CDCl 3) d 8.73 (s, 1 H), 8.62 (d, J = 4.5 Hz, 1 H), 8.01 (s, 1 H), 7.76 (m, 1 H), 7.41 (d, J = 5.1 Hz, 1 H) , 7.34 (dd, J = 8.1, 5.1 Hz, 1H), 7.05 (d, J = 5.1 Hz, 1H), 7.01 (s, 1H), 6.79 (t, J = 6.0 Hz, 1H), 4.74 (d, J = 6.0 Hz, 2H).

EXAMPLE 291 1 H NMR (DMSO-c / e) d 9.12 (s, 1 H), 8.40 (s, 1 H), 8.33 (s, 1 H), 8. 13 (m, 1H), 7.82 (d, J = 5.1 Hz, 1H), 7.40-7.39 (m, 2H), 7.22 (d, J = 5.1 Hz, 1H), 6.86 (s, 1H), 4.86 (s) , 2H).

EXAMPLE 292 1 H NMR (CDCl 3) d 8.23 (s, 1 H), 8.16 (d, J = 6.0 Hz, 1 H), 8.06 (s, 1 H), 7.31-7.05 (m, 5 H), 6.86 (m, 1 H), 5.87 ( s, 1H), 4.62 (d, J = 6.3 Hz, 2H), 2.09 (s, 6H).

EXAMPLE 293 1 H NMR (CDCl 3) d 8.14 (s, 1 H), 8.12 (d, J = 6.3 Hz, 1 H), 7.94 (s, 1 H), 7.29-7.16 (m, 6 H), 7.07 (m, 1 H ), 6.78 (t, J = 6.0 Hz, 1 H), 5.54 (s, 1 H), 4.44 (d, J = 6.0 Hz, 2H), 4.24 (t, J = 7.2 Hz, 1 H), 1.68 ( d, J = 7.2 Hz, 3H).

EXAMPLE 294 1 H NMR (CDCl 3) d 8.67 (s, 1 H), 8.59 (d, J = 4.8 Hz, 1 H), 8.01 (s, 1 H), 7.71 (m, 1 H), 7.52 (dd, J = 7.8, 1.8 Hz, 1 H), 7.40-7.19 (m, 4H), 6.78 (t, J = 6.0 Hz, 1 H), 6.32 (s, 1H), 4.67 (d, J = 6.0 Hz, 2H), 2.38 (s, 3H).

EXAMPLE 295 To a suspension of lithium aluminum hydride (10 mg, 0.26 mmol) in THF anhydride (2 ml) at 0 ° C was added, dropwise, a solution of the compound prepared in Example 283 (20 mg, 0.044 mmol) in THF anhydride (2 ml). The resulting mixture was refluxed for 1 hr and stirred at room temperature overnight, neutralized with dilute sulfuric acid and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography using a 5% MeOH in EtOAc solution as eluent (15 mg, 83% yield). LCMS: MH + = 410; 1 H NMR (CDCl 3) d 8.69 (s, 1 H), 8.61 (d, J = 3.9 Hz, 1 H), 8.05 (d, J = 2.1 Hz, 1 H), 7.74 (d, J = 7.8 Hz, 1 H), 7.52-7.31 (m, 5H), 6.97 (t, J = 6.3 Hz, 1 H), 6.55 (d, J = 2.7 Hz, 1 H), 6.20 (s, 1 H), 4.71 (d, J = 6.3 Hz, 2H), 4.52 (s, 2H).

EXAMPLE 296 M-CPBA (18 mg, 0.10 mmol) was added to a solution of the compound protected by N-Boc prepared in Example 294 (45 mg, 0.085 mmol) in CH 2 Cl 2 (4 mL) at -50 ° C. After stirring for 1 hr. hr at -50 ° C plus m-CPBA (4 mg, 0.02 mmol) was added The mixture was stirred for an additional 2 hr, diluted with CH 2 Cl 2 (20 ml), and washed with saturated NaHCO 3 (20 ml). Organic phase was dried over MgSO 4 and concentrated under reduced pressure The residue was purified by preparative thin layer chromatography using a 2.5% MeOH solution in CH 2 Cl 2 as eluent A solution of the protected N-Boc product was stirred (37 mg 80% yield, LCMS: MH + = 542) and TFA (1 ml) in CH 2 Cl 2 (2 ml) at room temperature for 2 hrs. The volatiles were removed under reduced pressure.The residue was dissolved in CH 2 Cl 2, neutralized with NaHCO 3 The organic phase was dried over MgSO and concentrated under reduced pressure. was purified by preparative thin layer chromatography using a 5% MeOH in EtOAc solution as eluent (26 mg, 89% yield). LCMS: MH + = 442; 1 H NMR (CDCl 3) d 8.71 (s, 1 H), 8.64 (d, J = 3.9 Hz, 1 H), 8.41 (m, 1 H), 8.03 (s, 1 H), 7.75-7.54 (m, 4H ), 7.36 (dd, J = 8.1, 5.1 Hz, 1 H), 6.81 (t, J = 6.0 Hz, 1 H), 6.34 (s, 1 H), 4.74 (d, J = 6.0 Hz, 2H), 3.25 (s, 3H).

EXAMPLE 297 To a solution of the compound protected by N-Boc prepared in Example 294 (56 mg, 0.11 mmol) in CH 2 Cl 2 (4 mL) at 0 ° C was added m-CPBA (42 mg, 0.24 mmol). After stirring for 2 hr at room temperature, more m-CPBA (13 mg, 0.075 mmol) was added. The mixture was stirred at room temperature overnight, diluted with CH2Cl2 (20 mL), and washed with saturated NaHCO3 (20 mL). The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography using a 2.5% MeOH solution in EtOAc as eluent. A solution of the obtained product protected by N-Boc (29 mg, 49% yield, LCMS: MH + = 558) and TFA (1 ml) in CH2Cl2 (2 ml) was stirred at room temperature for 2 hr. The volatiles were removed under reduced pressure. The residue was dissolved in CH 2 Cl 2, neutralized with saturated NaHCO 3, and extracted with CH 2 Cl 2, The organic phase was dried over MgSO 4 and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography using a 2.5% MeOH solution in EtOAc as eluent (21 mg, 90% yield). LCMS: MH + = 458; 1 H NMR (CDCl 3) d 8.64 (s, 2 H), 8.20 (m, 1 H), 8.01 (s, 1 H), 7.73- 7.60 (m, 3 H), 7.46 (m, 1 H), 7.35 (s, 1 H), 6.82 (t, J = 5.9 Hz, 1 H), 6.17 (s, 1 H), 4.65 (d, J = 5.7 Hz, 2 H), 3.60 (s, 3 H).

EXAMPLE 298 Essentially by the same procedure set forth in Preparative Example 127, substituting only the compound prepared in Preparative Example 189, the above compound was prepared. MS: MH + = 334; mp = 170-173 ° C.

EXAMPLES 299-300 Essentially by the same procedure set forth in Example 298, substituting only the compound shown in Table 27, Column 2, the compounds shown in Table 27, Column 3 were prepared: TABLE 27 EXAMPLE 301 To a solution of the compound prepared in Example Preparation 186 (0.1 g, 0.21 mmol) in THF (4.0 mL) at -78 ° C was added nBuLi (0.57 mL, 2.16 M in hexanes, 5.0 eq.) At -78 ° C. The reaction mixture was stirred 2 hours at -78 ° C, deactivated with H2O, warmed to room temperature, and extracted with EtOAc. The combined organics were dried over Na 2 SO, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC using a 2.5% solution (10% NH 4 OH in CH 3 OH) in CH 2 Cl 2 as eluent (0.013 g, 20% yield). MS: MH + = 326; mp = 71-72 ° C.

EXAMPLE 302 Essentially by the same procedure set forth in Example 301, substituting only the compound of Preparative Example 187, the above compound was prepared (0.049 g, 68% yield). MS: MH + = 344; mp = 69-71 ° C.

EXAMPLE 303 To a solution of the 3-H adduct of Preparative Example 187.1 (0.70 g, 2.32 mmol) in DMF (4.2 ml) at 0 ° C was added POCI3 (0.67 ml, 7.2 mmol) dropwise. The mixture was stirred for 14 h at room temperature, cooled to 0 ° C, and deactivated by the addition of ice. 1N NaOH was added carefully to adjust the pH to 8 and the mixture was extracted with CH2Cl2 (3 x 25 ml). The organic layers were combined, dried (Na2SO), filtered and concentrated under reduced pressure. The crude product was recrystallized from EtOAc to give 0.43 g (56%) of a yellow solid, mp 181-183 ° C; M + H = 330.

EXAMPLE 304 Step A To a solution of the aldehyde (100 mg, 0.30 mmol) of Example 303 in THF (1 ml) at 0 ° C was added cyclohexyl magnesium bromide (0.46 ml, 2.0M in Et 2 O) dropwise over 5 min. The resulting mixture was stirred at 0 ° C for 2 h and at room temperature for 12 h. The mixture was cooled to 0 ° C and treated with saturated aqueous NH CI. (3 ml) and CH2Cl2 (5 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 5 mL). The organic layers were combined, washed with brine (1 x 5 ml), dried (Na2SO4), filtered and concentrated under reduced pressure to give 110 mg (89%) of a pale yellow semi-solid. M + H = 414. This material was carried out crude until Step B without further purification.

Step B To a solution of alcohol (53 mg, 0.13 mmol) in CH2Cl2 (0.5 mL) at 0 ° C was added Et3SiH (24 μL, 0.15 mmol) followed by TFA (24 μL, 0.30 mmol). The mixture was stirred for 2 h at 0 ° C and at room temperature for 2 h at which time additional portions of Et 3 SiH (24 μl, 0. 5 mmol) and TFA (24 μl, 0.30 mmol) were added and the mixture was stirred for 3 h. at room temperature (until completed by TLC). The mixture was concentrated under reduced pressure and the crude residue was partitioned between CH2Cl2 (5 mL) and sat aqueous NaHCO3. (2.5 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 5 mL). The organic layers were combined, washed with brine (1 x 5 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (8 x 1000 mM) eluting with CH2Cl2 / MeOH (22: 1) to give 29 mg (56%) of a yellow semi-solid. M + H = 398.

EXAMPLES 305-312 Essentially by the same procedure set forth in Example 304, using the aldehyde of Example 303 and substituting the Grignard or organolith reagents shown in Column 2 of Table 28, the compounds were prepared in column 3 of Table 28: TABLE 28 EXAMPLE 313 At a reduction of the aldehyde (81 mg, 0.2 s mmol) of Example 303 in benzene (2.5 ml), carboethoxymethylene triphenyl phosphorane (0.12 g, 0.33 mmol) was added in one portion. The mixture was refluxed for 24 h, cooled to rt, and concentrated under reduced pressure. The mixture was diluted CH2Cl2 (50 mL), brine (2 mL) was added, and the layers were separated. The aqueous layer was extracted with CH2CI (2 x 4 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (8 x 1000 μM) eluting with CH 2 Cl 2 / MeOH (20: 1) to give 98 mg (100%) of white solid, mp 151-153 ° C; M + H = 400.

EXAMPLE 314 NaH (55 mg, 1.37 mmol) was added to the mixture and the mixture was stirred for 30 min. in a mixture of 0.59 g, 1.37 mmol) in THF (3 mL). The aldehyde (0.15 g, 0.46 mmol) of Example 303 was added in a single portion and the mixture was heated to reflux for 36 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was diluted CH2Cl2 (5 mL), brine (2 mL) was added, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2 x 4 ml). The organic layers were combined, dried (Na2SO), filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (8 x 1000 μM) eluting with CH 2 Cl 2 / MeOH (20: 1) to give 58 mg (32%) of a yellow solid, mp 138-141 ° C; M + H = 404.

EXAMPLE 315 To a solution of the aldehyde (0.20 g, 0.60 mmol) of Example 303 in THF (3 mL) was added Ti (i-OPr) 4 (0.36 mL, 1.21 mmol) dropwise followed by the addition of (S) - ( -) - 2-methyl-2-propanesulfinamide (74 mg, 0.61 mmol). The resulting mixture was stirred for 18 h at reflux, cooled to rt, and quenched with brine (2 mL). The mixture was filtered through a plug of Celite which was washed with EtOAc (2 x 2 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 4 ml). The organic layers were combined, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (8 x 1000 μM) eluting with CH2Cl2 / MeOH (20: 1) to give 0.21 g (80%) of yellow solid, mp 108-110 ° C; M + H = 433.

EXAMPLE 316 Prepared in the same manner as Example 315 with the proviso that (/?) - (-) - 2-methyl-2-propanesulfinamide is replaced to give 0.25 g (94%) as a yellow solid, mp 107-109 ° C; M + H = 433.

EXAMPLE 317 Step A To a solution of sulfinimine (50 mg, 0.12 mmol) of Example 16 in CH 2 Cl 2 (2.5 mL) at -40 ° C was added MeMgBr (96 mL, 0.29 mmol) dropwise. The mixture was stirred for 5 h at -40 ° C and stirred at room temperature for 12 h. An additional portion of MeMgBr (96 mL, 0.29 mmol) and the mixture was stirred for 12 h. Aqueous NH CI sat. (2 ml) and the mixture was extracted with EtOAc (3 x 4 ml). The organic layers were combined, dried (Na2SO4), filtered and concentrated under reduced pressure to give 30 mg (58%) of crude residue. This material was captured in the next step without purification.

Step To the crude material from Step A (30 mg, 0.067 mmol) in MeOH (2 mL) conc. HCl was added. (2 ml). The mixture was stirred at room temperature for 12 h and the mixture was concentrated until dried. The crude material was partitioned between CH2Cl2 (3 mL) and aqueous sat. NaHCO3. (2 ml) and the layers separated. The aqueous layer was extracted with CH2Cl2 (2 x 3 ml) and the organic layers were combined. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to give 6 mg (24%) of the title compound as a light yellow solid, mp 100-102 ° C; M + H = 345.

EXAMPLE 318 To a solution of the aldehyde (75 mg, 0.23 mmol) of Example 300 in THF / CH 2 Cl 2 (5 ml / 1 ml) at room temperature was added MeONH 2 HCl (38 mg, 0.46 mmol) followed by the dropwise addition of pyridine ( 46 μl, 0.57 mmol). The mixture was stirred for 72 h at room temperature at that time the mixture was concentrated until it was dried. The crude material was partitioned between CH CI2 (3 mL) and aqueous sat. NaHCO3. (2 ml) and the layers separated. The aqueous layer was extracted with CH2Cl2 (2 x 3 ml) and the organic layers were combined. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (3 x 1000 μM) eluting with CH 2 Cl 2 / MeOH (22: 1) to give 90 mg (100%) of a light yellow solid, mp 173-175 ° C; M + H = 359.

EXAMPLE 319 To a solution of the aldehyde (60 mg, 0.18 mmol) of Example 303 in EtOH (2.5 mL) was added oxindole (48 mg, 0.37 mmol) followed by piperidine (3 drops). The mixture was refluxed for 14 h and the mixture was cooled to room temperature. The resulting precipitate was filtered and washed with cold EtOH (2 x 2 ml). The product was dried under high vacuum to give 81 mg (100%) of the title compound as an orange / brown solid, mp 182-185 ° C; M + H = 445.

EXAMPLE 320 To a solution of the 3-H analog (106 mg, 0.35 mmol) of Preparative Example 187.10 in AcOH (2 mL) was added aqueous formaldehyde 37% (1.5 mL, 1.40 mmol) followed by piperidine (100 μL, 0.37 mmol). The resulting mixture was stirred at room temperature for 24 h and the AcOH was removed under reduced pressure. The mixture was diluted with water (2 ml) and neutralized with 2M NaOH until pH = 8. The aqueous layer was extracted with CH2Cl2 (3 x 7 ml) and the organic layers were combined. The organic layer was washed with brine (1 x 4 ml), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 96 mg (69%) of an off-white solid, mp 88-90 ° C; M + H 399.

EXAMPLES 321-322 Essentially by the same procedure set forth in Example 320, substituting only the amines in Column 2 of Table 29 and using the 3-H adduct of Preparative Example 187.10, the compounds were prepared in column 3 of Table 29: TABLE 29 EXAMPLE 323 To a solution of analog 3-H (113 mg, 0.38 mmol) of Preparative Example 187.10 in CH 2 Cl 2 (5 mL) at room temperature was added AICI 3 (215 mg, 1.61 mmol) followed by AcCl (100 mL, 1.40 mmol). The mixture was refluxed for 12 h and cooled to room temperature. The mixture was treated sequentially with 3M HCl (3 mL) followed by aqueous sat. NaHCO3. (until pH = 8). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 5 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (8 x 1000 mM) eluting with CH 2 Cl 2 / MeOH (20: 1) to give 68 mg (52%) of white solid, mp 220-221 ° C; M + H = 344.

EXAMPLE 324 Using the method described in Example 323, with the exception of the use of benzoyl chloride, the title compound was prepared in 61% yield as a white solid, mp 172-175 ° C; M + H = 406.

EXAMPLE 325 To a solution of ketone (100 mg, 0.29 mmol) from Example 323 in CH2Cl2 (2.5 mL) at 0 ° C was added MeMgBr (0.35 mL, 3.0 M in Et2O) dropwise. The resulting mixture was stirred for 18 h at room temperature and carefully deactivated by the addition of sat. Aqueous NH CI. (2 ml) and CH2Cl2 (2 ml) was added. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 4 mL). The organic layers were combined, dried (Na2SO), filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (8 x 1000 μM) eluting with CH 2 Cl 2 / MeOH (10: 1) to give 68 mg (52%) of a yellow solid, mp 160-162 ° C; M + H = 360.

EXAMPLE 326 To a solution of ketone (84 mg, 0.24 mmol) of Example 323 in MeOH / THF (1: 1; 2 ml total) at 0 ° C was added NaBH 4 (12 mg, 0.30 mmol) in one portion. The resulting mixture was stirred for 18 h at room temperature and an additional potion of NaBH (12 mg, 0.30 mmol) was added. The mixture was stirred for 12 h, at which time the mixture was quenched with ice followed by the addition of 1 M NaOH to regulate the pH = 9. The mixture was diluted with CH 2 Cl 2 (5 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 4 mL). The organic layers were combined, dried (Na2SO), filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (8 x 1000 μM) eluting with CH 2 Cl 2 / MeOH (10: 1) to give 25 mg (30%) of a yellow solid, mp 148-150 ° C; M + H = 346.

EXAMPLE 327 Using the same procedure as that described in Example 326, the ketone (84 mg, 0.21 mmol) was converted to 53 mg (62%) as a light yellow solid, mp 78-80 ° C; M + H = 408.

EXAMPLE 328 To a 3-H adduct solution (1.3 g, 4.31 mmol) of Preparative Example 187.10 in CH2Cl2 (50 mL) was added Eschenmoser salt (0.79 g, 4. 31 mmol) followed by the dropwise addition of TFA (0.56 ml, 7.33 mmol).

The mixture was stirred at room temperature for 48 h and diluted with CH2CI2 (250 ml). The organic layer was washed with aqueous sat. NaHCO3. (2 x 125 ml) to give 1.41 h (92%) of a yellow solid, mp 231-233 ° C; M + H = 359.

EXAMPLE 329 To a solution of the tertiary amine adduct (100 mg, 0.28 mmol) of Example 328 in 50% aqueous DMF (5 mL) in a pressure tube was added KCN (0.15 g, 2.32 mmol). The tube was capped and heated at 100 ° C for 96h. The mixture was cooled to room temperature and diluted with EtOAc (25 mL). The organic layer was washed with brine (1 x 5 ml) and water (1 x 5 ml). The organic layers were dried (Na 2 SO 4), filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (4 x 1000 μM) eluting with EtOAc to give 21 mg (30%) of brown solid, mp 152-155 ° C; M + H = 341.

EXAMPLE 330 To a solution of alcohol (45 mg, 0.14 mmol) from Example 17.10 in CH 2 Cl 2 (0.7 mL) at 0 ° C was added Et 3 S 1 H (26 μL, 0.16 mmol) followed by TFA (25 μL, 0.33 mmol). The mixture was stirred for 2 h at 0 ° C and at room temperature for 2 h at that time additional portions of Et3SiH (26 μL, 0.16 mmol) and TFA (25 μL, 0.33 mmol) were added and the mixture was stirred for 4 h at room temperature. environment (until it was completed by TLC). The mixture was concentrated under reduced pressure and the crude residue was partitioned between CH2Cl2 (3 mL) and aqueous sat. NaHCO3. (1.5 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 4 mL). The organic layers were combined, washed with brine (1 x 5 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (4 x 1000 mM) eluting with CH2Cl2 / MeOH (20: 1) to give 21 mg (48%) of a yellow solid, mp 146-148 ° C; M + H = 316.

EXAMPLE 331 To a solution of the 3-H adduct (90 mg, 0.30 mmol) of Preparative Example 187.10 in H2SO conc. (2 ml) at 0 ° C, steaming HNO3 (30 μl, 0.72 mmol) was added dropwise. The resulting mixture was stirred for 1 h at 0 ° C at that time ice (~ 1g) was added to the mixture. The resulting precipitate was collected and washed with water (2 x 2 ml) and CH 2 Cl 2 (2 x 2 ml). The crude product was dried under high vacuum to give 67 mg (60%) of the monosulfate salt as a yellow / orange solid, mp 250 ° C; M + H (free base) = 392.

EXAMPLE 332 Step A To a solution of the aldehyde (0.10 g, 0.39 mmol) of Preparative Example 168 in THF (2.5 mL) at 0 ° C was added CF3TMS (64 mL, 0.43 mmol) followed by CsF (10 mg). The resulting mixture was stirred for 2 h at 0 ° C and 2h at room temperature. 1M HCl (5 ml) was added and the mixture was diluted with CH2Cl2 (10 ml). The layers were separated, the aqueous layer was extracted with CH2Cl2 (2 x 10 ml), and the organic layers were combined. The organic layer was washed with brine (1 x 10 ml), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 127 mg (99%) of a yellow semi-solid. M + H = 328. The crude product was continued without further purification.

Step B Example 1, the 7-CI adduct (127 mg, 0.39 mmol) of Example 332, Step A was reacted with 3- (amnomethyl) pyridine (73 μl, 0.43 mmol) to give 80 mg (51%) of the compound title as a light yellow solid, mp 68-72 ° C; M + H = 400.

EXAMPLE 333 To a solution of aniline (200 mg, 0.69 mmol) of Preparative Example 174 in THF (6 ml) at room temperature was added aldehyde (114 mg, 0.83 mmol) of Preparative Example 256 followed by the dropwise addition of Ti (/ '-OPr) 4 (0.82 ml, 2.77 mmol). The mixture was stirred at reflux for 4 h and cooled to room temperature. NaCNBH3 (347 mg, 5.53 mmol) was added and the mixture was stirred for 2 h at room temperature. The mixture was cooled to 0 ° C, treated with 1 M NaOH (4 ml) and brine (1 ml) and stirred for 30 min. The mixture was extracted with CH2Cl2 (3 x 10 ml) and the organic layers were combined. The organic layer was washed with brine (1 x 7 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (8 x 1000 μM plates) eluting with CH 2 Cl 2 / MeOH (25: 1) to give 89 mg (31%) of the title compound as a yellow solid, mp 210-213. ° C; M + H = 411.

EXAMPLES 334-337 Essentially by the same procedure set forth in Example 333, using only the anilines shown in Column 2 of Table 30 and aldehydes shown in Column 3 of Table 30, the compounds were prepared in Column 4 of Table 30: TABLE 30 EXAMPLE 338 Step A The reaction of aniline (0.20 g, 0.69 mmol) with aldehyde (0.13 g, 0.83 mmol) under the reaction conditions described in Example 333 gave 70 mg (23%) of the thiomethyl derivative as a yellow solid. M + H = 428.

Step B To a solution of the thiomethyl derivative (60 mg, 0.14 mmol) of Example 338, Step A in dioxane (2 mL) was added Boc2O (61 mg, 0.28 mmol) followed by DMAP (21 mg, 0.17 mmol). The mixture was stirred for 14 h at room temperature and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (6 x 1000 μM plates) eluting with hexanes / EtOAc (4: 1) to give 61 mg (83%) of the title compound as a yellow solid. M + H = 528.

Step C To a solution of the thiomethyl derivative of Example 338, Step B (41 mg, 0.078 mmol) in CH 2 Cl 2 (2 mL) was added MCPBA (33 mg, 0.19 mmol) in one portion. The resulting mixture was stirred for 3 h at room temperature and the mixture was diluted with CH2Cl2 (5 mL) and aqueous sat. NaHCO3. (2.5 ml). The layers were separated, the aqueous layer was extracted with CH2Cl2 (2 x 5 mL), and the organic layers were combined. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to give 40 mg (92%) of sulfotate adduct as a light yellow solid. M + H = 560.

Step D To a flask loaded with sulfota of Example 338, Step C (75 mg, 0.13 mmol) and a rod for stirring was added morpholine (2 mL, 22 mmol). The mixture was refluxed for 12 h, cooled to rt, and concentrated until dried under high vacuum. The crude product was purified by preparative thin layer chromatography (6 x 1000 μM plates) eluting with CH 2 Cl 2 / MeOH (40: 1) to give 41 mg (68%) of the title compound as a yellow solid, mp 209-210 ° C; M + H = 466.

EXAMPLE 339 The title compound was prepared according to the procedure described in Example 338, with the proviso that benzyl amine is used to give 12 mg (70%) of a white solid, mp 194-196; M + H = 487.

EXAMPLE 340 Step A To a solution of 5-chloro adduct (0.15 g, 0.34 mmol) in dioxane / DIPEA (2.5 ml / 1.0 ml) at room temperature was added cyclopenfilamine (0.041 μl, 0.41 mmol) dropwise. The resulting solution was stirred at reflux for 16 h, cooled to rt, and concentrated under reduced pressure. The crude material was purified by preparative thin layer chromatography (8 x 1000 μM) eluting with CH2Cl2 / MeOH (25: 1) to give 148 mg (89%) of a yellow oil. M + H = 489.

Step B Removal of the t-butoxycarbonyl protecting group with TFA To a solution of the compound prepared in Example 340, Step A (135 mg, 0.28 mmol) in CH 2 Cl 2 (2 ml) at room temperature was added TFA (0.54 ml, 7.0 mmol) drop a drop. The resulting solution was stirred for 18 h at room temperature and concentrated under reduced pressure. The crude material was dissolved in CH2Cl2 (5 mL) and the organic layer was washed sequentially with aqueous sat. NaHCO3. (2 x 2 ml) and brine (1 x 2 ml). The organic layer was dried (Na2SO), filtered, and concentrated under reduced pressure. The crude material was purified by preparative thin layer chromatography (8 x 1000 μM) eluting with CH2Cl2 / MeOH (20: 1) to give 105 mg (97%) of white solid, mp 120-122 ° C; M + H = 389.

EXAMPLE 341 Step A Essentially by the same procedure set forth in Example 340, substituting only the appropriate amine, the above compound was prepared. MS: MH + = 431.

Step B Removal of the protective group of t-butoxycarbonyl with KOH.

To a mixture of the compound prepared in Example 341, Step A (0.14 g, 0.26 mmol) in EtOH: H 2 O (3 mL, 2: 1) was added KOH (0.29 g, 20 eq.) In one portion. The resulting solution was stirred at reflux for 14 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was taken up in CH2Cl2 (5 ml) and diluted with saturated NaHCO3 (2 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 4 mL). The combined organics were washed with brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (8 x 1000 μM) eluting with 5% MeOH solution in CH2Cl2 (0.066 g, 59% yield). MS: MH + = 432; mp = 219-221 ° C.

EXAMPLES 342-397 Essentially by the same procedure set forth in Example 340, substituting only the chlorides in Column 2 of Table 31 and removing the protective group of t-butoxycarbonyl by the method shown in Column 3 of Table 31, prepared the compounds shown in Column 4 of the table 31 TABLE 31 Additional data for selected examples shown below: EXAMPLE 392 1 H NMR (DMSO-de) d 8.65 (s, 1 H), 8.46 (d, J = 3.3 Hz, 1 H), 8.21 (t, J = 6.6 Hz, 1H), 7.90 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.35 (dd, J = 7.8, 4.8 Hz, 1H), 5.46 (s, 1H) , 4.61 (d, J = 6.9 Hz, 2H), 3.01 (s, 6H).

EXAMPLE 393 1 H NMR (CDCl 3) d 8.65 (s, 1 H), 8.60 (d, J = 4.8 Hz, 1 H), 7.76 (s, 1 H), 7.70 (m, 1 H), 7.32 (dd, J = 8.1, 4.8 Hz, 1H), 6.43 (t, J = 6.0 Hz, 1H), 5.08 (s, 1 H), 4.80 (m, 1 H), 4.56 (d, J = 6.0 Hz, 2H), 2.96 (d, J = 5.1 Hz, 3H).

EXAMPLE 394 1 H NMR (CDCl 3) d 8.68 (s, 1 H), 8.60 (d, J = 4.8 Hz, 1 H), 7.76 (s, 1 H), 7.72 (m, 1 H), 7.32 (dd, J = 7.8, 5.4 Hz, 1H), 6.55 (t, J = 5.7 Hz, 1H), 5.53 (s, 1H), 5.35 (s, 1H), 4.62 (d, J = 5.7 Hz, 2H), 2.49 (, 1H), 0.75 (m , 2H), 0.51 (m, 2H). Example 395: 1 H NMR (CDCl 3) d 8.65 (s, 1 H), 8.60 (d, J = 4.0 Hz, 1H), 7.75 (s, 1H), 7.69 (m, 1H), 7.33 (dd, J = 8.1.5.1 Hz, 1H), 6.45 (t, J = 6.0 Hz, 1 H), 5.07 (s, 1 H) ), 4.69 (m, 1 H), 4.54 (d, J = 6.0 Hz, 2H), 3.98 (m, 1 H), 3.79 (dd, J = 10.8, 2.4 Hz, 1H), 3.59 (dd, J = 11.1, 7.2 Hz, 1H), 1.59-1.36 (m, 4H), 0. 94 (t, J = 6.9 Hz, 3H). Example 396: 1 H NMR (CDCl 3) d 8.60 (s, 1 H), 8.56 (d, J = 4.2 Hz, 1H), 7.73 (s, 1H), 7.66 (m, 1H), 7.31 (dd, J = 7.8, 4.8 Hz, 1H), 6.51 (t, J = 6.0 Hz, 1H), 5.05 (s, 1H), 4.86 (d, J = 6.6 Hz, 1H), 4.50 (d, J = 6.0 Hz, 2H), 3.94 (m, 1H), 3.78 (dd, J = 11.1, 2.4 Hz, 1H), 3.57 (dd, J = 11.1, 7.2 Hz, 1H), 1.57- 1.34 (m, 4H), 0.91 (t, J = 7.2 Hz, 3H).

Example 397: 1 H NMR (CDCl 3) d 8.65 (s, 1 H), 8.59 (d, J = 4.5 Hz, 1 H), 7.75 (s, 1 H), 7.69 (m, 1 H), 7.31 (m, 1 H), 6.43 (t, J = 6.0 Hz, 1 H), 5.06 (s, 1 H), 4.88 (m, 1 H), 4.55 (d, J = 6.0 Hz, 2 H), 3.70 (m, 2 H) ), 3.38 (m, 2H), 1.79-1.61 (m, 4H).

EXAMPLES 398-416 Essentially by the same conditions set forth in Example 341, Steps A and B substituting only the compound prepared in Preparative Example 193.10, the compounds were prepared in column 4 of Table 32.

TABLE 32 Additional data for selected examples shown below: Example 414: 1 H NMR (DMSO-d 6) d 8.26 (s, 1 H), 8.23 (m, 1 H), 8.13 (m, 1 H), 7.90 (s, 1 H), 7.40-7.27 (m, 3H), 5.34 (s, 1H), 4.49 (d, J = 6.3 Hz, 2H), 2.56 (m, 1 H), 0.67 (m, 2H), 0.35 (m, 2H). Example 403: 1 H NMR (DMSO / 6 + CDCl 3) d 8.08 (s, 1H), 7.90 (d, J = 6.3 Hz, 1H), 7.49 (s, 1H), 7.34 (t, J = 6.3 Hz, 1H) , 7.16-7.09 (m, 2H), 5.65 (d, J = 6.6 Hz, 1H), 4.97 (s, 1H), 4.90 (s, 1H), 4.29 (d, J = 6.3 Hz, 2H), 3.70 ( m, 1H), 3.46 (m, 1H), 3.34 (m, 1H), 1.35-1.17 (m, 4H), 0.71 (t, J = 7.2 Hz, 3H). Example 404: 1 H NMR (DMSO-d 6) d 8.21 (s, 1 H), 8.12 (d, J = 6.6 Hz, 1H), 8.06 (m, 1H), 7.86 (s, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 5.28 (s, 1H), 4.70 (t, J = 5.1 Hz, 1H), 4.41 (d, J = 6.6 Hz, 2H), 4.00 ( s, 1H), 3.39 (m, 1H), 1.53 (m, 1H), 1.36-1.25 (m, 3H), 0. 86 (t, J = 7.0 Hz, 3H).

EXAMPLES 417- 421 By the procedure set forth in Chem. Pharm. Bul !. 1999, 47, 928-938, using the oxygen or sulfur nucleophiles shown in Column 2 as described in Table 33 and by using the cleavage method listed in Column 3 of Table 33, the compounds in column 4 of table 33: TABLE 33 EXAMPLE 422 To a solution of amino compound (18 mg, 0.043 mmol) of Example 373 in CH2Cl2 (1 mL) at room temperature was added DIPEA (10 μL, 0.056 mmol) followed by MeSO2CI (4 mL, 0.052 mmol). The mixture was stirred at room temperature for 12 h and was diluted with CH 2 Cl 2 (2 mL) and aqueous sat. NaHCO 3. (2 ml). The layers were separated and the organic layer was extracted with brine (1 x 2 ml). The organic layer was dried (Na2SO), filtered, and concentrated under reduced pressure. The crude material was purified by preparative thin layer chromatography (4 x 1000 μM) eluting with CH 2 Cl 2 / MeOH (20: 1) to give 16 mg (75%) of white solid, mp 152-154 ° C; M + H = 495.

EXAMPLES 423-424 By using the procedure described in Example 422, the amino compounds (Column 2) were transformed into the corresponding methylsulfonamides (Column 3) in Table 34.

TABLE 34 EXAMPLE 425 Step A: A mixture of the compound prepared in Preparative Example (132 mg, 0.25 mmol), tributylvinyltin (95 mg, 0.30 mmol) and tetrakis (triphenylphosphine) palladium (29 mg, 0.025 mmol) in dioxane anhydride (5 mL) was refluxed under N2 for 24 hr. The solvent was evaporated and the residue was purified by flash chromatography using 2: 1 CH2Cl2: EtOAc as eluent to give a yellow waxy solid (53 mg, 50%). LCMS: MH + = 428.

Step B: A mixture of the compound prepared in Example 425, Step A (50 mg, 0.12 mmol) and KOH (100 mg, 1.80 mmol) in ethanol (3 ml) and H 2 O (0.6 ml) was stirred at 70 ° C under N 2 for 24. hr. NaHCO3 (1.0 g), Na2SO4 (2.0 g), and CH2CI2 (20 ml) were added, the mixture was stirred and then filtered. The solvent was evaporated and the residue was purified by flash chromatography using 20: 1: 0.1 CH2Cl2: MeOH: conc.NH4OH as eluent to give yellow waxy solid (17 mg, 45%). LCMS: MH + = 328. Mp = 48-51 ° C.

EXAMPLE 426 Step A: Essentially by the same procedure set forth in Example 425, Step A, using only tributylmethyltinyltin, the compound shown above was prepared.

Step B: A mixture of the compound prepared in Example 426, Step A (150 mg, 0.34 mmol) and PtO2 (30 mg, 0.13 mmol) in glacial acetic acid (5 ml) was stirred under 1 atmosphere of H2 for 20 hr. The mixture was filtered, fresh PtO2 (30 mg, 0.13 mmol) was added and the mixture was stirred under 1 atmosphere of H2 for 2.5 hr. The mixture was poured into Na2CO3 (20 g) and H2O (200 ml) and this was extracted with CH2CI2 (4x20 ml). The combined extracts were dried over Na2SO4 and filtered. The solvent was evaporated and the residue was purified by flash chromatography using 1: 1 CH2Cl2: EtOAc as eluent to give yellow waxy solid (68 mg, 45%).

Step C: Essentially by the same procedure set forth in Example 425, Step B, substituting only the compound prepared in Example 426, Step B, the compound shown above was prepared, MS: MH + = 344, Mp = 110-112 ° C.

EXAMPLE 427 Step A: A mixture of the compound prepared in Preparative Example 194 (527 mg, 1.00 mmol), trimethyl (trifluoromethyl) silane (666 mg, 3.60 mmol), potassium fluoride (210 mg, 3.60 mmol), and Cul (850 mg) was stirred. mg, 4.46 mmol) in DMF anhydride (4 ml) in a closed pressure vessel at 80 ° C for 72 hr. CH2Cl2 (80 mL) was added and the mixture was filtered through Celite. The solvent was evaporated and the residue was purified by flash chromatography using 2: 1 CH2Cl2: EtOAc as eluent to give pale orange waxy solid (70 mg, 15%). LCMS: M + = 470.

Step B: TFA (0.70 ml) was added at 0 ° C under N2 to a stirred solution of the compound prepared in Example 427, Step A (70 mg, 0.15 mmol), in CH2Cl2 anhydride (3 ml). The mixture was stirred at 0 ° C for 10 min, then at 25 ° C for 2 hr. This was poured into 10% aqueous Na2CO3 (50 ml), extracted with CH2Cl2 (3x15 ml), dried over Na2SO, and filtered. The solvent was evaporated and the residue was purified by flash chromatography using EtOAc as eluent to give off-white solid (40 mg, 73%). LCMS: M + = 370, Mp = 156-158 ° C.

EXAMPLE 428 Step A: A mixture of the compound prepared in Preparative Example 193 (100 mg, 0.28 mmol), tetracyclopropyltin (91 mg, 0.32 mmol), Pd2dba3 (8.0 mg, 0.009 mmol) and Pd (Pt-Bu3) 2 (9.0 mg, 0.017 mmol) in dioxane anhydride (3 ml) was refluxed under N2 for 27 hr. The solvent was evaporated and the residue was purified by flash chromatography using 1: 1 CH2Cl2: EtOAc as eluent to give colorless waxy solid (38 mg, 38%). LCMS: MH + = 366.

Step B: A mixture of the compound prepared in Example 28, Step A (36 mg, 0.10 mmol) and KOH (300 mg, 5.40 mmol) in ethanol (3 ml), 1,2-dimethoxyethane (3.0 mio and H2O (0.8 ml) was refluxed. ) under N2 for 4 hr This was poured into saturated aqueous NaHC03 (100 ml), extracted with CH2Cl2 (5x10 ml), dried over Na2SO4, and filtered.The solvent was evaporated and the residue was purified by flash chromatography using 30: 1 EtOAc: MeOH as eluent to give colorless wax (18 mg, 69%) LCMS: MH + = 266.

Step C: N-bromosuccinimide (12 mg, 0.068 mmol) in CH3CN anhydride (2 ml) under N2 to a stirred solution of the compound prepared in Example 428, Step B (18 mg, 0.068 mmol), in CH3CN anhydride (2 ml). The mixture was stirred at 25 ° C for 2 h. The solvent was evaporated and the residue was purified by flash chromatography using EtOAc as eluent to give 5 mg (17%) of the dibromo compound (white solid, LCMS: MH + = 370, mp = 150-152 ° C) and 8 mg ( 34%) of the monobromo compound (colorless solid, LCMS: M + = 344, mp = 196-198 ° C).

EXAMPLE 429 Step A: 1,3-propansultam (72 mg, 0.60 mmol) in DMF anhydride (3 ml) was added under N2 for 60% NaH in mineral oil (36 mg, 0.90 mmol).

The mixture was stirred for 20 min, then the compound prepared in the Preparative Example 196 (200 mg, 0.46 mmol) was added. The mixture was stirred 100 ° C for 30 min, the solvent was evaporated and the residue was purified by flash chromatography using EtOAc as eluent to give a colorless solid (150 mg, 63%). LCMS: M + = 523.

Step B: TFA (1.5 ml) was added at 0 ° C under N2 to a stirred solution of the compound prepared in Preparative Example 196 (140 mg, 0.27 mmol), in CH2Cl2 anhydride (5 ml). The mixture was stirred at 0 ° C for 10 min, then at 25 ° C for 2 hr. This was poured into Na2CO3 (10 g), extracted with CH2Cl2. (3x50 ml), and filtered. The solvent was evaporated and the residue was purified by flash chromatography using 40: 1 EtOAc: MeOH as eluent to give white solid (32 mg, 28%). LCMS: M + = 423. Mp = 218-220 ° C. EXAMPLE 430 Where R2 = H, or Cl 3-Bromo-7-chloro-5- (2-chlorophenyl) pyrazolo [1,5-ajpyrimidine (1 equivalent) (prepared as described in Preparative Example 129) was dissolved, or 3-Bromo-7-chloro-5-phenylprazolo [1,5-a] pyrimidine (1 equivalent) (prepared as described in Preparative Example 127), R-? NH 2 (1.2 equivalents) diisopropyl ethylamine (2 equivalents) in 1,4-dioxane anhydride the mixture was heated to 75 ° C for the time set forth in Table 97. The solution was evaporated until it was dried the residue was subjected to chromatography on a gel column. silica as described in table 97, to give the title compound. Using the appropriate reagents essentially the same procedure as described above, the products of Examples 431 to 438 were prepared. Variations in the reaction conditions are listed in Table 35.

TABLE 35 The following provides additional physical data for the compounds: EXAMPLE 431 Reagents: 3-Bromo-7-chloro-5- (2-chlorophenyl) pyrazolo [1,5-ajpyrimidine (110mg, 0.318mmol) (prepared as described in Preparative Example 129); 3- (aminomethyl) piperidin-1 -carboxamide (60mg, 0.382mmol) (prepared as described in Preparative Example 241 above); diisopropyl ethylamine (0.11 1 ml, 0.636 mmol); 1,4-dioxane anhydride (2.5ml). Physical properties: HRFABMS: m / z 463.0628 (MH +). Calculated for C19H2? N6OBrCl: m / z 463.0649: dH (CDCl3) 1.38 (1 H, m, CH2), 1.52 (1H, m, CH2), 1.73 (1 H, m, CH), 1.93 ( 1 H, m, CH2), 2.02 (1H, m, CH2), 2.98 (1H, m, CH2), 3.06 (1H, m, CH2), 3.37 (2H, m, CH2), 3.58 (1H, m, CH2), 3.82 (1H, m, CH2), 4.87 (2H, bm, CONH2), 6.28 (1H, s, H6), 7.02 (1H, m, NH), 7.36 (2H, m, Ar-H), 7.45 (1H, m, Ar-H), 7.68 (1H, m, Ar-H) and 8.00 ppm (1H, s, H2); dc (CDCl 3) CH 2: 23.7, 28.1, 44.6, 45.5, 47.2; CH: 35.2, 87.4, 127.2, 130.1, 130.3, 131.6, 143.9: C: 83.1, 132.1, 138.6, 145.5, 146.5, 158.0, 158.4.

EXAMPLE 432: Reagents: 3-Bromo-7-chloro-5-phenylpyrazolo [1,5-a] pyrimidine (500mg, 1.62mmol) (prepared as described in Preparative Example 127); 3- (aminomethyl) piperidin-1-carboxamide (306mg, 1944mmol) (prepared as described in Preparative Example 241 above); diisopropyl ethylamine (0.566ml, 3.24mmol); 1,4-dioxane anhydride (13ml). Physical properties: HRFABMS: m / z 429.1031 (MH +). Calculated for C19H22N6OBr: m / z 429.1038; dH (CDCl 3) 1.44 (1 H, m, CH 2), 1.59 (1 H, m, CH 2), 1.79 (1 H, m, CH), 2.01 (1 H, m, CH 2), 2.08 (1 H, m, CH 2), 3.03 (1H, m, CH2), 3.13 (1H, m, CH2), 3.39 (1H, m, CH2), 3.47 (1H, m, CH2), 3.63 (1H, m, CH2), 3.90 (1H, m, CH2), 4.88 (2H, bm, CONH2), 6.40 (1H, s, H6), 6.90 (1H, m, NH), 7.53 (2H, m, Ar-H), 8.02 (1H, s, H2) and 8.12 (1H, m, Ar-H); dc (CDCl 3) CH 2: 23.7, 28.2, 44.7, 45.5, 47.3; CH: 35.2, 82.9, 127.5, 127.5, 128.7, 128.7, 130.0, 143.9; C: 83.0, 138.5, 145.8, 147.1, 158.3, 158.5.

EXAMPLE 433 Reagents: 3-Bromo-7-chloro-5- (2-chlorophenyl) pyrazolo [1,5-ajpyrimidine (347mg, 1.01 mmol) (prepared as described in Preparative Example 129); 3- (aminoquinol) piperidin-1-carboxamide (208 mg, 1.21 mmol) (prepared as described in Preparative Example 242 above); diisopropyl ethylamine (0.393 ml, 2.02 mmol); 1,4-dioxane anhydride (9ml). Physical properties: dH (CDCl 3) 1.24 (1 H, m, CH 2), 1.55 (1 H, m, CH), 1.72 (4 H, m, CH 2), 1.93 (1 H, m, CH 2), 2.69 (1 H , m, CH2), 2.94 (1 H, m, CH2), 3.55 (2H, m, CH2), 3.73 (1 H, m, CH2), 3.98 (1 H, m, CH2), 4.83 (2H, bm , CONH2), 6.55 (1 H, s, H6), 6.78 (1 H, m, NH), 7.41 (2H, m, Ar-H), 7.50 (1 H, m, Ar-H), 7.75 (1 H, m, Ar-H) and 8.04 ppm (1 H, s, H2); dc (CDCl 3) CH 2: 24.6, 30.7, 32.6, 39.9, 45.3, 49.3; CH: 33.3, 87.5, 127.4, 130.1, 130.2, 131.6, 143.8; C: 83.2, 132.1, 138.8, 145.7, 146.2, 158.1, 158.1.

EXAMPLE 434: Reagents: 3-Bromo-7-chloro-5- (2-c! Orophenyl) pyrazolo [1,5-ajpyrimidine (275 mg, 0.803 mmol) (prepared as described in Preparative Example 129); 4- (aminoethyl) piperidin-1 -carboxamide (165mg, 0. 963 mmol) (prepared as described in Preparative Example 243 above); diisopropyl ethylamine (0.311 ml, 0.963 mmol); 1,4-dioxane anhydride (7.2 ml). Physical properties: dH (d6-DMSO) 1.00 (2H, m, CH2), 1.50 (1 H, m, CH), 1.59 (2H, m, CH2), 1.67 (2H, m, CH2), 2.60 (2H, m, CH2), 3.48 (2H, m, CH2), 3.70 (2H, m, CH2), 5.84 (2H, bs, CONH2), 6.43 (1H, s, H6), 7.50 (2H, m, Ar- H), 7.62 (2H, m, Ar-H), 8.30 (1 H, s, H2) and 8.36 ppm (1 H, m, NH); dc (d6-DMSO) CH2: 31.5, 31.5, 34.8, 43.5, 43.5, 43.5; CH: 32.8, 86.8, 127.1, 129.7, 130.3, 131.0, 143.3; CH: 81.3, 131.0, 138.7, 145.1, 146.4, 157.3, 157.8.

EXAMPLE 435 Reagents: 3-Bromo-7-chloro-5-phenylpyrazolo [1,5-a] pyrimidine (174 mg, 0.507 mmol) (prepared as described in Example Preparation 129) and 3- (aminomethyl) -1-methylpiperidine (65mg, 0.507mmol) (prepared as described in Preparative Example 244 above); diisopropyl ethylamine (0.178 ml, 1014 mmol); 1,4-dioxane anhydride (2.5ml). Physical properties: HRFABMS: m / z 434.0742 (MH +). Calculated for C? 9H22N5BrCI: m / z 434.0747; dH (CDCl 3) 1.18 (1 H, m, CH 2), 1.68 (1 H, m, CH 2), 1.80 (1 H, m, CH 2), 1.87 (1 H, m, CH 2), 1.96 (1 H, m, CH), 2.14 (2H, m, CH2), 2.32 (3H, s, NCH3), 2.75 (1H, m, CH2), 2.29 (1 H, m, CH2), 3.42 (2H, m, -NHChbCH), 6.36 (1 H, s, H6), 6.64 (1 H, bm, NH), 7.41 (2 H, m, Ar-H), 7.51 (1 H, m, Ar-H), 7.74 (1 H, m, Ar-H) and 8.06 ppm (1 H, s, H2); dc (CDCl 3) CH 3: 46.6; CH2: 24.4, 27.9, 46.1, 56.1, 59.6; CH: 36.0, 87.4, 127.1, 130.1, 130.2, 131.6, 143.8; C: 83.2, 132.1, 138.9, 145.6, 146.4, 158.2.

EXAMPLE 436 Reagents: 3-Bromo-7-chloro-5-phenylpyrazolo [1,5-a] pyrimidine (111.4mg, 0.325mmol) (prepared as described in Preparative Example 129); 4- (aminomethyl) -1-methylpiperidine (50mg, 0.39mmol) (prepared as described in Preparative Example 245 above); diisopropyl ethylamine (0.1135ml, 0.65mmol); 1,4-dioxane anhydride (1.5ml). Physical data: HRFABMS: m / z 434.0735 (MH +). Calculated for C? 9H22N5BrCI: m / z 434.0747; dH (CDCl 3) 1.42 (2 H, m, CH 2), 1.72 (1 H, m, CH), 1.82 (2 H, m, CH 2), 1.93 (2 H, m, CH 2), 2.20 (3 H, s, NCH 3), 2.89 (2H, m, CH2), 3.34 (2H, m, -NHCH2CH), 6.31 (1 H, s, H6), 6.46 (1 H, m, NH), 7.36 (2H, m, Ar-H), 7.46 (1 H, m, Ar-H), 7.70 (1 H, m, Ar-H) and 8.00 ppm (1 H, s, H2); dc (CDCl 3) CH 3: 46.4; CH2: 30.2, 30.2, 48.0, 55.3, 55.3; CH: 35.4, 87.5, 127.2, 130.2, 130.2, 131.6, 143.8; C: 83.3, 132.2, 138.9, 145.7, 146.4, 158.1.

EXAMPLE 437 Reagents: 3-Bromo-7-chloro-5-phenylpyrazolo [1,5-a] pyrimidine (191 mg, 0.557 mmol) (prepared as described in Example Preparation 129); 3- (aminomethyl) benzonitrile (88.3mg, 0.668mmol) (prepared as described in Preparative Example 246 above); diisopropyl ethylamine (0.192ml, 1114mmol); 1,4-dioxane anhydride (4.5ml).

Physical data: HRFABMS: m / z 438.0125 (MH +). Calculated for C19H12N5BrCl: m / z 438.0121; dH (CDCl3) 4.76 (2H, d, -CH2NH-), 6.32 (1 H, s, H6), 7.00 (1 H, m, -CH2NH-), 7.40 (2H, m, Ar-H), 7.46 ( 1 H, m, Ar-H), 7.55 (1 H, m, Ar-H), 7.67 (2 H, m, Ar-H), 7.71 (1 H, m, Ar-H), 7.75 (1 H, m Ar-H) and 8.10 ppm (1 H, s, H2); dc (CDCl 3) CH 2: 45.5; CH: 88.2, 127. 2, 130.0, 130.2, 130.4, 130.6, 131.4, 131.6, 131.9, 144.1; C: 83.8, 113.4, 118. 3, 132.0, 137.8, 138.3, 145.6, 145.9, 158.0.

EXAMPLE 438 Reagents: 3-Bromo-7-chloro-5-phenylpyrazolo [1,5-a] pyrimidine (233.5 mg, 0.681 mmol) (prepared as described in Example Preparation 129); 4- (aminomethyl) benzonitrile (108mg, 0.817mmol) (prepared as described in Preparative Example 247 above); diisopropyl ethylamine (0.235ml, 1362mmol); 1,4-dioxane anhydride (5.3ml). Physical data: HRFABMS: m / z 438.0117 (MH +) Calculated for C20H14N5BrCI: m / z 438.0121; dH (CDCI3) 4.80 (2H, d, CH2), 6.30 (1 H, s, H6), 7.01 (1 H, m, NH), 7.40 (2H, m, Ar-H), 7.47 (1 H, m, Ar-H) , 7.70 (2H, m, Ar-H), 7.72 (2H, m, Ar-H), 7.80 (1 H, m, Ar-H) and 8.10 ppm (1 H, s, H2); dc (CDCl 3) CH 2: 45.8; CH: 88.2, 127.2, 127.7, 127.7, 130.2, 130. 4, 131.6, 132.9, 132.9, 144.1; C: 83.8, 112.2, 118.4, 132.0, 138.2, 141.5, 145. 5, 146.0, 158.0.

EXAMPLE 439 3-Bromo-7-chloro-5- (2-chlorophenyl) pyrazolo [1,5-ajpyrimidine (50mg, 0.146mmol) (prepared as described in Preparative Example 129) was dissolved in 1,4-dioxane anhydride (5mlen) a GeneVac Technologies carousel reaction tube: PS-diisopropyl ethylamine resin (161 mg, 0.5828 mmol) was added to each tube, and a freshly prepared 1 M solution of the appropriate R-? NH2 amine in 1,4-dioxane was added. anhydride (0.2185ml, 0.2185mmol) to each tube and the tubes were sealed and heated at 70 ° C for 78h with magnetic stirring in the reaction block.Each tube was filtered and the resin was washed with 1,4-dioxane anhydride and then with dichloromethane.The combined individual filtrates from each tube were evaporated until they were dried and each residue was re-dissolved in 1,4-dioxane anhydride (5ml) and placed in GeneVac reaction tubes. PS-isocyanate resin (594mg, 0.8742mmol) and PS-trisamine resin (129mg, 0.4371) were added mmoles) and the tubes were shaken at 25 ° C for 20 h in the reaction block. The resins were filtered and washed with 1,4-dioxane anhydride and dichloromethane. The filtrates from each tube were evaporated until they were dried and each residue was subjected to silica gel column chromatography using the column size and the eluent shown in Table 36, to give the title compound. TABLE 36 Additional physical data for the compounds are provided below: EXAMPLE 440: Physical properties: HRFABMS: m / z 428.0272 (MH +). Calculated for C19H16N5BrCI: m / z 428.0278; dH (CDCl3) 3.28 (2H, dd, C5H4NC? 2CH2NH-), 3.94 (2H, ddd, C5H4NCH2CH2NH-), 6.40 (1H, s, H6), 7.22-7.29 (3H, m, Ar-H), 7.38 -7.44 (2H, m, Ar-H), 7.51 (1 H, m, Ar-H), 7.68 (1 H, ddd, Ar-H), 7.73 (1H, Ar-H), 8.18 (1H, s) , H2) and 8.68ppm (1H, NH); dc (CDCl 3) CH 2: 36.4, 41.5; CH: 87.3, 122.1, 123.6, 127.1, 130.1, 130.1, 131.6, 137.0, 143.8, 149.5; C: 83.1, 132.1, 138.9, 145.7, 146.3, 158.0, 158.1. EXAMPLE 441: Physical properties: HRFABMS: m / z 428.0272 (MH +). Calculated for C? 9H? ßN5BrCl: m / z 428.0278; dH (CDCl3) 3.12 (2H, dd, C5H4NCH2CH2NH-), 3.77 (2H, ddd, C5H4NCH2CH2NH-), 6.40 (1H, s, H6), 6.59 (1 H, m, Ar-H), 7.34 (1H, bm, Ar-H), 7.39-7.45 (2H, m, Ar-H), 7.52 (1 H, m, Ar-H), 7.62 (1 H, m, Ar-H), 7.75 (1 H, m , Ar-H), 8.05 (1 H, s, H2) and 8.63ppm (1 H, m, NH); dc (CDCl 3) CH 2: 32.7, 43.1; CH: 87.5, 127.2, 130.2, 130.3, 131.6, 136.4, 142.9, 148.3, 149.8; C: 83.5, 132.0, 138.6, 145.6, 145.9, 158.1. EXAMPLE 442: Physical Properties: HRFABMS: m / z 428.0275 (MH +). Calculated for C19H? 6N5BrCI: m / z 428.0278; dH (CDCl3) 3.13 (2H, dd, C5H4NCH2CH2NH-), 3.80 (2H, ddd, C5H4NCH2CH2NH-), 6.42 (1H, s, H6), 6.53 (1H, m, Ar-H), 7.23 (2H, m, Ar-H), 7.40-7.46 (2H, m, Ar-H), 7.62 (1H, m, Ar-H), 7.76 (1 H, m, Ar-H), 8.07 (1 H, s, H2) and 8.63ppm (1 H, m, NH); dc (CDCl 3) CH 2: 34.7, 42.5; CH: 87.4, 124.5, 124.5, 127.2, 130.2, 130.3, 131.6, 144.0, 150.2, 150.2; C: 83.5, 132.0, 138.6, 145.6, 145.9, 146.6, 158.1. EXAMPLE 443: Physical properties: HRFABMS: m / z 463.1003 (MH +). Calculated for C2oH25N6BrCI: m / z 463.1013; dH (CDCl3) 1.98 (2H, m, = NCH2CH2CH2NH-), 2.43 (3H, s, NCH3), 2.67 (2H, m, = NCH2CH2CH2NH-), 2.70 (8H, piperazine CH2), 3.58 (2H, m, = NCH2CH2CH2NH-), 6.32 (1 H, s, H6), 7.37-7.43 (2H, m, Ar-H), 7.50 (1H, m, Ar-H), 7.73 (1H, m, Ar-H), 8.06 (1H, s, H2) and 8.60ppm (1 H, m, NH); dc (CDCl 3) CH 3: 46.1; CH2: 24.1, 42.8, 53.3, 54.6, 54.6, 57.5, 57.5; CH: 87.1, 127.0, 130.0, 130.1, 131.5, 143.4; C: 82.7, 132.1, 139.2, 145.7, 146.7, 158.0. EXAMPLE 444: Physical properties: HRFABMS: m / z 434.0742 (MH +). Calculated for C19H22N5BrCl: m / z 434.0747; dH (CDCl 3) 1.72 (1H, m, CH / CH 2), 1.78-1.90 (2H, m, CH / CH 2), 2.02 (3H, m, CH / CH 2), 2.50 (1 H, m, CH / CH 2) , 2.45 (3H, s, NCH3), 2.51 (1 H, m, CH / CH2), 3.23 (1 H, m, CH / CH2), 3.54 (1 H, m, CH / CH2), 3.60 (1 H , m, CH / CH2), 6.32 (1 H, s, H6), 7.38-7.44 (2H, m, Ar-H), 7.51 (1 H, m, Ar-H), 7.75 (1H, m, Ar -H), 7.96 (1 H, bm, NH) and 8.05 ppm (1 H, s, H2); dc (CDCl 3) CH 3: 40.7; CH2: 22.7, 29.3, 30.1, 39.4, 57.0; CH: 64.2, 87.1, 127.1, 130.0, 130.1, 131.6, 143.8; C: 82.8, 132.1, 139.1, 145.7, 146.4, 158.0. EXAMPLE 445: Physical Properties: HRFABMS: m / z 448.0910 (MH +). Calculated for C20H24N5BrCI: m / z 448.0904; dH (CDCl3) 1.90 (4H, m, CH2), 2.00 (4H, m, CH2), 2.84 (2H, m, CH2), 2.95 (4H, m, CH2), 3.51 (2H, m, CH2), 6.32 (1H, s, H6), 7.05 (1 H, bm, NH), 7.37-7.43 (2H, m, Ar-H), 7.50 (1 H, m, Ar-H), 7.73 (1 H, m, Ar-H) and 8.04 ppm (1 H, s, H2); dc (CDCl 3) CH 2: 23.4, 23.4, 24.8, 26.4, 41.8, 53.9, 53.9, 55.2; CH: 87.3, 127.1, 130.1, 130.2, 131.6, 143.7; C: 83.0, 132.0, 138.9, 145.7, 146.3, 158.1. EXAMPLE 446: Physical Properties: HRFABMS: m / z 448.0548 (MH +). Calculated for C19H20N5OBrCl: m / z 448.0540; dH (CDCl3) 1.94 (2H, m, CH2), 2.09 (2H, m, CH2), 2.49 (2H, m, CH2), 3.45 (2H, m, CH2), 3.51 (4H, m, CH2), 6.32 (1 H, s, H6), 7.37-7.44 (3 H, m, Ar-H / NH), 7.51 (1 H, m, Ar-H), 7.75 (1 H, m, Ar-H) and 8.10 ppm (1 H, s, H2); dc (CDCl 3) CH 2: 18.0, 26.3, 30.8, 39.2, 39.9, 47.5; CH: 87.0, 127.1, 130.1, 130.1, 131.6, 144.1; C: 82.9, 132.1, 138.9, 145.6, 146.2, 157.9, 176.2. EXAMPLE 447: Physical Properties: HRFABMS: m / z 436.0532 (MH +). Calculated for C? 8H20N5OBrCl: m / z 436.0540; dH (CDCl3) 2.60 (4H, bm, -N (CH2CH2) 2O), 2.83 (2H, m, = NCH2CH2NH-), 3.57 (2H, m, = NCH2CH2NH-), 3.83 (4H, m, -N (CH2CH2 ) 20), 6.37 (1H, s, H6), 6.99 (1 H, bm, NH), 7.38-7.45 (2H, m, Ar-H), 7.51 (1 H, m, Ar-H), 7.75 ( 1 H, m, Ar-H) and 8.09 ppm (1 H, s, H2); dc (CDCl 3) CH 2: 38.2, 53.3, 53.3, 56.2, 66.9, 66.9; CH: 87.6, 127.1, 130.1, 130.2, 131.6, 143.9; C; 83.1, 132.1, 138.9, 145.7, 146.2, 158.1. EXAMPLE 448: Physical properties: HRFABMS: m / z 450.0688 (MH +). Calculated for C19H22N5OBrCl: m / z 450.0696; dH (CDCl3) 1.98 (2H, m, = NCH2C? 2CH2NH-), 2.58 (4H, m, -NIChbCH ^ O), 2.67 (2H, m, = NCH2CH2CH2NH-), 3.59 (2H, m, = NCH2CH2CH2NH-), 3.94 (4H, m, -N (CH2CH2) 2O), 6.31 (1H, s, H6), 7.37-7.44 (2H, Ar-H), 7.51 (1 H, m, Ar-H), 7.78 (1 H, m, Ar-H), 8.08 (1 H, sr H2) and 8.60 ppm (1 H, bm, NH); dc (CDCl 3) CH 2: 23.7, 42.7, 52.9, 52.9, 58.0, 66.6, 66.6; CH: 87.0, 127.1, 130.0, 130.1, 131.5, 143.6; C: 82.8, 132.1, 139.1, 145.7, 146.7, 158.0. EXAMPLE 449: Physical properties: HRFABMS: m / z 381.0114 (MH +). Calculated for C15H15N4OBrCl: m / z 381.0118; dH (CDCl 3) 1.39 (3H, d, CHCH 3), 2.76 (1 H, bm, -OH), 3.7-1 (1 H, m,? CH 2 OH) l 3.81 (1 H, m, = CHCH 2 OH), 3.88 ( 1 H, m, = CjHCH2OH), 6.38 (1 H, s, H6), 7.38 (2H, m, Ar-H), 7.48 (1H, m, Ar-H), 7.68 (1H, m, Ar-H ) and 8.02 ppm (1H, s, H2); dc (CDCl 3) CH 3: 16.9; CH2: 65.0; CH: 50.0, 88.0, 127.1, 130.1, 130.3, 131.4, 143.8; C: 83.0, 132.0, 138.5, 145.6, 146.0, 158.2.

EXAMPLE 450 3-Bromo-7-chloro-5- (2-chlorophenyl) pyrazolo [1,5-ajpyrimidine (50mg, 0.146mmol) (prepared as described in Preparative Example 129) was dissolved in 1,4-dioxane anhydride (5ml) ) in a carousel reaction tube from GeneVac Technologies. PS-diisopropyl ethylamine resin (161mg, 0.5828mmol) was added to each tube. A freshly prepared solution of the appropriate amine R-? NH2 (0.219 mmol) in 1,4-dioxane anhydride (0.3 ml) was added to each tube, with the exception of Example 99-5 in which the amine was dissolved in MeOH 10% in 1, 4-dioxane (0.3ml), and the tubes were sealed and heated at 70 ° C for 74h with magnetic stirring in the reaction block. Each tube was filtered and the resin was washed with 1,4-dioxane anhydride and then with dichloromethane. The combined individual fillets from each tube were evaporated until dried and each residue was re-dissolved in 1,4-dioxane anhydride (5ml) and placed in GeneVac reaction tubes. To each tube was added PS-isocyanate resin (594mg, 0.8742mmol) and PS-trisamine resin (129mg, 0.4371mmol) and the tubes were shaken at 25 ° C for 20h in the reaction block. The resins were filtered and washed with 1,4-dioxane anhydride and dichloromethane. The filtrates from each tube were evaporated until they were dried and each residue was subjected to silica gel column chromatography using the column size and eluent shown in Table 37, to give the title compounds.

TABLE 37 Additional physical data for the compounds are provided below: EXAMPLE 451: Physical properties: HRFABMS: m / z 381.0115 (MH +). Calculated for C15H15N4OBrCl: m / z 381.0118; [a] 25 ° c + 1.4 ° (c = 0.25, MeOH); dH (CDCl3) 1.44 (3H, d, -CHCH3), 3.773.89 (1H, dd, CHCHsOH), (1H, dd, CHCH2OH), 3.94 (1H, m, CHCH2OH), 6.41 (1H, s, H6) , 6.58 (1H, d, NH), 7.41 (2H, m, Ar-H), 7.51 (1H, m, Ar-H), 7.74 (1H, m, Ar-H) and 8.04 ppm (1H, s, H2); dc (CDCl 3) CH 3: 17.1; CH2: 65.5; CH: 49.9, 88.0, 127.1, 130.1, 130.2, 131.6, 143.8; C: 83.2, 132.1, 138.7, 145.6, 145.8, 158.1. EXAMPLE 452: Physical properties: HRFABMS: m / z 381.0115 (MH +). Calculated for C15H15N4OBrCI: m / z 381.0118; [a] D25 ° c + 6.5 ° (c = 0.32, MeOH); dH (CDCl3) 1.44 (3H, d, -CHCH3), 3.78 (1H, dd, CHCOH), 3.89 (1H, dd, CHCH2OH), 3.96 (1H, m, CHCH2OH), 6.41 (1H, s, H6), 6.58 (1H, d, NH), 7.41 (2H, m, Ar-H), 7.51 (1H, m, Ar-H), 7.75 (1H, m, Ar-H) and 8.04 ppm (1H, s, H2 ); dc (CDCl 3) CH 3: 17.1; CH2: 65.5; CH: 49.9, 88.0, 127.1, 130.1, 130.3, 131.6, 143.8; C: 83.2, 132.1, 138.6, 145.6, 145.8, 158.1. EXAMPLE 453: Physical properties: HRFABMS: m / z 381.0115 (MH +). Calculated for C15H15N4OBrCl: m / z 381.0118; [a] D25 ° c + 9.4 ° (c = 0.27, MeOH); dH (CDCl3) 1.33 (3H, d, CH3), 2.25 (1H, bs, OH), 3.37 (1H, dd, CH2), 3.51 (1H, m, CH2), 4.16 (1H, m, CHOH), 6.35 (1H, s, H6), 6.93 (1H, m, NH), 7.40 (2H, m, Ar-H), 7.50 (1H, m, Ar-H), 7.70 (1H, m, Ar-H) and 8.04 ppm (1H, s, H2); dc (CDCl 3) CH 3: 20.8; CH2: 49.2; CH: 65.7, 87.8, 127.1, 130.1, 130.2, 131.2, 143.9; C: 83.1, 132.1, 138.5, 145.6, 146.6, 158.3. EXAMPLE 454: Physical properties: HRFABMS: m / z 381.0112 (MH +). Calculated for C15H15N4OBrCl: m / z 381.0118; [a] D25 ° c -3.2 ° (c = 0.29, MeOH); dH (CDCl3) 1.32 (3H, d, CH3), 2.48 (1H, bs, OH), 3.35 (1H, dd, CH2), 3.49 (1H, m, CH2), 4.15 (1H, m, CHOH), 6.34 (1H, s, H6), 6.93 (1H, m, NH), 7.39 (2H, m, Ar-H), 7.49 (1H, m, Ar-H), 7.68 (1H, m, Ar-H) and 8.03 ppm (1H, s, H2); dc (CDCl 3) CH 3: 20.8; CH2: 49.2; CH: 65.7, 87.7, 127.1, 130.1, 130.3, 131.4, 143.9; C: 83.0, 132.0, 138.6, 145.6, 146.6, 158.3 EXAMPLE 455: Physical properties: HRFABMS: m / z 397.0054 (MH +). Calculated for C15H15N4O2BrCl: m / z 397.0067; [α] D25 ° c -9.5 ° (c = 0.28, MeOH); DH (CDCl 3) 3.18 (2 H, bs, OH), 3.47 (1 H, dd, CH 2), 3.58 (1 H, dd, CH 2), 3.63 (1 H, dd, CH 2 OH), 3.70 (1 H, dd, Cj H 2 OH) , 3.98 (1 H, m, CH), 6.35 (1 H, s, H6), 7.10 (1 H, m, NH), 7.37 (2 H, m, Ar-H), 7.46 (1 H, m, Ar -H), 7.64 (1H, m, Ar-H) and 8.01 ppm (1 H, s, H2); Dc (CDCl 3) CH 2: 44.7, 64.0; CH: 69.7, 87.7, 127.0, 130.1, 130.3, 131.3, 143.9; C: 82.9, 132.0, 138.4, 145.4, 146.7, 158.3. EXAMPLE 456: This enantiomer can be prepared in essentially the same manner as described above. EXAMPLE 457: Physical properties: HRFABMS: m / z 395.0260 (MH +). Calculated for C 16 H 17 N 4 O BrCl: m / z 395.0274; [a] D25 ° c -34.3 ° (c = 0.28, MeOH); DH (CDCl 3) 1.08 (3H, dd, CH 3), 1.78 (1 H, m, CH 2), 1.86 (1 H, m, CH 2), 2.35 (1 H, bs, CH 2 OH), 3.71 (1 H, m, CHNH), 3.81 (1 H, dd, CJ ± -OH), 3.90 (1 H, dd, CH2OH), 6.42 (1 H, s, H6), 6.53 (1 H, m, NH), 7.41 (2H, m, Ar-H), 7.51 (1 H, Ar-H), 7.75 (1 H, m, Ar-H) and 8.04 ppm (1 H, s, H2); dc (CDCl 3) CH 3: 10.5; CH2: 24. 5, 63.7; CH: 55.9, 88.0, 127.1, 130.1, 130.2, 131.6, 143.8; C: 83.2, 132.1, 138. 6, 145.6, 146.3, 158.1. EXAMPLE 458: Physical properties: HRFABMS: m / z 395.0274 (MH +). Calculated for C 16 H 17 N 4 O BrCl: m / z 395.0274; [a] D25 ° c + 27.5 ° (c = 0.25, MeOH); DH (CDCl 3) 1.05 (3H, dd, CH 3), 1.76 (1H, m, CH 2), 1.85 (1 H, m, CH 2), 2. 28 (1 H, bs, CH 2 OH), 3.67 (1 H, m, CHNH), 3.77 (1 H, dd, CtbOH), 3.84 (1 H, dd, CH 2 OH), 6.49 (1 H, s, H 6), 6.66 (1H, m, NH), 7.39 (2H, m, Ar-H), 7.49 (1H, Ar-H), 7.71 (1 H, m, Ar-H) and 8.04 ppm (1 H, s, H2); dc (CDCl 3) CH 3: 10.5; CH2: 24. 3, 63.3; CH: 56.1, 88.0, 127.1, 130.1, 130.3, 131.5, 143.8; C: 83.0, 132.1, 138. 6, 145.6, 146.3, 158.2. EXAMPLE 459: Physical properties: HRFABMS: m / z 395.0264 (MH +). Calculated for C 16 H 17 N 4 O BrCl: m / z 395.0274; dH (CDCl3) 1.77 (2H, m, -NHCH2CH2CH2CH2OH), 1.90 (1 H, bm, -NHCH2CH2CH2CH2OH), 1.93 (2H, m, -NHCH2CH2CH2CH2OH), 3.54 (2H, m, -NHCH2CH2CH2CH2OH), 3.77 (2H, m , -NHCH2CH2CH2CH2OH), 6.37 (1 H, s, H6), 6.72 (1 H, m, -NHCH2CH2CH2CH2OH), 7.41 (2H, m, Ar-H), 7.51 (1 H, m, Ar-H), 7.75 (1 H, m, Ar-H) and 8.06 ppm (1 H, s, H2); Dc (CDCl 3) CH 2: 25.7, 29.7, 42.2, 62.2; CH: 87.4, 127.1, 130.1, 130.2, 131.6, 143.8; C: 83.1, 132.1, 138.8, 145.6, 146.3, 158.1.

EXAMPLE 460: 4- Acid Amide. { f3-bromo-5- (2-chlorophenyl) pyrazolofl.5-a1-pyrimidin-7-ylamino1methyl} piperidine-1-carboxylic A. 4- tert-butyl ester. { [3-Bromo-5- (2-chlorophenyl) pyrazolori. 5-a1-pyrimidin-7-ylamino-1-methyl) -piper-dine-1-carboxylic acid: 3-Bromo-7-chloro-5- (2-chlorophenyl) pyrazolo [1,5-ajpyrimidine (300 mg, 0.875 mmol) (prepared as described in Preparative Example 129) was dissolved in 1,4-dioxane anhydride (6.8) ml). 4- (Aminomethyl) piperidin-1-carboxylic acid tert-butyl ester (225mg, 1.05mmol) and diisopropyl ethylamine (0.3055ml, 1.75mmol) were added and the mixture was heated at 75 ° C for 24h. The solution was evaporated until it was dried and the residue was chromatographed on a column of silica gel (15x5cm) using dichloromethane as the eluent to give 4-tert-butyl ester. { [3-bromo-5- (2-chlorophenyl) pyrazolo [1, 5-a] pyrimidin-7-lamino] methyl} piperidin-1-carboxylic acid (461.2 mg, 100%): FABMS: m / z 520.1 (MH +); HRFABMS: m / z 520.1111 (MH +). Calculated for C 23 H 28 N 5 O 2 BrCl: m / z 520.1115; dH (CDCl 3) 1.30 (2H, m, CH 2), 1. 51 (9H, s, -COOC (CH3) 3), 1-85 (2H, d, CH2), 1.95 (1 H, m, CH), 2.76 (2H, m, CH2), 3.40 (2H, m, CH2), 6.37 (1 H, s, H6), 6.55 (1 H, m, NH), 7.42 (2H, m, Ar-H), 7.52 (1 H, m, Ar-H), 7.76 (1 H, m, Ar-H) and 8.07 ppm (1 H, s, H2); dc (CDCl 3) CH 3: 28.5, 28.5, 28.5; CH2: 29.1, 29.1, 43.5, 43.5, 47.9; CH: 36.3, 87.5, 127.2, 130.2, 130.3, 131.6, 143.9; C: 79.7, 83.3, 132.1, 138.6, 145.4, 146.3, 154.7, 158.1.

B. r3-bromo-5- (2-chlorophenyl) pyrazolori, 5-a1-pyridin-7-illpiperidin-4-ylmethylamine It was dissolved 4-. { [3-Bromo-5- (2-chlorophenyl) pyrazolo [1, 5-a] pyrimidin-7-ylamino] methyl} piperidin-1-carboxylic acid tert-butyl ester (441 mg, 0.847 mmol) (prepared as described in Example 460, Step A above) in methanol (4.5 ml) and conc. sulfuric acid was added. 10% (v / v) in 1,4-dioxane (11.46ml). The mixture was stirred at 25 ° C for 0.5h. The product the product was processed as described in Preparative Example 241, step B and subjected to silica gel column chromatography (15x5cm) using 8% (10% conc. Ammonium hydroxide in methanol) -dichloromethane as the eluent to give [3-bromo-5- (2-chlorophenyl) pyrazolo [1, 5-a] pyrimidin-7-yl] piperidin-4-ylmethanamine (314.4mg, 88%): FABMS: m / z 420.0 (MH +); HRFABMS: m / z 420.0585 (MH +).

Calculated for C18H2oN5BrCI: m / z 420.0591; dH (CDCl 3) 1.34 (2 H, m, CH 2), 1.86 (2 H,, CH 2), 1.91 (1 H, m, CH), 2.10 (1 H, bm, piperidine-NH), 2.67 (2 H, m, CH 2 ), 3.18 (2H, m, CH2), 3.38 (2H, m, CH2), 6.37 (1 H, s, H6), 6.53 (1 H, m, NH), 7.42 (2H, m, Ar-H) , 7.52 (1 H, m, Ar-H), 7.76 (1H, m, Ar-H) and 8.06 ppm (1H, s Ar-H); dc (CDCl 3) CH 2: 31.2, 31.2, 46.2, 46.2, 48.4; CH: 36.4, 89.5, 127.1, 130.1, 130.5, 131.6, 143.8; C: 83.2, 132.1, 138.9, 145.6, 146.4, 158.1.

C. 4- acid amide. { [3-bromo-5- (2-chlorophenyl) pyrazolo ["1,5-alpyrimidin-7-ylamino-1-methyl-piperidin-1-carboxylic acid] [3-Bromo-5- (2-chlorophenyl) pyrazolo [1,5-a] pyrimidin-7-yl] piperidin-4-ylmethylamine (57 mg, 0.136 mmol) was dissolved (prepared as described in Example 460, Step B above) in dichloromethane anhydride (1.2 ml) and trimethylsilylisocyanate (0.091 ml, 0.679 mmol) was added. The mixture was stirred at 25 ° C for 2.5 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO), filtered and evaporated until dried. The residue was subjected to chromatography on a silica gel column (30x2.5cm) using 3% (10% conc. Ammonium hydroxide in methanol) -dichloromethane as the eluent to give 4-amide. { [3-bromo-5- (2-chlorophenyl) pyrazolo [1, 5-a] pyrimidin-7-ylamino] methyl} piperidin-1-carboxylic acid (53.7 mg, 86%): FABMS: m / z 463.1 (MH +); HRFABMS: m / z 463.0647 (MH +). Calculated for C19H2? N6OBrCI: m / z 463.0649; dH (d6-DMSO) 1.09 (2H, m, CH2), 1.63 (2H, m, CH2), 1.87 (1 H, m, CH), 2.60 (2H, m, CH2), 3.53 (2H, bm, CONH2 ), 3.91 (2H, d, CH2), 6.52 (1 H, s, H6), 7.50 (2H, m, Ar-H), 7.62 (2H, m, Ar-H), 8.33 (1 H, s, H2) and 8.52 ppm (1 H, m, NH); dc (d6-DMSO) CH2: 30.1, 30.1, 44.2, 44.2, 47.7; CH: 36.4, 88.2, 128.1, 130.7, 131.4, 132.1, 147.9; C: 82.1, 132.1, 139.4, 145.7, 147.9, 158.1, 158.8.

EXAMPLE 461 Amide of 2 - acid. { 2-R 3 -bromo-5- (2-chlorophenyl) pyrazolori, 5-a 1-pyrimidin-7-ylaminoethyl} p -peridin-1-carboxylic acid A. 2- tert-butyl ester. { 2- [3-bromo-5- (2-chlorophenyl) prazolo [1,5-alpyrimidin-7-ylamino-1-yl] piperidin-1-carboxylic acid 3-Bromo-7-chloro-5- (2-chlorophenyl) pyrazolo [1,5-ajpyrimidine (400 mg, 1166 mmol) (prepared as described in Preparative Example 129) was dissolved in 1,4-dioxane anhydride (5.7 ml). 2-Aminoethylpiperidin-1-carboxylic acid tert-butyl ester (266mg, 1166mmol) and diisopropyl ethylamine (0.409ml, 2.33mmol) were added and the mixture was heated at 75 ° C for 48h. Additional diisopropyl ethylamine (0.204ml, 1166mmol) was added and heating continued for a total of 58h. The solution was evaporated until it was dried and the residue was chromatographed on a column of silica gel (15x5cm) using dichloromethane followed by 0.3% (10% conc. Ammonium hydroxide in methanol) -dichloromethane as the eluent to give tert. -butyl ester of 2- acid. { [3-bromo-5- (2-chlorophenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino] ethyl} piperidin-1-carboxylic acid (491.1 mg, 79%): FABMS: m / z 534.1 (MH +); HRESIMS: m / z 534.12797 (MH +).

Calculated for C 24 H 30 N 5 O 2 B 1 -CI: m / z 534.12714; dH (CDCl 3) 1.50 (1 H, m, CH 2), 1.51 (9 H, s, COOC (CH 3) 3), 1.57 (2 H, m, CH 2), 1.68 (2 H, m, CH 2), 1.76 (2 H, m , CH2), 2.24 (1 H, bm, CH2), 2.82 / 3.40 / 3.54 / 4.08 / 4.51 (5H, m, CH / CH2), 6.34 (1 H, s, H6), 7.41 (2H, m, Ar -H), 7.51 (1 H, m, Ar-H), 7.76 (1 H, m, Ar-H) and 8.08 ppm (1 H, s, H2); dc (CDCl 3) CH 3: 28.5, 28.5, 28.5; CH2: 19.2, 25.5, 29.2, 29.2, 39.2, 67.1; CH: -47.4, 87.1, 127.1, 130.1, 130.1, 131.6, 143.9; C: 80.0, 83.0, 132.1, 138.9, 145.7, 146.2, 158.0.

B. [3-bromo-5- (2-chlorophenyl) pyrrazolori, 5-a1pyrimidin-7-iri (2-piperidin-2-ylethyl) amine 2- Tert-butyl ester was dissolved. { [3-Bromo-5- (2-chlorophenyl) pyrazolo [1,5-a] pyrimidin-7-ylamino] ethyl} piperidin-1-carboxylic acid (465mg, 0.869mmol) (prepared as described in Example 461, Step A above) in methanol (4.5ml) and conc. sulfuric acid was added. 10% (v / v) in 1, 4-dioxane (11.76ml). The mixture was stirred at 25 ° C for 1.5 h. The product the product was processed as described in Preparative Example 241, step B and subjected to chromatography on a silica gel column (15x5cm) using 3.5% (conc. 10% ammonium hydroxide in methanol) -dichloromethane as the eluent to give [3-bromo-5- (2-chlorophenyl) pyrazolo [1, 5-a] pyrimidin-7-yl] piperidin-2-ylethyl) amine (365.6mg, 97%): FABMS: m / z 434.1 (MH +); HRFABMS: m / z 434.0726 (MH +). Calculated for C19H22N5BrCl: m / z 434.0747; dH (CDCl 3) 1.24 (1 H, m, CH 2), 1.41 (1 H, m, CH 2), 1.49 (1 H, m, CH 2), 1.66 (1 H, m, CH 2), 1.73 (1 H, m, CH 2) , 1.81 (1 H, m, CH 2), 1.88 (2 H, m, CH 2), 2.68 (1 H, m, CH 2), 2.78 (1 H, m, CH 2), 3.20 (1 H, m, CH), 3.55 (1 H, m, CH2), 3.60 (1 H, m, CH2), 6.32 (1 H, s, H6), 7.41 (2 H, m, Ar-H), 7.51 (1 H, m, Ar- H), 7.74 (1 H, m, Ar-H), 7.78 (1 H, m, NH) and 8.05 ppm (1 H, s, H2); dc (CDCl 3) CH 2: 24.7, 26.8, 33.1, 35.2, 40.3, 47.0; CH: 55.7, 87.2, 127.1, 130.0, 130.1, 131.5, 143.8; C: 82.9, 132.1, 139.0, 145.7, 146.5, 158.1.

C. 2- acid amide. { 2-R3-Bromo-5- (2-chlorophenyl) pyrazolori, 5-alpyrimidin-7-ylamino-ethyl) piperidin-1-carboxylic acid [3-Bromo-5- (2-chlorophenyl) pyrazolo [1, 5-a] pyrimidin-7-yl] piperidin-2-ylethyl) amine (200 mg, 0.46 mmol) (prepared as described in Example 461) was dissolved. , Step B above) in dichloromethane anhydride (2 ml) and trimethylsilylisocyanate (0.31 ml, 2.3 mmol) was added. The mixture was stirred at 25 ° C for 1.25h. Additional trimethylsilylisocyanate (0.155ml, 1.15mmol) was added and stirring continued for a total of 3h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO), filtered and evaporated until dried.

The residue was subjected to chromatography on a silica gel column (30x2.5cm) using 2% (10% conc. Ammonium hydroxide in methanol) -dichloromethane as the eluent to give 2- acid amide. { 2- [3-Bromo-5- (2-chlorophenyl) pyrazolo [1,5-a] pyrimidin-7-ylamine] etl} piperidin-1-carboxylic acid (106.3 mg, 48%): FABMS: m / z 477.0 (MH +); HRFABMS: m / z 477.0804 (MH +). Calculated for C2oH23N6OBrCl: m / z 477.0805; dH (d6-DMSO) 1.29 (1H, m, CH2), 1.52 (5H, m, CH2), 1.72 (1 H, m, CH2), 2.05 (1 H, m, CH2), 2.51 (2H, s, CONH2), 2.79 (1 H, dd, CH), 3.31 (1 H, m, CH2), 3.34 (1 H, m, CH2), 3.76 (1 H, m, CH2), 4.30 (1 H, bm, CH2), 6.42 (1 H, s, H6), 7.50 (2H, m, Ar-H), 7.60 (1 H, m, Ar-H), 7.63 (1 H, m, Ar-H), 8.29 ( 1 H, s, H2) and 8.38 ppm (1 H, dd, NH); dc (d6-DMSO) CH2: 18.6, 25.2, 28.2, 38.4, 38.6, 54.8; CH: 46.7, 86.6, 127.1, 129.7, 130.3, 131.0, 143.4; C: 81.2. 131.0, 138.7, 145.1, 146.4, 158.2.

EXAMPLE 462 To a solution of the compound prepared in Example 204 (1.11 g, 2.12 mmol) in acetonitrile anhydride (20 ml) was added TMSl (1.70 g, 8.52 mmol), dropwise at room temperature. After 10 minutes the acetonitrile was removed in vacuo. The resulting yellow foam was treated with 2N HCl solution (7 ml) and then immediately washed with Et2O (5X). The pH of the aqueous solution was adjusted to 10 with 50% NaOH (aq) and the product was isolated by saturation of the solution with NaCl (s) followed by extraction with CH2Cl2 (5X) to give the crystalline product (733 mg, 89 % of performance). MH + = 387; m. p. = 207.5 ° C.

EXAMPLES 463-472 Essentially by the same procedure set forth in Example 462, substituting only the compounds shown in Column 2 of Table 38, prepared the compounds shown in Column 3 of Table 38.

TABLE 38 EXAMPLE 473 Step A: A solution of sulfonic acid (560 mg, 1.17 mmol) in 5 ml of Dry DMF was cooled to 0 ° C and SOCl2 (278 mg, 2.34 mmol) was added. The reaction mixture was brought to RT and stirred until the next day. The next day the contents were poured on ice and the pH was carefully regulated to 8. The product was extracted for EtOAc and the solvent was removed after drying (Na2SO4) to give 240 mg (41%) of the crude sulphonyl chloride which was used for the next step without further purification. 1 H NMR (CDCl 3) d 8.20-8.10 (m, 1H), 8.10-7.95 (m, 3H), 7.65 (d, 2H), 7.45-7.35 (m, 1 H), 7.35-7.20 (m, 1 H) , 7.15-7.05 (m, 1 H), 6.95 (t, 1 H), 4.85 (d, 2H).

Step B: A solution of the compound prepared in the Example was treated 473, Step A (120 mg, 0.24 mmol) in 10 mL of THF with 2 mL of 1 M MeNH2 (2.00 mmol) in THF at room temperature until the next day. The solvent was removed and the residue was purified by chromatography (silica, hexane: EtOAc (4: 1 → 1: 1)) to give 56 mg (48%) of the sulfonamide. 1 H NMR (DMSO-d 6) d 9.05 (t, J = 9 Hz, 1 H), 8.35 (s, 1 H), 7.90 (t, J = 7.5 Hz, 1 H), 7.75 (d, J = 9 Hz, 2H), 7.62 (d, J = 9 Hz, 2H), 7.55-7.46 (m, 1 H), 7.45-7.38 (m, 1 H), 7.38-7.25 (m, 1H), 6.50 (s, 1H) , 4.80 (d, 2H), 3.30 (s, 3H) LCMS: MH + = 492.1.

EXAMPLE 474 Essentially by the same procedure set forth in Example 473, substituting only dimethylamine, the above compound was prepared. 1 H NMR (CDCl 3) d 8.14 (t, J = 9 Hz, 1 H), 8.00 (s, 1 H), 7.76 (d, J = 9 Hz, 2H), 7.54 (d, J = 9 Hz, 2H) , 7.34-7.44 (m, 1 H), 7.26 (t, J = 9 Hz, 1 H), 7.14-7.04 (m, 1 H), 6.93 (t, J = 6 Hz, 1 H), 6.45 (s) , 1 H), 4.75 (d, 2H), 2.70 (s, 6H). LCMS: MH + = 504.2.

EXAMPLE 475 A mixture of the compound prepared in Example 129 (300 mg, 0.66 mmol), NaOH (5 g), CH 3 OH -H 2 O (100 ml, 90:10) was stirred at 25 aC for about 15 h. The progress of the hydrolysis was verified by TLC. The reaction mixture was concentrated to remove the methanol. The concentrate was diluted with 50 ml water, and extracted with ether to remove any unreacted ester. The aqueous solution obtained in this way was neutralized with 3 N HCl to pH 4 to obtain free acid, filtered and washed repeatedly with water. The acid was dried in vacuo (270 mg, 93%) and used without further purification.

EXAMPLE 476-479 Essentially by the same procedure set forth in Example 475, substituting only the compounds in column 2 of table 39, the compounds were prepared in column 3 of table 39.

TABLE 39 Additional data for selected examples shown below: Example 476: 1 H NMR (CDCl 3) d 8.15 (m, 2 H), 8.0 (m, 1 H), 7.6 (m, 1 H), 7.3 (m, 2 H), 6.6 (s, 1 H), 4.2 (d, 2H).

Example 477: 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.4 (m, 1 H), 7.25 (dd, 1 H), 7.15 (dd, 1 H), 7.0 (t, 1 H), 6.5 (s, 1 H), 3.8 (dt, 2H), 2.6 (t, 2H). Example 479: 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.4 (m, 1 H), 7.25 (dd, 1 H), 7.15 (dd, 1 H), 6.8 (t, 1 H), 3.5 (dt, 2H), 2.4 (t, 2H), 1.8 (m, 4H).

EXAMPLE 480 A mixture of the acid of Example 475 (85 mg, 0.193 mmol) and Et3N (20 mg, 0.193 mmol) in THF (20 ml) was stirred at 25 aC for 15 min. Isobutyryl chloroformate (28 mg, 0.205 mmol) was added to the reaction mixture and stirred for 10 min followed by the addition of NH 4 OH solution (0.5 ml). The reaction mixture was stirred for 1 hr and concentrated until dried. The dry mass was purified by column chromatography.

EXAMPLES 481-509 Essentially by the same procedure set forth in Example 480, substituting only the carboxylic acid shown in Column 2 of Table 40 and the amine shown in Column 3 of Table 40, the compounds shown in the Column were prepared. 4 of table 40.

TABLE 40 Additional data for selected examples given below: Example 481: 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.7 (d, 2 H), 7.4 (s, 1 H), 7.35 (d, 2H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.95 (t, 1H), 6.5 (s, 1H), 6.25 (bs, 1H), 4.7 (d, 2H), 3.0 (d, 3H) ). Example 482: 1 H NMR (CDCl 3) d 8.15 (dt, 1H), 8.0 (s, 1H), 7.45-7.35 (m, 4H), 7.25 (d, 2H), 7.15 (dd, 1H), 6.7 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.1 (s, 3H), 3.0 (s, 3H). Example 483: 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.8 (bs, 1 H), 7.7 (d, 1 H), 7.5 - 7.3 (m, 3 H), 7.25 (d, 1H), 7.15 (dd, 1H), 6.75 (t, 1 H), 6.5 (s, 1 H), 6.2 (bs, 1 H), 4.7 (d, 2H), 3.0 (d, 3H). Example 484: 1 H NMR (CDCl 3) d 8.15 (dt, 1H), 8.0 (s, 1H), 7.7 (d, H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H) , 7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 6.0 bs, 1H), 4.7 (d, 2H), 4.25 (m, 1H), 1.2 (d, 6H).

Example 485: 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.7 (d, 2 H), 7.4 (d, 2 H), 7.35 (s, 1 H), 7.25 (dd, 1 H) , 7.1 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H), 6.3 (t, 1H), 4.7 (d, 2H), 2.9 (m, 1H), 0.8 (bt, 2H), 0.6 (bt, 2H). Example 486: 1 H NMR (CDCl 3) d 8.15 (dt, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.4 (d, 2H), 7.35 (d, 1H), 7.25 (dd, 1H) , 7.1 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1H), 6.2 (t, 1H), 4.7 (d, 2H), 3.3 (dd, 2H), 1.05 (m, 1H), 0.5 (m, 2H), 0.25 (m, 2H). Example 487: 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.7 (d, 2 H), 7.4 (d, 2 H), 7.35 (m, 1 H), 7.25 (dd, 1 H) , 7.15 (dd, 1H), 6.85 (t, 1H), 6.5 (s, 1H), 6.2 (bs, 1H), 4.7 (d, 2H), 4.6 (m, 1H), 2.4 (m, 2H), 1.95 (m, 1H), 1.75 (m, 2H). Example 488: 1 H NMR (CDCl 3) d 8.5 (t, 1 H), 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.7 (d, 2 H), 7.4 (d, 2 H), 7.35 (m, 1 H) , 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1 H), 6.5 (s, 1 H), 5.9 (bs, 1 H), 4.7 (d, 2H), 1.4 (s, 9H). Example 489: 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.7 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 6.0 bs, 1H) , 4.7 (d, 2H), 4.4 (m, 1H), 2.05 (m, 2H), 1.7 (m, 4H), 1.4 (m, 2H). Example 490: 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.7 (d, 2 H), 7.4 (d, 2 H), 7.35 (m, 1 H), 7.25 (dd, 1 H) , 7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 6.5 (bs, 2H), 4.7 (d, 2H), 4.1 (m, 1H), 3.9 - 3.7 (m, 3H) ), 3.3 (m, 1H), 2.0 -1.9 (m, 4H). Example 491: 1 H NMR (CDCl 3) d 8.15 (dt, 1H), 8.0 (s, 1H), 7.45-7.35 (m, 5H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.7 (bs, 2H), 3.3 (bs, 2H), 1.7 (bs, 4H), 1.5 (bs, 2H). Example 492: 1 H NMR (CDCl 3) d 8.15 (dt, 1H), 8.0 (s, 1H), 7.45-7.35 (m, 5H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.85 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.8- 3.4 (bm, 8H). Example 493: H NMR (CDCl 3) d 8.15 (dt, 1H), 8.0 (s, 1H), 7.45-7.35 (m, 5H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.80 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 4.0 (m, 2H), 3.6 (m, 2H), 2.8-2.45 (m, 4H). Example 494: 1 H NMR (CH 3 OD) d 8.15 (s, 1H), 8.0 (dt, 1H), 7.45-7.35 (m, 5H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.80 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.7 (bs, 2H), 3.4 (bs, 2H), 2.5-2.4 (m, 4H), 2.2 (s, 3H). Example 495: 1 H NMR (CDCl 3) d 8.15 (dt, 1H), 8.0 (s, 1H), 7.45 -7.35 (m, 5H), 7.25 (dd, 1H), 7.1 (dd, 1H), 6.80 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.75 (bs, 2H), 3.35 (bs, 2H), 2.4 (bs, 2H), 2.3 (s, 3H), 2.2 (bs, 2H) ). Example 496: 1 H NMR (CDCl 3) d 7.95 (s, 1 H), 7.9 (dt, 1 H), 7.8 (t, 1H), 7.7 (d, 2H), 7.15 (m, 4H), 7.05 (dd, 1H), 6.9 (dd, 1H), 6.2 (s, 1H), 4.5 (d, 2H), 3.6 (t, 2H) ), 3.3 (dt, 2H). Example 497: 1 H NMR (CH 3 OD) d 8.1 (s, 1 H), 7.9 (dt, 1 H), 7.8 (d, 2 H), 7.5 (d, 2 H), 7.4 (m, 1 H), 7.3 (dd, 1 H) , 7.2 (dd, 1H), 6.4 (s, 1H), 4.7 (d, 2H), 3.5 (t, 2H), 2.7 (m, 2H), 2.6 (bs, 4H), 1.8 (bs, 4H). Example 498: 1 H NMR (CDCl 3) d 8.5 (t, 1 H), 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.8 (d, 2 H), 7.4 (d, 2 H), 7.35 (m, 1 H) , 7.25 (dd, 1H), 7.15 (dd, 1H), 6.8 (t, 1 H), 6.5 (s, 1 H), 4.7 (d, 2H), 3.7 - 2.5 (m, 4H), 2.35 (s) , 3H), 2.2 (m, 1 H), 1.9-1.6 (m, 6H). Example 499: 1 H NMR (CDCl 3) d 8.15 (dt, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.4 (d, 2H), 7.35 (m, 1H), 7.25 (dd, 1H) , 7.15 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 4.7 (d, 2H), 3.7 (m, 4H), 3.5 (dt, 2H), 2.6 (t, 2H), 2.5 (m, 4H). Example 500: 1 H NMR (CH 3 OD) d 8.15 (s, 1 H), 7.9 (dt, 1 H), 7.8 (d, 2H), 7.45 (d, 2H), 7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 6.4 (s, 1H), 4.75 (d, 2H), 4.2 ( m, 1 H), 3.4-2.8 (m, 7H), 1.9-1.6 (m, 4H). Example 501: 1 H NMR (CDCl 3) d 8.05 (dt, 1 H), 8.0 (s, 1 H), 7.6 (d, 2 H), 7.4 (s, 1 H), 7.35 (d, 2 H), 7.25 (dd, 1 H) , 7.1 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1 H), 6.4 (t, 1 H), 4.7 (d, 2H), 4.2 (d, 2H), 2.3 (bs, 1 H). Example 502: H NMR (CDCl 3) d 8.15 (dt, 1H), 8.0 (s, 1H), 7.75 (d, 2H), 7.45 (s, 1H), 7.4 (d, 2H), 7.3 (dd, 1H) , 7.1 (dd, 1H), 6.8 (t, 1H), 6.5 (s, 1H), 6.1 (bs, 1H), 4.7 (d, 2H), 3.5 (dq, 2H), 1.2 (t, 3H). Example 503: 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.8 (d, 2 H), 7.4 (d, 2 H), 7.35 (m, 1 H), 7.25 (dd, 1 H) , 7.15 (dd, 1H), 6.9 (t, 1H), 6.5 (s, 1 H), 6.4 (t, 1 H), 4.75 (d, 2H); 4.1 (m, 2H). Example 504: 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.8 (d, 2 H), 7.45 (d, 2 H), 7.4 (m, 1 H), 7.25 (dd, 1 H) , 7.1 (dd, 1H), 6.8 (t, 1H), 6.6 (t, 1H), 6.5 (s, 1H), 4.7 (d, 1H), 3.6 (m, 2H), 2.8 (t, 2H), 2.6 (q, 2H), 1.3 (t, 3H). Example 505: 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.4 (m, 1H), 7.25 (dd, 1H), 7.15 (dd, 1H), 7.0 (t, 1H), 6.5 (s, 1H), 3.8 (m, 2H), 2.7 (t, H), 3.0 (d, 3H) ). Example 506: 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.4 (m, 1 H), 7.25 (dd, 1 H), 7.15 (dd, 1 H), 7.0 (t, 1 H), 6.5 (s, 1H), 3.8 (m, 2H), 3.6 (m, 6H), 3.4 (m, 2H), 2.7 (t, 2H). Example 507: 1 H NMR (CDCl 3) d 8.15 (dt, 1 H), 8.0 (s, 1 H), 7.4 (m, 1 H), 7.25 (dd, 1 H), 7.15 (dd, 1 H), 7.0 (t , 1 H), 6.5 (s, 1 H), 3.9 (t, 2H), 3.8 (dt, 2H), 3.7 (t, 2H), 2.7 (t, 2H), 2.6 (m, 4H). Example 508: 1 H NMR (CH 3 OD) d 8.1 (s, 1 H), 7.95 (dt, 1 H), 7.5 (m, 1 H), 7.35 - 7.2 (m, 2 H), 6.5 (s, 1 H), 3.6 (m, 4H), 3.25 (m, 4H), 2.4 (t, 2H), 2.05 (dt, 2H).

EXAMPLE 509 A solution of NaOH (59 mg, 1.47 mmol) in 1 mL of water was added to a suspension of NH2OH.HCl (102 mg, 1.47 mmol) in 10 mL of methanol at 0 ° C. After 5 min, the compound prepared in Example 210.10 (208 mg, 0.49 mmol) was added and the reaction mixture was refluxed until the next day. The solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The EtOAc layer was dried (Na2SO) and the solvent was evaporated.

The resulting crude amidoxime was suspended in trimethyl orthoformate containing the catalytic amount of the PTS acid and refluxed until the next day. The solvent was removed and the residue was taken up in EtOAc. The EtOAc layer was washed with aq NaHCO3 followed by water and brine. The solvent was evaporated and the residue was purified by chromatography (silica, hexane: EtOAc (1: 1)) to give 80 mg (35%) of the oxadiazole. 1 H NMR (CDCl 3) s, 1 H), 8.20-8.10 (m, 3 H), 8.03 (s, 1 H), 7.53 (d, J = 9 Hz, 2 H), 7.45-7.36 (m, 1 H), 7.30- 7.22 (m, 2H), 7.16-7.08 (m, 1 H), 6.80 (t, J = 5 Hz, 1 H), 6.56 (s, 1 H). LCMS: MH + = 465.2.

EXAMPLE 510 Essentially by the same procedure set forth in Example 509, substituting only the compound prepared in Preparative Example 192, the above compound was prepared, yield = 75; MH + = 53; m. p. = 79.3 ° C.

EXAMPLE 511 A mixture of nitrile (235 mg, 0.56 mmol) and Me3SnN3 (343 mg, 1.67 mmol) in 20 ml of dry toluene was refluxed for 2 days under Ar. The solvent was removed in vacuo and the residue was dissolved in dry methanol. The gaseous HCl was bubbled through the solution for 15 min and the reaction mixture was allowed to stand overnight at room temperature. The next day, the solvent was removed, the residue was captured in water and the pH was adjusted to 5. The precipitated product was extracted into EtOAc. Evaporation of the EtOAc layer after drying (Na2SO4) gave the residue which was purified by chromatography (silica, DCM: MeOH (98: 2- »95: 5)) to give 50 mg (19%) of the pure tetrazole. 1 H NMR (CD3OD) d 8.10 (s, 1 H), 8.00 (d, J = 9 Hz, 2H), 7.90 (t, J = 7 Hz, 1H), 7.65 (d, J = 9 Hz, 2H), 7.50-7.40 (m, 1H), 7.30-7.10 (m, 2H), 6.45 (s, 1 H), 4.80 (s, 2H); LCMS: MH + = 465.0.

EXAMPLE 512 Essentially by the same procedure set forth in Example 511, substituting only the compound prepared in Example 192, the above compound was prepared. Performance = 64; MH + = 453; m. p. = 238.9 ° C.

EXAMPLE 513 The compound prepared in Example 157 was dissolved in dioxane (30 ml) and a solution of HCl-dioxane (4 M, 30 ml) was added. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was evaporated under reduced pressure and ethyl acetate (200 ml) was added. The organic solution was washed with 1 N sodium hydride followed by saturated brine. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. MH + = 442.1.

EXAMPLE 514-526 Essentially by the same procedure set forth in Example 513, substituting only the compounds shown in Column 2 of Table 41, the compounds shown in Column 3 of Table 41 were prepared.

TABLE 41 EXAMPLES 528-564 General procedure for the formation of the parallel library of 5-piperidinyl: To a mixture of the starting material (80 mg, 0.21 mmol) shown in Column 2 of Table 42 in CH2Cl2 anhydride (1.5 mL) was added DIPEA (75 μl, 0.42 mmol) and the appropriate end reagent (1.1 equiv., 0.23 mmol). After 1 to 2 h, the reaction mixture was applied to a 1000 micron preparative TLC plate and subsequently developed using 8-10% EtOH-CH2CI2 as eluent to give the compounds shown in Column 3 of the table 42 TABLE 42 Additional data for selected examples given below. Example 534: 1 H NMR (300MHz, CDCl 3) d 8.66 - 8.62 (s, 1H), 8. 62 - 8.58 (d, 1H), 7.95 (s, 1H), 7.72 - 7.68 (d, 1H), 7.36 - 7.31 (dd, 1H), 6. 66 - 6.62 (t, 1H), 5.93 (s, 1H), 4.65 - 4.62 (d, 2H), 3.86 - 3.82 (d, 1H), 3.65 -3.58 (171, 1H), 3.26-3.12 (dd, 4H) ), 3.02 -2.80 (m, 3H), 2.10-2.00 (m, 1H), 1. 67-1.57 (m, 3H). Example 535: 1 H NMR (300MHz, CDCl 3) d 8.66 - 8.62 (s, 1H), 8. 62 - 8.58 (d, 1H), 7.95 (s, 1H), 7.72 - 7.67 (d, 1H), 7.36 - 7.30 (dd, 1H), 6. 70 - 6.64 (t, 1 H), 5.90 (s, 1 H), 4.63 - 4.61 (d, 2H), 3.93 - 3.86 (m, 1 H), 3.69 -3.61 (m, 4H), 3.27 -3.23 (m m, 4H), 3.10-3.01 (dd, 1H), 2.93- 2.84 (m, 2H), 2. 08 - 2.03 (m, 1 H), 1.90 - 1.57 (m, 4H). Example 536: 1 H NMR (300 MHz, CDCl 3) d 8.67 (s, 1 H), 8.62 - 8.58 (d, 1 H), 7.96 (s, 1 H), 7.72 - 7.68 (d, 1 H), 7.36 - 7.30 (dd, 1 H ), 6.79 - 6.72 (t, 1H), 5.96 (s, 1H), 4.86 (br s, 2H), 4.66 - 4.63 (d, 2H), 3.89 - 3.73 (m, 2H), 3.55 - 3.32 (m, 2H), 3.00 - 2.89 (m, 1 H), 2.10 - 1.97 (m, 2H), 1.70 - 1.53 (m, 2H). Example 537: 1 H NMR (300 MHz, CDCl 3) d 8.66 (s, 1 H), 8.62 - 8.58 (d, 1 H), 7.98 (s, 1 H), 7.77 - 7.76 (t, 1 H), 7.72 - 7.69 ( d, 1 H), 7.63 - 7.59 (m, 1H), 7.56 (s, 1H), 7.36 - 7.29 (dd, 1H), 6.83 - 6.79 (t, 1H), 5.96 (s, 1H), 4.67 - 4.64 (d, 2H), 3.98 - 3.93 (dd, 1 H), 3.79 - 3.68 (m, 2H), 3.37 - 3.28 (m, 1H), 3.03 -2.94 (m, 1H), 2.12-1.99 (m, 1H), 1.76-1.56 (m, 3H). Example 544: 1 H NMR (300 MHz, CDCl 3) d 8.66 - 8.62 (d, 1 H), 8.61 - 8.58 (dd, 1 H), 7.95 (s, 1 H), 7.72 - 7.67 (d, 1 H), 7.36 - 7.30 (dd , 1H), 6.80-6.62 (br s, 1H), 5.88 (s, 1H), 4.63 (s, 2H), 3.08-2.95 (m, 2H), 2.87-2.80 (m, 2H), 2.04 (m, 1H), 1.85-1.78 (m, 4H), 1.52-1.44 (m, 1H), 0.87-0.82 (m, 2H), 0.72-0.66 (m, 2H). Example 545: 1 H NMR (300 MHz, CDCl 3) d 8.66 (s, 1 H), 8.62 - 8.58 (br t, 1 H), 7.97 (s, 1 H), 7.73 - 7.68 (d, 1 H), 7.36 - 7.30 (br t, 1 H), 6.79 - 6.72 (br t, 1 H), 5.96 (s, 1 H), 4.64 (br s, 2 H), 4.59 - 4.46 (br d, 1 H), 3.95 - 3.74 (br m, 1H), 3.57 - 3.49 (dd, 1H), 3.10 - 3.01 (dd, 1H), 2.86 - 2.70 (m, 2H), 2. 13 (s, 3H), 2.06-2.00 (m, 2H), 1.65-1.48 (m, 2H). Example 551: 1 H NMR (300 MHz, CDCl 3) d 8.67 (s, 1 H), 8.63 - 8.59 (d, 1 H), 7.96 (s, 1 H), 7.74 - 7.69 (d, 1 H), 7.36 - 7.30 (dd, 1 H ), 6.69 - 6.64 (t, 1H), 5.95 (s, 1H), 4.67 - 4.63 (d, 2H), 3.853.65 (m, 1H), 3.75 - 3.65 (m, 1H), 3.25 - 3.18 (dd, 1H), 3.03 - 2.90 (m, 2H), 2.81 (s, 6H), 2.03 - 1.95 (m, 1H), 1.89-1.68 (171, 3H). Example 552: 1 H NMR (300 MHz, CDCl 3) d 8.67 (s, 1 H), 8.62 -8.59 (d, 1 H), 7.95 (s, 1 H), 7.74 - 7.69 (d, 1 H), 7.36 - 7.31 (dd, 1 H ), 6.67 - 6.60 (t, 1 H), 5.98 (s, H), 4.67 - 4.63 (d, 2H), 3.92 - 3.86 (m, 1 H), 3.85 - 3.75 (m, 1H), 3.40 -3.30 (dd, 1H), 3.27- 3.16 (m, 1H), 3.10-2.86 (m, 2H), 2.10- 1.78 (m, 3H), 1.40-1.30 (d, 6H) . Example 553: 1 H NMR (300 MHz, CDCl 3) d 8.67 (s, 1 H), 8.62 (br s, 1 H), 7.96 (s, 1 H), 7.74 - 7.69 (d, 1 H), 7.36 - 7.31 (dd, 1 H) , 6.70 - 6.66 (t, 1 H), 5.98 (s, 1 H), 4.67 - 4.63 (d, 2 H), 3.88 - 3.81 (m, 1 H), 3.71 - 3.65 (m, 1 H), 3. 20 - 3.11 (dd, 1 H), 3.02 - 2.91 (m, 1 H), 2.90 - 2.80 (m, 4H), 2.01 - 1.80 (m, 3H).

Example 559: 1 H NMR (300MHz, CDCl 3) d 8.66 -8.60 (d, 1 H), 8.50 - 8.44 (dd, 1 H), 8.01 (s, 1 H), 7.93 (m, 1 H), 7.48 - 7.40 (dd, 1 H), 6.08 (s, 1 H), 4.80 - 7.74 (s, 2H), 4.32 -4.19 (br d, 2H), 3.10 - 2.86 (m, 2H), 1.95 - 1.68 (m, 4H) ). Example 563: 1 H NMR (300MHz, CDCl 3) d 8.66 (s, 1 H), 8.62 - 8.58 (d, 1 H), 7.96 (s, 1 H), 7.73 - 7.68 (d, 1 H), 7.36 - 7.30 (dd, 1 H), 6.96 - 6.86 (br s, 1 H), 6.79 - 6.74 (t, 1 H), 6.00 (s, 1 H), 4.67 - 4.64 (d, 2 H), 4.37 - 4.30 (dd, 1 H), 4.22 - 4.13 (m, 1 H), 3.97 - 3.86 (dd, 1 H), 3.73 - 3.64 (m, 1 H), 3.17 - 3.14 (d, 3 H), 3.07 - 2.99 (m, 1 H ), 2.20 - 1.97 (m, 2H), 1.68 - 1.48 (m, 2H).

General procedure 1: procedure for parallel synthesis of amide formation The parallel synthesis was carried out in reaction blocks of 96 polypropylene wells with a removable top cover and a fixed bottom cover.

Each reaction well was prepared with a 20 micron polypropylene bottom frit and the maximum volume was 3 ml. The collection block was not equipped with a lower frit. To each reaction well was added a solution of an amine (0.021 mmol) dissolved in a mixture of DMF-THF-MeCN (4: 3: 3 v / v, 0.95 ml), EDC resin (P-EDC, Polymer Laboratories Ltd., 43 mg, 0.063 mmol), 1-hydroxybenzotriazole (HOBt, 5.67 mg, 0.042 mmol) and a solution of a carboxylic acid in dimethylformamide (1 M, 0.0315 ml, 0.0315 mmol). The reaction mixture was stirred at room temperature for 16 h. The solution of the crude product was filtered in a reaction well loaded with trisamine resin (P-NH2, Argonaut Tech. Inc., 30 mg, 0.126 mmol) and isocyanate reagent (P-NCO, Argonaut Tech. Inc., mg, 0.063 mmol). The reaction mixture was stirred at room temperature for 16 h and filtered on the collection block. The product solution was evaporated under reduced pressure to give the desired amide product.

General procedure 2: procedure for parallel synthesis of sulfonamide formation The parallel synthesis was carried out in reaction blocks of 96 polypropylene wells with a removable top cover and a fixed bottom cover. Each reaction well was prepared with a 20 micron polypropylene bottom frit and the maximum volume was 3 ml. The collection block was not equipped with a lower frit. To each reaction well was added a solution of an amine (0.021 mmol) dissolved in a mixture of DMF-THF-MeCN (3: 2: 2 v / v, 0.95 ml), DIEA resin (P-DIEA, Argonaut Tech Inc., 18 mg, 0.063 mmol) and a solution of a sulfonyl chloride in dimethylformamide (1 M, 0.0315 ml, 0.0315 mmol). The reaction mixture was stirred at room temperature for 16 h. The solution of the crude product was filtered in a reaction well loaded with trisamine resin (P-NH2, Argonaut Tech. Inc., 30 mg, 0.126 mmol) and sodium isocyanate (P-NCO, Argonaut Tech. Inc., 35 mg, 0.063 mmol). The reaction mixture was stirred at room temperature for 16 h and filtered on the collection block. The product solution was evaporated under reduced pressure to give the desired sulfonamide product.

General procedure 3: procedure for the parallel synthesis of urea formation The parallel synthesis was carried out in reaction blocks of 96 polypropylene wells with a removable top cover and a fixed bottom cover. Each reaction well was prepared with a 20 micron polypropylene bottom frit and the maximum volume was 3 ml. The collection block was not equipped with a lower frit. To each reaction well was added a solution of an amine (0.021 mmol) dissolved in a mixture of DMF-MeCN (1: 1 v / v, 0.95 ml) and a solution of an isocyanate in dichloromethane (0.33 M, 0.126 ml, 0.042 mmol). The reaction mixture was stirred at room temperature for 16 h. The solution of the crude product was filtered in a reaction well loaded with trisamine resin (P-NH2, Argonaut Tech. Inc., 30 mg, 0.126 mmol) and isocyanate reagent (P-NCO, Argonaut Tech. Inc., mg, 0.063 mmol). The reaction mixture was stirred at room temperature for 16 h and filtered on the collection block. The product solution was evaporated under reduced pressure to give the desired urea product.

General procedure 4: procedure for the parallel synthesis of reductive alkylation The parallel synthesis was carried out in reaction blocks of 96 polypropylene wells with a removable top cover and a fixed bottom cover.

Each reaction well was prepared with a 20 micron polypropylene bottom frit and the maximum volume was 3 ml. The collection block was not equipped with a lower frit. To each reaction well was added a solution of an amine (0.021 mmol) dissolved in a mixture of AcOH-DCE (1: 99 v / v, 0.5 ml), a solution of an aldehyde or ketone in dichloroethane (1 M, 0.147). ml, 0.147 mmol), and a solution of tetramethylammonium triacetoxyborohydride (11 mg, 0.042 mmol) dissolved in AcOH-DCE mixture 1: 99 v / v, 0.5 ml). The reaction mixture was stirred at room temperature for 3 days. The solution of the crude product was filtered in a reaction well loaded with Lanterns sulfonic acid resin (P-SO3H, MimotopesPty Ltd., 0.3 mmol). The reaction mixture was stirred at room temperature for 2 h and decanted. The Lanterns product resin was washed with methanol (1 ml) three times. A solution of ammonia in methanol (2 M, 1.2 ml) was added. The reaction mixture was stirred at room temperature for 30 min. and it was filtered in the collection block. The product solution was evaporated under reduced pressure to give the desired tertiary amine product.

General procedure 5: Procedure for the parallel synthesis of 7, N-substituted pyrazole, 5a-1-pyrimidines To 3-bromo-7-chloro-5- (2-chloro-phenyl) -pyrazolo [1,5-a] pyrimidine (9.0 mg, 0.03 mmol) in tetrahydrofuran was added di- / so-propylethylamine (12 μl, 0.07 ), followed by cyclopropylmethylamine (70 μl, 0.07 mmol, 1 M solution in DMF). The reaction mixture was heated to 70 ° C for 36 h and then cooled to RT. The mixture was treated with (P-NCO, Argonaut Tech. Inc. 70 mg, 0.12 mmol), and P-CO3"(Argonaut Tech. Inc. 70 mg, 0.24 mmol) and stirred at room temperature for 12-18 h. The solution was filtered and evaporated until dried to give the observed product m / z 375.21.

General procedure 6: Procedure for the parallel synthesis of pyrazolori, 5-N-substituted 5alpyrimidines General Protocols: Parallel synthesis was carried out in 96-well polypropylene blocks, as described elsewhere in this. In the case that heating was required, the reactions were performed in 2.5 ml glass tubes individually sealed with a polypropylene mat and heating was achieved by a 96 well heat transfer block.

Step A: To 3-bromo-5-chloro-7-N-Boc-a! Kylamino-pyrazolo [1,5-a] pyrimidine (17 mg, 0.04 mmol) in p-dioxane DIEA (9 μl) was added. , 0.05), followed by cyclopropyl-methylamine (80 μl, 0.08 mmol, 1M solution in isopropanol). The reaction mixture was heated at 90 ° C for 36 h and then cooled to room temperature. The mixture was treated with P-NCO (Argonaut Tech. Inc. 70 mg, 0.12 mmol) and P-CO 3"(Argonaut Tech. Inc. 70 mg, 0.24 mmol) and stirred at room temperature for 12-18 h. The solution was filtered and evaporated until dried to give the product.

Step B (acid): The product of STEP A was captured in 35% TFA / DCM and stirred for 4 h followed by a high vacuum concentration. The residue was treated with 10% HCl (aq) in stirred MeOH for 2 h and then concentrated to give the desired product. M / z 375.21 was observed.

Step B (basic): The product from step A was captured in EtOH and treated with Ambersep® 900-OH ion exchange resin (Acras, 100mg), heated at reflux for 48 h with slight agitation. The reaction mixture was cooled to room temperature, filtered and concentrated to give the desired product.

EXAMPLE 565 By using the procedure set forth in General Procedure 1 and the compound of Example 462 shown above, the compounds were prepared with the observed m / z shown in Table 43.

EXAMPLE 566 Through the use of the procedure set forth in General Procedure 1 and the compound of Example 471 shown above, the compounds shown in Table 44 were prepared with the observed m / z.

EXAMPLE 567 By using the procedure set forth in General Procedure 1 and the compound of Example 515 shown above, the compounds shown in Table 45 were prepared with the observed m / z.

EXAMPLE 568 Through the use of the procedure set forth in General Procedure 1 and the compound of Example 513 shown above, the compounds shown in Table 46 were prepared with the observed m / z.

EXAMPLE 569 By using the procedure set forth in General Procedure 1 and the compound of Example 526 shown above, the compounds shown in Table 47 were prepared with the observed m / z.

EXAMPLE 570 Through the use of the procedure set forth in the Procedure General 1 and the compound of Example 524 shown above, the compounds shown in Table 48 were prepared with the observed m / z.

EXAMPLE 571 By using the procedure set forth in General Procedure 1 and the compound of Example 525 shown above, the compounds shown in Table 49 were prepared with the observed m / z.

EXAMPLE 572 Through the use of the procedure set forth in General Procedure 1 and the compound of Example 526.10 shown above, the compounds shown in Table 50 were prepared with the observed m / z.

EXAMPLE 573 By using the procedure set forth in General Procedure 1 and the compound of Example 518 shown above, the compounds shown in Table 51 were prepared with the observed m / z.

EXAMPLE 574 Through the use of the procedure set forth in General Procedure 1 and the compound of Example 519 shown above, the compounds shown in Table 52 were prepared with the observed m / z.

EXAMPLE 575 By using the procedure set forth in General Procedure 1 and the compound of Example 520 shown above, the compounds shown in Table 53 were prepared with the observed m / z.

EXAMPLE 576 By using the procedure set forth in General Procedure 1 and the compound of Example 522 shown above, the compounds shown in Table 54 were prepared with the observed m / z.

EXAMPLE 577 By using the procedure set forth in General Procedure 1 and the compound of Example 523 shown above, the compounds shown in Table 55 were prepared with the observed m / z.

EXAMPLE 578 By using the procedure set forth in General Procedure 2 and the compound of Example 462 shown above, the compounds shown in Table 56 were prepared with the observed m / z.

EXAMPLE 579 By using the procedure set forth in General Procedure 2 and the compound of Example 471 shown above, the compounds shown in Table 57 were prepared with the observed m / z.

EXAMPLE 580 By using the procedure set forth in General Procedure 2 and the compound of Example 515 shown above, the compounds shown in Table 58 were prepared with the observed m / z.

EXAMPLE 581 By using the procedure set forth in General Procedure 2 and the compound of Example 513 shown above, the compounds shown in Table 59 were prepared with the observed m / z.

By using the procedure set forth in General Procedure 2 and the compound of Example 513 shown above, the compounds shown in Table 60 were prepared with the observed m / z.

EXAMPLE 583 By using the procedure set forth in General Procedure 2 and the compound of Example 524 shown above, the compounds shown in Table 61 were prepared with the observed m / z.

EXAMPLE 584 By using the procedure set forth in General Procedure 2 and the compound of Example 525 shown above, the compounds shown in Table 62 were prepared with the observed m / z, EXAMPLE 585 By using the procedure set forth in General Procedure 2 and the compound of Example 526.10 shown above, the compounds shown in Table 63 were prepared with the observed m / z.

EXAMPLE 586 By using the procedure set forth in General Procedure 2 and the compound of Example 518 shown above, the compounds shown in Table 64 were prepared with the observed m / z.

EXAMPLE 587 By using the procedure set forth in General Procedure 2 and the compound of Example 519 shown above, the compounds shown in Table 65 were prepared with the observed m / z.

EXAMPLE 588 Through the use of the procedure set forth in General Procedure 2 and the compound of Example 520 shown above, the compounds shown in Table 67 were prepared with the observed m / z.

EXAMPLE 589 By using the procedure set forth in General Procedure 2 and the compound of Example 521 shown above, the compounds shown in Table 68 were prepared with the observed m / z.

EXAMPLE 590 Through the use of the procedure set forth in General Procedure 2 and the compound of Example 523 shown above, the compounds shown in Table 69 were prepared with the observed m / z.

EXAMPLE 591 By using the procedure set forth in General Procedure 3 and the compound of Example 462 shown above, the compounds shown in Table 70 were prepared with the observed m / z.

EXAMPLE 592 Through the use of the procedure set forth in General Procedure 3 and the compound of Example 471 shown above, the compounds shown in Table 71 were prepared with the observed m / z.

EXAMPLE 593 By using the procedure set forth in General Procedure 3 and the compound of Example 513 shown above, the compounds shown in Table 72 were prepared with the observed m / z.

EXAMPLE 594 Through the use of the procedure set forth in General Procedure 3 and the compound of Example 524 shown above, the compounds shown in Table 73 were prepared with the observed m / z.

EXAMPLE 595 By using the procedure set forth in General Procedure 3 and the compound of Example 524 shown above, the compounds shown in Table 74 were prepared with the observed m / z.

EXAMPLE 596 By using the procedure set forth in General Procedure 3 and the compound of Example 519 shown above, the compounds shown in Table 75 were prepared with the observed m / z.

EXAMPLE 597 By using the procedure set forth in General Procedure 3 and the compound of Example 520 shown above, the compounds shown in Table 76 were prepared with the observed m / z.

EXAMPLE 598 By using the procedure set forth in General Procedure 3 and the compound of Example 521 shown above, the compounds shown in Table 77 were prepared with the observed m / z.

EXAMPLE 599 By using the procedure set forth in General Procedure 3 and the compound of Example 523 shown above, the compounds shown in Table 78 were prepared with the observed m / z.

EXAMPLE 600 By using the procedure set forth in General Procedure 4 and the compound of Example 462 shown above, the compounds shown in Table 79 were prepared with the observed m / z.

EXAMPLE 601 By using the procedure set forth in General Procedure 4 and the compound of Example 471 shown above, the compounds shown in Table 80 were prepared with the observed m / z.

EXAMPLE 602 Through the use of the procedure set forth in General Procedure 4 and the compound of Example 525 shown above, the compounds shown in Table 81 were prepared with the observed m / z.

EXAMPLE 603 By using the procedure set forth in General Procedure 4 and the compound of Example 526.10 shown above, the compounds shown in Table 82 were prepared with the observed m / z.

EXAMPLE 604 By using the procedure set forth in General Procedure 4 and the compound of Example 521 shown above, the compounds shown in Table 83 were prepared with the observed m / z.

EXAMPLE 605 By using the procedure set forth in General Procedure 4 and the compound of Example 523 shown above, the compounds shown in Table 84 were prepared with the observed m / z.

EXAMPLE 606 By using the procedure set forth in General Procedure 5 and the compound of Preparative Example 81 shown above, the compounds shown in Table 85 were prepared with the observed m / z.

EXAMPLE 607 By using the procedure set forth in General Procedure 6 and the compound of Preparative Example 196, the compounds shown in Table 86 were prepared with the observed m / z.

EXAMPLE PREPARATION 500 Piperidine-2-ethanol (127 g, 980 mmol) in 95% EtOH (260 mL) was added to acid (S > (+) - camphorsulfonic acid (228.7 g, 1.0 eq.) In 95% EtOH (150 mL) and the resulting solution was heated to reflux, Et2O (600 ml) was added to the hot solution and the solution was cooled to room temperature and allowed to stand for 3 days.The resulting crystals were filtered and dried in vacuo (25 g): mp 173-173 ° C (lit. 168 ° C)., the salt was dissolved in NaOH (3M, 100 ml) and stirred 2 hours and the resulting solution was extracted with CH2Cl2 (5 x 100 ml). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to give (S) ~ piperidin-2-ethanol (7.8 g) a portion of which was recrystallized from Et2O: mp = 69-70 ° C (lit. 68-69 ° C); [a] D = 14.09 ° (CHCI3, c = 0.2).

PREPARED EXAMPLE 501 Essentially by the same procedure set forth in Preparative Example 500 substituting only (R) - (-) - camphor sulfonic acid, ('Rj-piperidine-2-ethanol. (1.27 g) was prepared: [a] D = 11.3 ° ( CHCI3, c = 0.2).

PREPARED EXAMPLE 502 To a pressure flask loaded with a solution of c / 's- (1R, 2S) - (+) - 2- (benzylamino) -cyclohexanemethanol (1g, 4.57 mmol) in MeOH (35 mL) was added 20% by weight Pd (OH) 2 (0.3g,> 50% wet) in one portion. The mixture was stirred under 50 psi of H2 in a Parr hydrogenation apparatus for 12 h. The mixture was purged to N2 and filtered through a pad of Celite. The plug was washed generously with MeOH (2 x 25 ml) and the resulting filtrate was concentrated under reduced pressure to give 0.57g (97%) of a white solid. M + H = 130.

PREPARED EXAMPLE 503 Step A: To a 3-Br adduct solution (1.1 g, 4.1 mmol) of Preparative Example 142 in THF (40 mL) at 0 ° C was added CH3SNa (0.32 g, 4.53 mmol) in one portion. The heterogeneous mixture was stirred for 72 h at room temperature and the mixture was concentrated under reduced pressure. The crude product was partitioned between water (10 ml) and EtOAc (30 ml) and the layers were separated. The organic layer was washed with brine (1 x 10 ml) and dried (Na2SO4). The organic layer was filtered and concentrated under reduced pressure to give 1.0 g (88%) of a yellow solid, mp 150-152 ° C; M + H = 280. This material was taken over Step B without further purification.

Step B: To a solution of thiomethyl derivative (1.5 g, 5.37 mmol) from Step A in dioxane / DIPEA (15 ml / 4 ml) at room temperature was added amino alcohol (1.3 g, 8.06 mmol) of Preparative Example 10. The mixture was heated to reflux for 48 h, cooled to rt, and concentrated under reduced pressure. The crude product was purified by flash chromatography using CH2Cl2 / MeOH (30: 1) as eluent to give 1.8 g of the product (90%) as a crystalline yellow solid, mp 167-169 ° C; M + H = 373.

Step C: To a solution of thiomethyl derivative (2.2 g, 5.92 mmol) from Step B in CH2Cl2 (20 mL) at 0 ° C was added MCPBA (1.53 g, 8.9 mmol) in one portion. The resulting mixture was stirred for 2 h at 0 ° C at which time the mixture was diluted with CH 2 Cl 2 (20 mL) and aqueous sat. NaHCO 3. (15 ml). The layers were separated and the organic layer was washed with aqueous sat. NaHCO3. (15 ml) and brine (1 x 15 ml). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to give 2.0 g of a brown solid (87%). mp 181-183 ° C; M + H = 388.

PREPARED EXAMPLE 504 The title compound (racemic) was prepared according to the procedure set forth in Preparative Example 503, with the proviso that the commercially available c / s-hydroxymethyl-1-cyclohexylamine hydrochloride was replaced in Step B.

PREPARED EXAMPLE 505 Step A: Treatment of the thiomethyl derivative (2.0 g, 7.2 mmol) from Step A of Preparative Example 503 with (S) -piperidine-2-ethanol (1.2 g, 9.3 mmol) of Preparative Example 500 under conditions identical to those described in Step B of Preparative Example 503, 0.90 g (34%) of the title semi-solid compound, mp 173-175 ° C, was prepared. M + H = 372.

Step B: Following the procedure of Step C in the Preparative Example 503, the thiomethyl derivative (0.30 g, 0.81 mmol) was treated with MCPBA (0.21 g, 1.2 mmol) to give 0.31 g (99%) of the title compound as a viscous yellow oil. M + H = 388.

PREPARED EXAMPLE 506 The title compound (racemic) was prepared according to the procedure set forth in Preparative Example 505, with the proviso that commercially available piperidin-2-ethanol was replaced. M + H = 388.

PREPARED EXAMPLE 507 T-BuOK (112.0g, 1.00 mol) was stirred under N2 in dry Et2O (3.0 L) in a 5L flask equipped with an addition funnel. A mixture of butyronitrile (69.0 g, 1.00 mol) and ethylformate (77.7 g, 1.05 mol) was added dropwise over 3 hrs, then the reaction mixture was stirred overnight at room temperature. The mixture was cooled to 0 ° C, AcOH (57 ml) was added, the mixture was filtered, and the solid was washed with Et2O (500 ml). The combined filtrates were evaporated at room temperature in a rotovap to give pale yellow oil (95.1g). The oil was dissolved in dry EtOH (100 ml), 99% hydrazine monohydrate (48 ml) was added, then AcOH (14 ml) was added, and the mixture was refluxed under N2 until the next day. The solvents were evaporated and the resulting oil was chromatographed on silica gel with CH2Cl2: 7N NH3 in MeOH. 22.4 g (20%) of 3-amino-4-ethylpyrazole was obtained as clear oil which solidified upon standing.

PREPARED EXAMPLE 508 Step A: The pyrazole of Preparative Example 507 (9.80g) and dimethylmalonate (45ml) were stirred and refluxed under N2 for 3 hrs. The excess dimethylmalonate was evaporated in vacuo and the residue was chromatographed with 15: 1 CH2CI2: MeOH to give pale yellow solid (10.6 g, 57%). LCMS: MH + = 212.

Step B: Dry MeOH was added. (200 ml) under N2 to a mixture of the amide from Step A (11.9 g, 56.4 mmol) and sodium methoxide (4.57 g, 84.6 mmol). The mixture was stirred and refluxed under N2 for 5 h, cooled to rt, and conc. HCl was added. (20 ml). The solvents were evaporated and the residue was suspended in H2O (300 ml). the solid was filtered, washed on a filter with 2x300 ml of H 2 O, and dried under vacuum at 100 ° C. 7.40 g (73%) of cream solid was obtained. LCMS: MH + = 180.

Step C: POCI3 (100 ml) and N, N-dimethylaniline (20 ml) were added N2 to the diketone from Step B (7.70 g), and the mixture was stirred and refluxed for 20 hrs under N2. Then, it was cooled to room temperature, carefully poured into 1 L of crushed ice, and extracted with EtOAc (2x500 mL). The extracts were washed with H2O (500 ml), dried over Na2SO4, filtered and the solvent was evaporated. The residue was chromatographed with CH2Cl2 to give pale yellow solid (8.20 g, 90%). LCMS: MH + = 216.

PREPARED EXAMPLE 508.10 Essentially by the same procedure set forth in Preparative Example 508, substituting only the compound of Preparative Example 1, the above compound was prepared. LCMS: MH + = 228.

PREPARED EXAMPLE 509 A mixture of the dichloride of Preparative Example 508 (3.13 g, 14.5 mmol), the amine was stirred. HCl from Preparative Example (3.00g, 18.9 mmol), DIPEA (7.5 mL), and dry NMP (40 mL) plus dry dioxane (40 mL) at 60 ° C for 4 days under N2. Then, the solvents were distilled in vacuo and the residue was chromatographed with 6: 1 EtOAc: MeOH and then chromatographed 12: 1 CH CI2: MeOH. The solid obtained in this way was suspended in H2O (100 ml), filtered, washed on a filter with H2O (2x100 ml), and dried in vacuo. Pale pink solid was obtained (2.37 g, 54%). M + H = 304.

PREPARED EXAMPLES 510-516 Essentially by the same procedure set forth in Preparative Example 509 only by substituting the amines in column 2 of Table 500 and the chlorides shown in column 3 of Table 500, the compounds shown in column 4 of Table 500 are prepared.

TABLE 500 PREPARATORY EXAMPLE 517 Essentially by the same procedure set forth in Preparative Example 184, substituting only the amines in Column 2 of Table 501, the compounds shown in Column 3 of Table 501 were prepared.

TABLE 501 PREPARED EXAMPLE 520-521 Essentially by the same procedure set forth in Preparative Example 192, substituting only the compounds in column 2 of Table 502, the compounds shown in Column 3 of Table 502 were prepared.

TABLE 502 EXAMPLE 1000 A mixture of the compound prepared in Preparative Example 509 (1.50 g, 4.94 mmol) with the amino alcohol of Preparative Example 500 (1.91 g, 14.8 mmol) in dry NMP (3 mL) was stirred under N2 at 160 ° C for 48 hr. The NMP was distilled in vacuo and the residue was chromatographed first with 5: 1 EtOAc: MeOH, then the crude product was re-chromatographed with 10: 1 CH2Cl2: MeOH. White solid was obtained (460 mg, 24%). LCSM: MH + = 397; mp = 113-115 ° C.

EXAMPLE 1001: The main isolated secondary product (540 mg, 29%) was the deoxygenated product. (LCMS: MH + = 381; mp = 49-52 ° C): EXAMPLES 1002 - 1014 Essentially by the same procedure set forth in Example 1000, substituting only the amines in Column 2 of Table 1000 and the chlorides in Column 3 of Table 1000, the compounds were prepared in column 4 of Table 1000.

TABLE 1000 EXAMPLE 1015 To a solution of the sulfoxide of Preparative Example 505 (0.10 g, 0.28 mmol) in? J-BUOH in a sealed tube was added Et3N (0.13 mL, 1.0 mmol) followed by the amine dihydrochloride (0.13 g, 0.65 mmol) of Example Preparation 216. The tube was sealed and heated to 100 ° C, cooled to room temperature, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (6 x 1000 μM) eluting with CH 2 Cl 2 / MeOH (20: 1) to give 50 mg (40%) of a pale white solid, mp 182-185 ° C; M + H = 446.

EXAMPLES 1016-1026 Essentially by the same procedure set forth in Example 1015, substituting only the sulfoxide shown in Column 2 of Table 1001 and the amine in Column 3 of Table 1001, the compounds shown in Column 4 of Quad 001 were prepared .

TABLE 1001 EXAMPLES 1027-1038 Essentially by the same conditions set forth in Example 341, Steps A and B substituting only the amines in Column 2 of Table 1002 and the compound prepared in Example Preparative 193.10, the compounds were prepared in column 4 of the table 1002.

PICTURE 1002 EXAMPLES 1039-1041 Essentially by the same procedure set forth in Example 340 substituting only the amines in Column 2 of Table 1003, the compounds shown in Column 4 of Table 1003 were prepared. TABLE 1003 EXAMPLES 1042-1057: Essentially by the same procedure set forth in Example 340, using only the appropriate 5-chloroderivative and substituting the amines in Column 2 of Table 1004, the compounds shown in Column 4 of Table 1004 were prepared.

PICTURE 1004 TEST: Baculovirus constructs: Cyclins A and E were cloned into pFASTBAC (Invitrogen) by PCR, with the addition of a GluTAG sequence (EYMPME) at the amino terminus to allow purification on anti-GluTAG affinity columns. The expressed proteins were of a size of approximately 46kDa (cyclin E) and 50kDa (cyclin A). CDK2 was also cloned into pFASTBAC by PCR, with the addition of a hemagglutinin epitope tag at the carboxy terminal end (YDVPDYAS). The expressed protein was of an approximate size of 34kDa.

ENZYME PRODUCTION: Cyclins A, E and CDK2 expressing recombinant baculovirus in SF9 cells at a multiplicity of infection (MOI) of 5, for 48 hrs. The cells were harvested by centrifugation at 1000 RPM for 10 minutes. The pellets containing cyclin (E or A) were combined with pellets of cells containing CDK2 and used on ice for 30 minutes five times, the pellet volume of lysis pH buffer containing 50mM Tris pH 8.0, 0.5% NP40 , 1 mM DTT and protease / phosphatase inhibitors (Roche Diagnostics GmbH, Mannheim, Germany). The mixtures were stirred for 30-60 minutes to promote the formation of the cyclin-CDK2 complex. Then the mixed lysates were turned down 15000 RPM for 10 minutes and the supernatant was retained. Then, 5ml of anti-GluTAG beads (per one liter of SF9 cells) were used to capture cyclin-CDK2 complexes. The bound beads were washed three times in pH lysis buffer. The proteins were eluted competitively with a pH-lysis buffer containing 100-200ug / ml of the GluTAG peptide. The eluate was dialyzed until the following day in 2 liters of kinase pH regulator containing 50 mM Tris pH 8.0, 1 mM DTT, MgCl210 mM, 100uM sodium orthovanadate and 20% glycerol. The enzyme was stored in aliquots at -70 ° C.

IN VITRO KINASE ASSAY: CDK2 kinase assays (either cyclin A or E-dependent) were carried out in 96-well low protein binding well plates (Corning Inc, Corning, New York). The enzyme was diluted to a final concentration of pH kinase buffer of 50 μg / ml containing 50 mM Tris pH 8.0, 10 mM MgCl 2) 1 mM DTT, and 0.1 mM sodium orthovanadate. The substrate that was used in these reactions was a biotinylated peptide derived from Histone H1 (from Amersham, UK). The substrate was dissolved on ice and diluted 2 μM in the kinase pH buffer. The compounds were diluted in 10% DMSO for desirable cooking. For each kinase reaction, 20 μl of the 50 μg / ml enzyme solution (1 μg of enzyme) and 20 μl of the 1 μM substrate solution were mixed, then combined with 10 μl of the diluted compound in each well for analysis. The kinase reaction was initiated by the addition of 50 μl of 4 μM ATP and 1 μCi of 33P-ATP (from Amersham, UK). The reaction was allowed to run for 1 hour at room temperature. The reaction was stopped by the addition of 200 μl of termination pH buffer containing 0.1% Triton X-100, 1 mM ATP, 5 mM EDTA, and 5 mg / ml of SPA beads coated with streptavidin (from Amersham, UK) for 15 minutes. minutes The SPA beads were then captured on a 96 well GF / B filter plate (Packard / Perkin Elmer Life Sciences) using a Universal Filtermate harvester (Packard / Perkin Elmer Life Sciences.). Nonspecific signals were removed by washing the beads twice with 2M NaCl, then twice with 2M NaCl with 1% phosphoric acid. The radioactive signal was then measured using a TopCount 96-well liquid scintillation counter (from Packard / Perkin Elmer Life Sciences). DETERMINATION OF IC50: Dose-response curves were plotted from the inhibition data generated, each in duplicate, from serial dilutions of 8-point inhibitor compounds. The concentration of the compound was plotted against the% kinase activity, calculated by CPM of the treated samples divided by CPM from the untreated samples. To generate the IC5o values, the dose-response curves were adapted to a standard sigmoid curve and the IC50 values are derived by non-linear regression analysis. The IC5o values thus obtained for the compounds of the invention are shown in Table 87. These kinase activities were generated by the use of cyclin A or cyclin E using the aforementioned assay.

BOX 87 As demonstrated above by the assay values, the compounds of the present invention exhibit excellent CDK inhibitory properties. While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. It is intended that all such alternatives, modifications and variations be understood in the spirit and scope of the present invention.

TABLE 43 Compound m / z Compound m / z Ej Product miz Product miz Product i Product 1EJ 2. miz 2. mfe 1 Ex Product 1 Ex Product 2. mfe 2 mfe i Ex 1 Ej Product Product miz 2. mfe 1 Ex L Ex Product 2 m & Product 2. miz: TABLE 44 1. Ex. 2. 1. E¡. 2. miz Product mfe lEj.

Product 1EJ Product 2. miz 2. mfz 1 E, lEj. Product Product 2 p? Z 2. my 1 EJ Product Product i 2. miz 2. mfz 1 Ex 1 Ex Product Product 2. miz 2. miz I.Ej.

Product 1 Ex Product 2 inz 2 mftz 1 Ex lEj Producer Product 2. miz 2.mfe 1 Ex Product Product lEj. 2. miz 2. m / z TABLE 45 I.Ej 1 Ex 1 Ex Product Product Product 2. mfe 2. iz 2. mfe 1 Ex 1 Ex l Ex.

Porduct Product Product 2. m £ z Z mfe 2. m / z 1. 4532 14537 14542 2.578.32 2. 582.32 2. 588.32 1 Ej l Ex Product Product Product lEj 2. mfc 2. miz 2. mfe LEj Product Product LEj. mfe 2 mfe TABLE 46 lEj.2. Product Product? G.2. miz mrZ 1 Ex 2 1 Ex 2 Product Product miz miz 1 Ex.2. 1.EJ.2. Product Product miz miz 1 Ej.2. I.Ej.2.

Product Product mfe miz 1 Ex.2. lEj.2.

Product Product miz miz 1. Ex.2. Product Product 1 EJ 2 miz miz TABLE 47 i Z -EJ.Z Product Product 1-Ex.Z Product piüz miz miz -EJ.Z Product EtZ miz Product 1EIZZ miz Product pWz. Product miz TABLE 48 Ex. 2. Product 1. Ex. Z Product 1 miz miz 1 Ej 2 1 Ej.2.

Product Product miz miz 1 Ex.2. 1 Ex.2 Product Product miz miz V Ex 2 LE 2 Product Product miz miz: 1 Ex.2 Product Product 1 Ex.2. me miz 1 Ex 2. lEj 2 Product Product miz miz 1 Ex 2 Ex 2 Product Product miz miz TABLE 49 n. ^, 1 EJ 2 1 Ej 2 1 EJ 2 Product? _ Product Product miz mfe mfe 1 Ex 2 1 Ex 2 L Ex. 2.

Product Product Product mfe mfe mfe 1 Ej 2 1 Ej 2. 1. Ej 2.

Product Product Product mfe mfe mfe TABLE 50 -EJ.Z 1. Ej-Z Product Product miz miz LEj 2. Product Product 1.q.2. me miz lEj 2 Product Product lEj.2. mfe miz LEj 2. I.Ej.2.

Product Product miz miz LEj 2 Product Product LEj.2 miz miz lEj 2 Product Product l.l-j.2. miz miz lEj.2 lEj.2 Product Product miz miz LEj 2 Product Product I.Ej.2. miz miz Product L 2. Product lEj.2. miz miz TABLE 51 Z 1.EJ.Z EJ.Z Product 1EJ. Product Product thousand thousand mfi 1 Ex.2. I.Ej.2. lEj.2.

Product Product Product miz miz miz 1 Ex 2. 1 Ex. 2 Product Product Product 1 Ex. 2. mfe miz mfe 1 Ex.2. Product Product? .g.? Product I.Ej-2. miz miz miz TABLE 52 1EJ.Z 1.EJ.Z Product Product miz miz LEj 2. lEj 2.

Product Product miz miz LEj.2. LEj.2.

Product Product miz mfe 1. EJ 2. 1. Ex 2.

Product Product miz miz lEj 2.

Producer i.q 2. Product miz mfe LE 2 L 2.

Product Product miz miz lEj.2.

Product q 2. Product mfe mfe TABLE 53 1. EJ.Z -E1Z 1E1.Z Product Product Product mfe miz miz Z Product 1 Ex. Z Product -EJ. Product -EJ.Z m / z miz m / z 1. Ex. 2. 1. Ex. 2. 1 Ex. 2.

Product Product Product m / z m / z m / z TABLE 54 1. g.2. to 1 Ex.2. 1EJ.2.

Product Product Product m / z m / z mfe 1 Ex.2 .Ej.2. LEj.2.

Product Product Product mfe mfe miz lEj ". . I.Ej.2. I.Ej.2 Product 1_ Product Product. mfe mfe mfe Product -EJ.Z Product mfe 1 mEi? Z Pioducto 1 mitz TABLE 55 1 Ex.2. 1.EJ.2. 2.

Product Product 1 Ex. Product miz miz. mz LEj.2. Product Product 1.EJ.2. miz miz TABLE 56 1.EJ.Z -EJ.Z Product Product miz thousand Product 1EJ.Z Product 1"Ef mfe mfe TABLE 57 1 Ex. Z lEj.Z Product Product miz miz TABLE 58 1 Ex. 2. 1 Ex. 2.

Product Product mfe mfe Product LEj.2 LE, .2 miz Product miz 1 Ej- Z Product Product lEj.2. miz miz 1. Ex. 2.

Product mfe TABLE 59 1. Ex. 2. L Ex. Z 1 Ex. Z Product Product Product mfe mfe mfe 1. E1.Z 1.EJ.Z 1-Ej.Z Product Product Product m / z mz miz TABLE 60 1-Ej.Z 1.EJ.Z 1. Ej. Z Product Product Product mfe mfe mfe lEj.2 Porducto Product 1. ELZ Product ig. Z mfe m / z miz 1-Ej.Z Product Product 1.EJ.Z 1.EJ.Z Product miz mfe mfe 1. EJ 2 Product mfe TABLE 61 TABLE 62 TABLE 63 TABLE 64 TABLE 65 TABLE 67 TABLE 68 TABLE 69 TABLE 70 TABLE 71 TABLE 72 TABLE 73 TABLE 74 3 TABLE 75 1. Ex.2. 1.Ej.2. 1. Ex.2.

Product Product Product m / z m / z m / z 1. Ex. 2. 1. Ex. 2. Product Product 1. Ex. 2. Product m / z m / z m / z 1. Ex. 2. 1. Ex. 2. 1. Ex. 2.

Product Product Product m / z m / z m / z TABLE 76 1. Ex. 2. 1. Ex. 2. 1. Ex. 2.

Product Product Product m / z m / z m / z 1. Ex. 2. 1. Ex. 2. 1. Ex. 2.

Product Product Product m / zm / zm / z 1. Ex. 2. 1. Ex. 2. Product Product n UrUiU? R? * TlU- ~ i 1. Ex. 2. m / zm / zm / z TABLE 77 1 Ex. 2. 1. Ex. 2.

Product Product m / z m / z TABLE 78 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z TABLE 79 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z miz 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. Product 1. Ex. 2. Product m / z m / z TABLE 80 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z I. Clj. Product 2. TABLE 81 1. Ex. 2. 1. Ex. 2. 1. Ex. 2.

Product Product Product m / z miz m / z 1. Ex. 2. 1. Ex. 2. 1. Ex. 2.

Product Product Product m / z miz m / z 1. Ex. 2.

Product m / z TABLE 82 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 62 1. Ex.2. 1. Ex.2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z TABLE 83 1. Ex. 2. 1. Ex. 2. 1. Ex. 2.

Product Product m / z t? / Z Product m / z 1. Ex. 2. 1. Ex. 2. Product Product Product m / z m / z 1. Ex. 2. 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z Product m / z 1. Ex. 2.

Product rn / z TABLE 84 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z TABLE 85 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z miz TABLE 86 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2. 1. Ex. 2.

Product Product m / z m / z 1. Ex. 2.

Product m / z

Claims (52)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound represented by the structural formula: or a pharmaceutically acceptable salt or solvate of said compound, wherein: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including the N-oxide of said heteroaplo), - (CHR5) n-aryl, - (CHR5) n-heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (O2) R5, - C (O) R5, -C (O) NR5R10, - SO3H, -SR10, -S (O2) R7, -S (O2) NR5R10, -N (R5) S (O2) R7, -N (R5) C (O) R7 and - N (R5) C (O) NR5R10; R2 is selected from the group consisting of R9, alkyl, alkenyl, alkynyl, CF3, heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R9 groups which may be the same or different and are independently selected from the list of R9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups, aryl fused to an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which may be identical or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups, heteroaryl fused with an aryl or heteroaryl group, (CHJm- ^ N- 8 ? / (CH2) ms \ '/ V o, .arilo X_. p8 M- N-R8; ar? l ° N-R8 X and YYRB wherein one or more of the aryl and / or one or more of the heteroaryl in the definitions set forth above for R 2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group that it consists of halogen, -CN, -OR5, -SR5, -S (02) R6, -S (02) NR5R6, -NR5R6, -C (O) NR5R6, CF3, alkyl, aryl and OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, -OR6, -SR6, -C (O) N (R5R6), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 the heterocyclyl moieties whose structures are shown immediately above for R3 may be unsubstituted or optionally substituted independently with one or more portions which may be be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) pOR5, -OR5, -NR5R6, - (CR4R5) PNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (O2) R6, -S (O2) NR5R6, -N (R5) S (O2) R7, -N ( R5) C (O) R7 and -N (R5) C (O) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring possesses an -OR5 portion; R 4 is H, halo or alkyl; R5 is H, alkyl, aryl or cycloalkyl; R6 is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, - OR5 , -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (O2) R5, -C (O) R5, -C (O) NR5R10, -SO3H, -SR10, -S (O2) R7, -S (O2) NR5R10, -N (R5) S (O2) R7, --N (R5) C (O) R7 and -N (R5) C (O) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5, - C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (O2) R5, -C (O) NR4R5, -C (O) R5, -SO3H, -SR5, -S (O2) R7, -S (O2) NR4R5, -N (R) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR4R5; or optionally (i) R5 and R 0 in the portion -NR5R10, or (ii) R5 and R6 in the NR5R6 portion, can be joined to form a cycloalkyl or heterocyclyl portion, with each of said cycloalkyl or heterocyclyl portions being unsubstituted or optionally substituted independently with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or substituted optionally independently with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (O2) R5, -C (O) NR5R10, -C (O) R5, -SR10, -S (O2) R10, -S (O2) NR5R10, -N (R5) S (O2) R10, -N ( R5) C (O) R10 and -N (R5) C (O) NR5R10; R8 is selected from the group consisting of R6, -OR6, -C (O) NR5R10, -S (O2) NR5R10, -C (O) R7, -C (= N-CN) -NH2, -C (= NH ) -NHR5, heterocyclyl, and -S (O2) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R10, -C (O2) R6, -C (O) NR5R10, -OR6, -SR6, -S (O2) R7, -S (O2) NR5R10, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R10; m is 0 to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R2 is phenyl, R3 is not alkyl, alkynyl or halogen, and that when R2 is aryl, R is not j (CHR) n NR5R > and with the additional proviso that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms.

2. The compound according to claim 1, further characterized in that R is - (CHR 5) n -aryl, MCHR5) n-heteroaryl, alkyl, cycloalkyl, heterocyclyl or heteroarylalkyl (including N-oxide of said heteroaryl), where each of said alkyl, aryl, cycloalkyl, heterocyclyl and heteroaryl may be unsubstituted or optionally substituted with one or more portions as recited in claim 1; R2 is halogen, alkyl, haloalkyl, CN, cycloalkyl, heterocyclyl or alkynyl; R3 is H, lower alkyl, aryl, heteroaryl, cycloalkyl, -NR5R6, wherein said alkyl, aryl, heteroaryl, cycloalkyl and the heterocyclyl structures shown immediately above for R3 are optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CF3, OCF3, lower alkyl, CN, -C (O) R5, -S (O2) R5, -C (= NH) -NH2, -C (= CN) -NH2, hydroxyalkyl, alkoxycarbonyl, -SR5, and OR5, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring possesses an -OR5 portion; R 4 is H or lower alkyl; R5 is H, lower alkyl or cycloalkyl; n is 1 to 2; and p is 1 or 2.

3. The compound according to claim 2, further characterized in that R is hydroxyalkyl, - (CHR5) n-aryl or - (CHR5) n-heteroaryl, wherein each of said aryl and heteroaryl is unsubstituted or substituted with one or more groups which may be the same or different, each group being selected independently from the group consisting of heteroaryl, amine, heterocyclyl, -C (O) N (R5R6), -S (O2) R5, -S (O2) N (R5R6), alkoxy and halo.

4. The compound according to claim 2, further characterized in that R2 is Br, Cl, CF3, CN, lower alkyl, cyclopropyl, alkynyl, alkyl substituted with -OR6 or tetrahydrofuranyl.

5. The compound according to claim 2, further characterized in that R3 is H, lower alkyl, aryl, heteroaryl, cycloalkyl, wherein each of said alkyl, aryl, heteroaryl, cycloalkyl and the heterocyclyl structures shown immediately above for R3 are optionally substituted with one or more portions which may be the same or different, each portion being selected independently from the group consisting of halogen, CF3, OCF3, lower alkyl, CN and OR5, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring possesses a -OR5 portion.

6. The compound according to claim 2, further characterized in that R4 is H or lower alkyl.

7. The compound according to claim 2, further characterized in that R5 is H.

8. The compound according to claim 2, further characterized in that n is 1.

9. The compound according to claim 1, further characterized in that p is 1.

10. The compound according to claim 2, further characterized in that R is benzyl or hydroxyalkyl.

11. The compound according to claim 2, further characterized in that R is pyrid-3-ylmethyl, wherein said pyridyl can be unsubstituted or optionally substituted with one or more portions as set forth in claim 1.

12. - The compound according to claim 2, further characterized in that R is pyrid-4-ylmethyl, wherein said pyridyl can be unsubstituted or optionally substituted with one or more portions as set forth in claim 1.

13.- The compound according to claim 2, further characterized in that R is the N-oxide of pyrid-2-ylmethyl, pyrid-3-ylmethyl or pyrid-4-ylmethyl, wherein each of said pyridyl groups may be unsubstituted or substituted optionally with one or more portions as set forth in claim 1.

14. The compound according to claim 4, further characterized in that R2 is Br.

15. The compound according to claim 1. cation 4, further characterized in that R2 is Cl.

16. The compound according to claim 4, further characterized in that R2 is ethyl.

17. The compound according to claim 4, further characterized in that R2 is cyclopropyl.

18. The compound according to claim 4, further characterized in that R2 is ethynyl.

19. The compound according to claim 2, further characterized in that R3 is lower alkyl, cycloalkyl, heterocyclyl, aryl or -N (R5R6).

20. The compound according to claim 19, further characterized in that R3 is isopropyl.

21. The compound according to claim 19, further characterized in that R3 is cyclohexyl or norbornyl, wherein each of said cyclohexyl or norbornyl can be unsubstituted or substituted with one or more portions which can be equal or different, each portion independently of the group consisting of alkyl and hydroxyalkyl.

22. The compound according to claim 19, further characterized in that R3 is unsubstituted phenyl.

23. The compound according to claim 19, further characterized in that R3 is a phenyl substituted with one or more portions that can be the same or different, each portion being selected independently of the group consisting of F, Br, Cl and CF3.

24. The compound according to claim 19, further characterized in that R5 of said -N (R5R6) is H or hydroxyalkyl, and R6 of said -N (R5R6) is selected from the group consisting of alkyl, hydroxyalkyl, cycloalkyl and methylenedioxy, wherein each of said alkyl and cycloalkyl may be unsubstituted or substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of amine, ethoxycarbonyl, amide, hydroxyalkyl, hydroxy.

25. The compound according to claim 19, further characterized in that R5 and R6 of said -N (R5R6) are joined to form a heterocyclyl portion, wherein said heterocyclyl portion may be unsubstituted or optionally independently substituted with one or more groups that can be the same or different, each group being selected from the group consisting of hydroxyalkyl, amide, -C (O) R5, >. ; C (CH3) 2, -S (O2) R5, -S (02) N (R5R6), -C (= NH) N (R5R6) and -C (= N-CN) N (R5R6).

26. The compound according to claim 25, further characterized in that said heterocyclyl portion formed by R5 and R6 is a pyrrolidine or piperidine ring.

27.- A compound of formula: or an acceptable salt for pharmaceutical use or solvate thereof.

28. - A compound of formula: or an acceptable salt for pharmaceutical use or solvate thereof.

29.- A compound of the formula: or an acceptable salt for pharmaceutical use or solvate thereof.

30.- A compound of formula: or an acceptable salt for pharmaceutical use or solvate thereof.

31.- A compound of the formula: or an acceptable salt for pharmaceutical use or solvate thereof.

32. The use of at least one compound of claim 1 in the manufacture of a medicament for inhibiting one or more cyclin-dependent kinases in a patient.

33. The use of at least one compound of claim 1 in the manufacture of a medicament for treating one or more diseases associated with a cyclin-dependent kinase in a patient.

34. The use claimed in claim 33, wherein said cyclin-dependent kinase is CDK2.

35. The use claimed in claim 33, wherein said cyclin-dependent kinase is mitogen-activated protein kinase (MAPK / ERK).

36. The use claimed in claim 33, wherein said cyclin-dependent kinase is glycogen synthase kinase 3 (GSK3beta).

37.- The use claimed in claim 33, wherein said disease is selected from the group consisting of: cancer of the bladder, breast, colon, kidney, liver, lung, small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, including squamous cell carcinoma; leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma; acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctantoma, follicular thyroid cancer and Kaposi's sarcoma.

38.- The use of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof; and an antineoplastic agent for the manufacture of a medicament for treating one or more diseases associated with cyclin-dependent kinases in a mammal.

39.- The use claimed in claim 38, wherein said anti-neoplastic agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, CPT-11, irinotecan, camptostar, topotecan , paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methotrexate, 5FU, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin , cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN ™, Pentostatin, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitramycin, Deoxicoformycin, Mitomycin-C, L-Asparagi nasa, Teniposide 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin , Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, CPT-11, Anastrazole, Letrazole, Capecitabine, Reloxafina, Droloxafina or Hexamethylmelamine.

40.- A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 in combination with at least one pharmaceutically acceptable carrier.

41.- The pharmaceutical composition according to claim 38, further characterized by additionally comprising one or more anti-neoplastic agents selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, CPT-11, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen , 5-fluorouracil, methotrexate, 5FU, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard , Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramide, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine Phosphate, Pentostatin, Vinblastine, Vincristine, Vindesine, Bleomycin , Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxicoformycin, Mitomycin-C, L-Asparaginase, Teniposide, 17 - Etinil radiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolon propionate, Testolactone, Megestrolacetate,Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesterone acetate, Leuprolide, Flutamide, Toremifene, Goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, CPT-11, Anastrazole, Letrazol, Capecitabine, Reloxafina, Droloxafina or Hexamethylmelamine.

42. The compound according to claim 1, further characterized in that it is in purified form.

43. - A compound of the formula: or an acceptable salt for pharmaceutical use or solvate thereof.

44. - A compound of the formula: or an acceptable salt for pharmaceutical use or solvate thereof.

45.- A compound of the formula: or an acceptable salt for pharmaceutical use or solvate thereof.

46.- A compound of the formula: or an acceptable salt for pharmaceutical use or solvate thereof.

47. - A compound of the formula: or an acceptable salt for pharmaceutical use or solvate thereof. 48.- A compound of the formula: or an acceptable salt for pharmaceutical use or solvate thereof. 49.- A compound of the formula: or an acceptable salt for pharmaceutical use or solvate thereof. 50.- A compound of the formula: or an acceptable salt for pharmaceutical use or solvate thereof. 51.- A compound of the formula: or an acceptable salt for pharmaceutical use or solvate thereof. 52.- A compound of the formula: or an acceptable salt for pharmaceutical use or solvate thereof.