MX2008006707A - Spirocyclic compounds as hdac inhibitors - Google Patents

Abstract

The present invention relates to a novel class of substituted spirocyclic compounds. re resented Formula (II). These compounds can inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention may also be useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases. The present invention further provides pharmaceutical compositions comprising the compounds of the instant invention and safe dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of these compounds in vivo.

Description

ESPIROCICLIC COMPOUNDS AS INHIBITORS OF HISTONE DEACETILASE FIELD OF THE INVENTION The present invention relates to a new class of substituted spirocyclic compounds. These compounds can inhibit histone deacetylase and are suitable for use in the selective induction of terminal differentiation, and arrest of cell growth and / or apoptosis of neoplastic cells, thereby inhibiting the proliferation of said cells. In this manner, the compounds of the present invention are useful for treating a patient having a tumor characterized by the proliferation of neoplastic cells. The compounds of the invention may also be useful in the prevention and treatment of diseases mediated by TRX, such as autoimmune, allergic and inflammatory diseases, and in the prevention and / or treatment of diseases of the central nervous system (CNS), such as diseases neurodegenerative BACKGROUND OF THE INVENTION HDAC inhibition can suppress gene expression, including expression of genes related to tumor suppression. The inhibition of histone deacetylase can lead to histone deacetylase-mediated transcriptional repression of tumor suppressor genes. For example, inhibition of histone deacetylase can provide a method for treating cancer, hematological disorders, such as hematopoiesis, and metabolic disorders related to genetics. More specifically, transcriptional regulation is an important event in cellular differentiation, proliferation, and apoptosis. There are several lines of evidence that histone acetylation and deacetylation are mechanisms by which transcriptional regulation is achieved in a cell (Grunstein, M., Nature, 389: 349-52 (1997)). It is thought that these effects occur through changes in the structure of chromatin by altering the affinity of histone proteins for DNA wrapped in the nucleosome. There are five types of histones that have been identified. The histones H2A, H2B, H3 and H4 are found in the nucleosome, and H1 is a linker located between nucleosomes. Each nucleosome contains two histones of each type within its nucleus, except for H1, which is present alone in the outer portion of the nucleosome structure. It is believed that when the histone proteins are hypoacetylated, there is a higher affinity of the histone to the phosphate structure of the DNA. This affinity causes the DNA to bind tightly to the histone and makes the DNA inaccessible to the regulatory elements and machinery of transcription. The regulation of acetylated states occurs through the balance of activity between two enzyme complexes, histone acetyl transferase (HAT) and histone deacetylase (HDAC).

It is thought that the hypoacetylated state inhibits the transcription of acetylated DNA. This hypoacetylated state is catalyzed by large multiprotein complexes that include HDCA enzymes. In particular, HDAC have been shown to catalyze the removal of acetyl groups from the histones of the chromatin nucleus. It has been shown in several cases that the alteration of HAT or HDAC activity is involved in the development of a malignant phenotype. For example, in acute promyelocytic leukemia, the oncoprotein produced by the fusion of PML and RAR alpha appears to suppress the transcription of specific genes through the recruitment of HDAC (Lin, RJ et al., Nature 397: 811-14 (1998)) . In this way, the neoplastic cell is unable to complete the differentiation and leads to excessive proliferation of the leukemic cell line. U.S. Patent Nos. 5,369,108, 5,932,616, 5,700,811, 6,087,367 and 6,511,990, the contents of which are hereby incorporated by reference, describe hydroxamic acid derivatives useful for selectively inducing terminal differentiation, growth arrest cellular or apoptosis of neoplastic cells. In addition to its biological activity as antitumor agents, these hydroxamic acid derivatives have recently been identified as being useful for treating or preventing a wide variety of diseases and conditions mediated by thioredoxin (TRX), such as inflammatory diseases, allergic diseases, autoimmune diseases, diseases associated with oxidative stress or diseases characterized by cellular hyperproliferation (U.S. Application No. 10 / 369,094, filed February 15, 2003, the overall content of which is hereby incorporated by reference). In addition, these hydroxamic acid derivatives have been identified as being useful for treating diseases of the central nervous system (CNS) such as neurodegenerative diseases and for treating brain cancer (See, US Application No. 10 / 273,401, filed on 16 October 2002, the global content of which is hereby incorporated by reference). In view of the wide diversity of applications for compounds containing hydroxamic acid moieties, the development of new inhibitors having improved properties, for example, increased potency or increased bioavailability is highly desirable.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a new class of substituted spirocyclic compounds. These compounds, which can be used to treat cancer, inhibit histone deacetylase and are suitable for use in the selective induction of terminal differentiation, and the arrest of cell growth and / or apoptosis of neoplastic cells, thereby inhibiting the proliferation of said cells. In this manner, the compounds of the present invention are useful for treating a patient having a tumor characterized by the proliferation of neoplastic cells. The compounds of the invention may also be useful in the prevention and treatment of diseases mediated by TRX, such as autoimmune, allergic and inflammatory diseases, and in the prevention and / or treatment of diseases of the central nervous system (CNS), such as diseases neurodegenerative The present invention further provides pharmaceutical compositions comprising the compounds of the present invention, and safe dosage regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of these compounds in vivo. The present invention relates to compounds represented by Formula II and pharmaceutically acceptable salts, solvates and hydrates thereof, as indicated herein.

The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of the embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds represented by Formula II: wherein A, B and D are independently selected from CR12, NR1a, C (O) and O; E is selected from a bond, CR12, NR1a, C (O) and O; where at least one of A, B, D or E is CR12; and with the proviso that when A is O, then E is not O; - it is an optional double link; ^ J is an aryl or heteroaryl, optionally substituted with 1 to 3 substituents selected from R7; is an aryl or heteroaryl; R1 is independently selected from hydrogen, C6 alkyl, (CR62) nR10, (CR62) nC (0) R4, (CR62) nC (0) OR4, (CR62) nC (0) NR52, (CR62) nS (O) 2R4, (CR62) nOH and halo; R1a is independently selected from hydrogen, CrC6 alkyl, (CR62) nR10, (CR62) nC (O) R4, (CR62) nC (O) OR4, (CR62) nC (0) NR52 or (CR62) nS (0) 2R4; L1 is selected from a bond, - CR112 -, -C (O) NR5 -, -NR5C (0) - and -C (0) -; R3 is selected from H, unsubstituted or substituted C6 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, halo, CN, amide, carboxyl, C-? - C7 alkoxy, C? -C7 haloalkyl, haloalkyloxy C-? -C7, hydroxyalkyl CC, C7 alkenyl, C7 alkynyl, alkyl C -? - C7-C (= 0) O-, C1-C7 alkyl (= 0) -I hydroxyalkoxy, -NHSO2, -SO2NH, alkyl CrC7-NHSO2-, alkyl CrC7-SO2NH-, alkyl CrC-sulphonyl, alkylC? -C7-amino, dialkyl (C1-C7) -amino and L2-R12, R4 is independently selected from H, CrC6 alkyl, aryl and heterocyclyl, wherein the alkyl, aryl or heterocyclyl may be optionally substituted; R5 is independently selected from hydrogen, C-C-alkyl and aryl, which may be optionally substituted with 1 to 3 substituents selected from C-? -C6 alkyl, aryl, heteroaryl or halo; R6 is independently selected from hydrogen, C-C-alkyl, aryl, OR11, halo, and NR11; wherein the alkyl or aryl may be optionally substituted with 1 to 3 substituents selected from d-Cß alkyl, aryl, heteroaryl or halo; R7 is independently selected from hydrogen, OH, NR112, nitro, CN, amide, carboxyl, C7 alkoxy, dC6 alkyl, C7 haloalkyl, CrC7 haloalkyloxy, CC hydroxyalkyl, C? -C7 alkenyl, CrC7 alkyl C (= O) 0-, C7-C7 alkyl (= 0) -, CrC7 alkynyl, halo, amide, hydroxyalkoxy, -NR11S02, -S02NR11, CrC7-NR11SO2- alkyl, C7-C07-S02NR11- alkyl, C7-sulphonyl alkyl group , CrC7-amino alkyl and dialkyl (C C7) -amino; R10 is independently selected from aryl and heterocyclyl, which may be optionally substituted; R11 is independently selected from hydrogen, unsubstituted or substituted C-C-alkyl, and unsubstituted or substituted aryl; L 2 is selected from a bond, C 1 -C 4 alkylene, d-C 4 alkynyl, C 4 alkenyl, -O-, -S-, -NH-, -C (= O) NH-, -NHC (= O) - , -NHC (= 0) NH-, -SO2NH-, -NHSO2-, -SO2-, -C (= 0) - and -C (= O) O-; R12 is selected from: substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted C3-C8 cycloalkyl; m is 0, 1 or 2; n is independently selected from 0, 1, 2, 3 and 4; p is 0, 1 or 2, with the proviso that the sum of the variables m and p is not greater than 2; q is 1, 2, 3 or 4; or a stereoisomer or a pharmaceutically acceptable salt thereof.

An additional embodiment refers to compounds represented by Formula III: where XesCHoN; and the remaining substituents and variables are as defined above in Formula II, or a stereoisomer or a pharmaceutically acceptable salt thereof. A further embodiment of the invention is a compound of Formula III, wherein AesCR12, C (O), NR1auO; BesCR12, NR1aoC (O); DesCR12oNR1a; E is a link, CR12 or C (O); and the remaining substituents and variables are as defined above in Formula III, a stereoisomer or a pharmaceutically acceptable salt thereof.

The specific embodiments representing non-limiting examples of the compounds of the present invention are provided in the Experimental Section shown hereinafter. Specific examples of the compounds of the present invention include:? / - (2-Aminophenyl) -6- (4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) nicotinamide; ? / - (2-aminophenyl) -6- (7-benzyl-2,7-diazaspiro [4.4] non-2-yl) nicotynamide; 7- (5- { [(2-aminophenyl) amino] carbonyl} pyridin-2-yl) -? / - phenyl-1-oxa-2,7-diazaspiro [4.4] non-2-en- 3-carboxamide; ? / - (2-aminophenyl) -6- [3- (4-fluorobenzyl) -2-oxo-1-oxa-8-azaspiro [4.5] dec-8-yl] nicotinamide; ? / - (4-Aminobiphenyl-3-yl) -6- (4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) nicotinamide; 7- (5- { [(4-aminobiphenyl-3-yl) amino] carbonyl} pyridin-2-yl) -? / - (2-phenylethyl) -1 -oxa-2,7-diazaspiro [ 4.4] non-2-en-3-carboxamide; 6- (7-acetyl-2,7-diazaspiro [4.4] non-2-yl) -? / - (4-aminobiphenyl-3-yl) nicotynamide; ? / - [2-Amino-5- (2-thienyl) phenyl] -6- (2,8-diazaspiro [4.5] dec-8-yl) nicotinamide; 6- (2-Acetyl-2,7-diazaspiro [4.5] dec-7-yl) -? / - [2-amino-5- (2-thienyl) phenyl] -nicotinamide; 7- (5- { [(4-aminobiphenyl-3-yl) amino] carbonyl}. Pihdin-2-yl) -? / - ethyl-2,7-diazaspiro [4.5] decane-2-carboxamide; ? / - [2-Amino-5- (2-thienyl) phenyl] -6- (4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) nicotinamide; 6- (7-acetyl-2,7-diazaspiro [4.4] non-2-yl) -? / - [2-amino-5- (2-thienyl) phenyl] nicotinamide; ? / - [2-Amino-5- (2-thienyl) phenyl] -6- (2-oxo-1-oxa-3,8-diazaspiro [4.5] dec-8-yl) nicotinamide; ? / - [2-amino-5- (2-thienyl) phenyl] -6- (3-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] dec-8-yl) nicotinamide; ? / - [2-amino-5- (2-thienyl) phenyl] -6- (2-oxo-1-oxa-3,8-diazaspiro [4.5] dec-8-yl) nicotinamide; ? / - (4-aminobiphenyl-3-yl) -6- (3-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] dec-8-yl) nicotinamide; ? / - (4-aminobiphenyl-3-yl) -6- (2-oxo-1-oxa-3,8-diazaspiro [4.5] dec-8-yl) nicotinamide; ? / - [2-Amino-5- (2-thienyl) phenyl] -6- (1, 8-diazaspyrro [4.5] dec-8-yl) nicotinamide; ? / - (4-Amino-1-phenyl-1-1 / - / - pyrazol-3-yl) -6- (4-oxo-1-phenyl-1,3,8-triazaspiro- [4.5] dec- 8-yl) nicotinamide; 6- (7-acetyl-2,7-diazaspiro [4.4] non-2-yl) -? / - (4-amino-1-phenyl-1 H -pyrazol-3-yl) nicotinamide; ? / - [4-amino-1 - (3-chlorophenyl) -1 / - / -pyrazol-3-yl-4- (2-8-diaza-spiro) -4.5 -8-de-8-yl-nicotinamide; 8- (5- { [(4-Aminobiphenyl-3-yl) amino) carbonyl} pyridin-2-yl) -? / 3-phenyl-? / 2- (2-phenylethyl) -2,8-diazaspiro [4.5] decane-2,3-dicarboxamide; 8- (5- { [(4-Aminobiphenyl-3-yl) amino] carbonyl} pyridin-2-yl) -? / - (2-phenylethyl) -1-oxa-2,8-diazaspiro [ 4.5] dec-2-en-3-carboxamide; 6- (2-acetyl-2,8-diazaspiro [4.5] dec-8-yl) -? / - [2-amino-5- (2-thienyl) phenyl] -nicotinamide; ? / - (4-aminobiphenyl-3-yl) -6-. { 2 - [(2,4-dimethyl-1,3-thiazol-5-yl) sulfonyl] -2,8-diazaspiro [4.5] dec-8-yl} nicotinamide; 8- [5- ( { [2-amino-5- (2-thienyl) phenyl] amino} carbonyl) pyridin-2-yl] -N- (2-phenylethyl) -2,8-diazaspiro [ 4.5] decane-2-carboxamide; ? / - (2-aminophenyl) -6-. { 3- [2- (methylamino) -2-oxoethyl] -4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl} nicotinamide; ? / - (2-aminophenyl) -6- [3- (2-anilino-2-oxoethyl) -4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl] nicotinamide; ? / - (2-aminophenyl) -6- [3- (1H-benzimidazol-2-ylmethyl) -4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl] nicotinamide; 8- [5- ( { [2-Amino-5- (2-tethenyl) pheny] amino} carbonyl) pyridin-2-yl] -? / - ethyl-1, 8-diazaspiro [4.5] decane-1-carboxamide; ? / - (4-Aminob-phenyl-3-yl) -6- (7-pyrimidin-2-yl-2,7-diazaspiro [4.4] non-2-yl) nicotinamide; ? / - (4-aminobiphenyl-3-yl) -6- [7- (phenylsulfonyl) -2,7-diazaspiro [4.4] non-2-yl] nicotinamide; 7- (5- { [(4-aminobiphenyl-3-yl) amino] carbonyl}. Pyridin-2-yl) -? / - [(1 S) -1-phenylethyl] -2,7-diazaspiro [4.4] nonan-2-carboxamide; 7- (5- { [(2-Aminophenyl) amino] carbonyl} pyridin-2-yl) -2,7-diazaspiro [4.4] nonan-2-carboxylate of pyridin-3-ylmethyl; ? / - (2-aminophenyl) -6- (7-benzoyl-2,7-diazaspiro [4.4] non-2-yl) nicotinamide; ? / - (2-aminophenyl) -6- [7- (4-methoxybenzyl) -2,7-diazaspiro [4.4] non-2-yljnicotinamide; 8- (5- { [(2-aminophenyl) amino] carbonyl} pyridin-2-yl) -? / - (4-fluorophenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide; ? / - (2-aminophenyl) -6- [7- (quinolin-8-ylsulfonyl) -2,7-diazaspiro [4.4] non-2-yl] nicotinamide; ? / - (2-aminophenyl) -6-. { 7 - [(2,4-dimethyl-1,3-thiazol-5-yl) sulfonyl] -2,7-diazaspiro [4.4] non-2-yl} nicotinamide; 8- (5- { [(4-Aminobiphenyl-3-yl) amino] carbonyl}. Pyridin-2-yl) -? / - (2-phenylethyl) -2,8-diazaspiro [4.5] decane- 2-carboxamide; ? / - (4-Aminobiphenyl-3-yl) -4- (1, 8-diazaspiro [4.5] dec-8-ylmethyl) benzamide; ? / - (4-aminobiphenyl-3-yl) -4 - [(4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) methyl] benzamide; ? / - (4-aminobiphenyl-3-yl) -4- (1, 8-diazaspiro [4.5] dec-8-ylcarbonyl) benzamide; ? / - (4- { [(4-aminobiphenyl-3-yl) amino] carbonyl} phenyl) -7-benzyl-2,7-diazaspiro [4.4] nonan-2-carboxamide; ? / - (4- { [(4-aminobiphenyl-3-yl) amino] carbonyl} phenyl) -2,7-diazaspiro [3.5] nonan-7-carboxamide; ? / - (4-Aminobiphenyl-3-yl) -6- (2,8-diazaspiro [4.5] dec-8-yl) -1-benzothiophen-2-carboxamide; ? / - (4-Aminobiphenyl-3-yl) -4- (1, 8-diazaspiro [4.5] dec-8-yl) benzamide; ? / - (2-Amino-5-thien-2-ylphenyl) -2- (4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) -1,3-thiazole -5-carboxamide; 7- (5- { [(2-Aminophenyl) amino] carbonyl} pyridin-2-yl) -2,7-diaza-spiro [3.5] nonan-2-carboxylate of re-butyl; 7- (5- { [(2-Aminophenyl) amino] carbonyl} pyridin-2-yl) -2,7-diazaspiro- [3.5] nonan-2-carboxylic acid benzyl ester; ? / - [2-Amino-5- (2-thienyl) phenyl] -6- (2,7-diazaspiro [3.5] non-7-yl) nicotinamide; or a stereoisomer or a pharmaceutically acceptable salt thereof.

Chemical Definitions As used herein, "alkyl" is intended to include straight and branched chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, it is defined that d-do, as in "C1-C10 alkyl", includes groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear or branched organization. For example, "alkyl d-do" specifically includes methyl, ethyl, n-propyl, / -propyl, n-butyl, f-butyl, / -butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on. . The term "cycloalkyl" means a saturated, aliphatic, monocyclic hydrocarbon group having the specified number of carbon atoms. The cycloalkyl is optionally linked (ie, forming a bicyclic moiety), for example with a methylene, ethylene or propylene bond. The link may be optionally substituted or branched. The cycloalkyl can be fused with an aryl group such as phenyl, and it is understood that the cycloalkyl substituent is linked by the cycloalkyl group. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on. In one embodiment of the invention, the term "cycloalkyl" includes the groups described just above and further includes hydrocarbon, aliphatic, unsaturated, monocyclic groups. For example, "cycloalkyl" as defined in this embodiment includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl, and so forth. In one embodiment, if the number of carbon atoms is not specified, "alkyl" refers to alkyl d-d2 and in a further embodiment, "alkyl" refers to Ci-Ce alkyl. In one embodiment, if the number of carbon atoms is not specified, "cycloalkyl" refers to C3-do cycloalkyl and in a further embodiment, "cycloalkyl" refers to C3-C7 cycloalkyl. In one embodiment, examples of "alkyl" include methyl, ethyl, n-propyl, / -propyl, n-butyl, f -butyl and / -butyl. The term "alkylene" means a hydrocarbon diradical group having the specified number of carbon atoms. For example, "alkylene" includes -CH2-, -CH2CH2- and the like. In one embodiment, if the number of carbon atoms is not specified, "alkylene" refers to alkylene d-C 2 and in a further embodiment, "alkylene" refers to C 6 alkylene. When used in the expressions "alkylaryl", "alkylcycloalkyl" and "alkylheterocyclyl" the term "alkyl" refers to the alkyl portion of the moiety and does not describe the number of atoms in the aryl and heteroaryl moiety of the moiety. In one embodiment, if the number of carbon atoms is not specified, the "alkyl" of "alkylaryl", "alkylcycloalkyl" and "alkylheterocyclyl" refers to CC? 2 alkyl and in a further embodiment, the expression refers to alkyl d-C6. If the number of carbon atoms is not specified, the term "alkenyl" refers to a non-aromatic hydrocarbon radical, linear, branched or cyclic, containing 2 to 10 carbon atoms and at least one carbon-carbon double bond. Preferably, a carbon-to-carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. In this manner, "C2-C6 alkenyl" means an alkenyl radical having from 2 to 6 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The linear, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated. The term "alkynyl" refers to a linear, branched or cyclic hydrocarbon radical containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three triple carbon-carbon bonds can be present. In this manner, "C2-C6 alkynyl" means an alkynyl radical having from 2 to 6 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl and so on. The linear, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated. In certain cases, the substituents can be defined with a range of carbons that include zero, such as (C0-C6) alkylene-aryl. If aryl is taken as phenyl, this definition would include phenyl by itself as well as -CH2Ph, -CH2CH2Ph, CH (CH3) CH2CH (CH3) Ph, and so on. In one embodiment, as used herein, "aryl" is intended to mean any stable, monocyclic or bicyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphtyl, tetrahydronaphthyl, indanyl and biphenyl. In the cases in which the aryl substituent is bicyclic and a ring is non-aromatic, it is understood that the connection is made by the aromatic ring.

In another embodiment, "aryl" is an aromatic ring of 5 to 14 carbon atoms, and includes a carbocyclic aromatic group fused with a 5- or 6-membered cycloalkyl group such as indane. Examples of carbocyclic aromatic groups include, but are not limited to, phenyl, naphthyl, eg, 1-naphthyl and 2-naphthyl; anthracenyl, for example, 1-anthracenyl, 2-anthracenyl; phenanthrenyl; fluorenonyl, for example, 9-fluorenonyl, indanyl and the like. A carbocyclic aromatic group is optionally substituted with the indicated number of substituents, described below. The term "heteroaryl," as used herein, represents a stable, monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains 1 to 4 heteroatoms selected from the group consisting of O, N and S. In another embodiment, the term "heteroaryl" refers to an aromatic, monocyclic, bicyclic or tricyclic ring, of 5 to 14 carbon atoms in the ring and of one to four heteroatoms selected from O, N or S. The groups heteroaryl within the scope of this definition include but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline. As with the definition of heterocycle shown below, it is understood that "heteroaryl" also includes the? / -oxide derivative of any nitrogen-containing heteroaryl. In the cases in which the heteroaryl substituent is bicyclic and a ring is non-aromatic or does not contain heteroatoms, it is understood that the binding is carried out by the aromatic ring or by the ring containing heteroatoms, respectively. In another embodiment, "heteroaryl" is a monocyclic aromatic ring, bicyclic or tricyclic 5 to 14 carbon atoms in the ring and one to four heteroatoms selected from O, N or S. Examples of heteroaryl include, but are not limited pyridyl, for example, 2-pyridyl (also called α-pyridyl), 3-pyridyl (also called β-pyridyl) and 4-pyridyl (also referred to as (D-pyridyl); thienyl, for example, 2-thienyl and 3-pyridyl; thienyl; furanyl, e.g. 2-furanyl and 3-furanyl; pyrimidyl, e.g., 2-pyrimidyl and 4-pyrimidyl; imidazolyl, e.g., 2-imidazolyl; pyranyl, e.g., 2-pyranyl and 3-pyranyl; pyrazolyl, e.g., 4-pyrazolyl and 5-pyrazolyl; thiazolyl, e.g., 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; thiadiazolyl; isothiazolyl; oxazolyl, e.g., 2-oxazolyl, 4-oxazolyl and 5-oxazolyl isoxazolyl, pyrrolyl, pyridazinyl, pyrazinyl and the like The heterocyclic aromatic (or heteroaryl) groups as defined previously, they may be optionally substituted with the indicated number of substituents, as described below for aromatic groups. In one embodiment, "heteroaryl" may also include a "condensed polycyclic aromatic", which is a heteroaryl fused with one or more heteroaryl rings or non-aromatic heterocyclics. Examples include quinolinyl and isoquinolinyl, e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl and 8-quinolinyl, 1- isoquinolinyl, 3-quinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl and 8-isoquinolinyl; benzofuranyl, for example, 2-benzofuranyl and 3-benzofuranyl; dibenzofuranyl, for example, 2,3-dihydrobenzofuranyl; dibenzothiophenyl; benzothienyl, for example, 2-benzothienyl and 3-benzothienyl; indolyl, for example, 2-indolyl and 3-indolyl; benzothiazolyl, for example, 2-benzothiazolyl; benzooxazolyl, for example, 2-benzooxazolyl; benzimidazolyl, for example, 2-benzoimidazolyl; isoindolyl, for example, 1-isoindolyl and 3-isoindolyl; benzotriazolyl; purinyl; tianaphtenyl, pyrazinyl and the like. The aromatic, polycyclic, fused ring systems may be optionally substituted with the indicated number of substituents, as described herein. The term "heterocycle" or "heterocyclyl" as used herein is meant to indicate an aromatic or non-aromatic heterocycle of 3 to 10 members containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes groups bicyclic A non-aromatic heterocycle may be fused with an aromatic aryl group such as phenyl or aromatic heterocycle. Thus, "heterocyclyl" includes the heteroaryls mentioned above, as well as dihydro and tetrahydro analogs thereof. Other examples of "heterocyclyl" include, but are not limited to, the following: azetidinyl, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl , isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, napthpyridinyl, oxadiazolyl, oxazolyl, oxazolyl, oxazolino, soxazolino, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl , Dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydro, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihyrothienyl, dihydrotriazolyl, dihydroazetidinyl, rnetilenodioxibenzoílo, tetrahydrofuranyl and tetrahydrothienyl, and / - oxides thereof. The binding of a heterocyclyl substituent can be carried out by a carbon atom or by a heteroatom. In one embodiment, "heterocycle" (also referred to herein as "heterocyclyl"), is a monocyclic, bicyclic or tricyclic, saturated or unsaturated ring, having 5 to 14 carbon atoms in the ring and one to four heteroatoms selected from O , N, S or P. examples of heterocyclic rings include, but not limited to: pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl, piperazinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahidrodropiranilo, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, dihydropyrazinyl, tetrahydropyrazinyl, dihydropyridyl, tetrahydropyridyl and the like. An "alkylaryl group" (arylalkyl) is an alkyl group substituted with an aromatic group, preferably a phenyl group. A preferred alkylaryl group is a benzyl group. Suitable aromatic groups are described herein and suitable alkyl groups are described herein. Suitable substituents for an alkylaryl group are described herein. An "alkylheterocyclyl group" is an alkyl group substituted with a heterocyclyl group. Suitable heterocyclyl groups are described herein and suitable alkyl groups are described herein. Suitable substituents for an alkylheterocyclyl group are described herein. An "alkylcycloalkyl group" is an alkyl group substituted with a cycloalkyl group. Suitable cycloalkyl groups are described herein and suitable alkyl groups are described herein. Suitable substituents for an alkylcycloalkyl group are described herein. An "aryloxy group" is an aryl group that is attached to a compound by oxygen (e.g., phenoxy). An "alkoxy group" (alkyloxy), as used herein, is a C 1 -C 12 straight or branched chain or C 3 -C 12 cyclic alkyl group that is connected to a compound by an oxygen atom. Examples of alkoxy groups include but are not limited to methoxy, ethoxy and propoxy. An "arylalkoxy group" (arylalkyloxy) is an arylalkyl group that is linked to a compound by an oxygen on the alkyl portion of the arylalkyl (e.g., phenylmethoxy). An "arylamino group" as used herein, is an aryl group that is attached to a compound by a nitrogen. As used herein, an "arylalkylamino group" is an arylalkyl group that is linked to a compound by a nitrogen on the alkyl portion of the arylalkyl. An "alkylsulfonyl group" as used herein, is an alkyl group that is linked to a compound by the sulfur of a sulfonyl group. As used herein, many residues or groups are indicated as "substituted or unsubstituted." When a residue is said to be substituted, this means that any portion of the remainder that is known to one skilled in the art as available for substitution may be substituted. The term "optionally substituted with one or more substituents" means a substituent, two substituents, three substituents, four substituents or five substituents. For example, the substitutable group can be a hydrogen atom that is replaced by a group other than hydrogen (ie, a substituent group). Multiple substituent groups may be present. When multiple substituents are present, the substituents may be the same or different and the substitution may be at any of the substitutable sites. Such substitution means are well known in the art. For purposes of exemplification, which should not be construed as limitations on the scope of this invention, some examples of groups that are substituents are: alkyl groups (which may also be substituted, with one or more substituents), alkoxy groups (which may be substituted) , a halogen group or halo (F, Cl, Br, I), hydroxy, nitro, oxo, -CN, -COH, -COOH, amino, azido,? / - alkylamino or? /,? / - dialkylamino (where the alkyl groups can also be substituted),? / - arylamino or N, N-diarylamino (where the aryl groups can also be substituted), esters (-C (O) -OR, where R can be a group such as alkyl, aryl , etc., which may be substituted), ureas (-NHC (O) -NHR, where R may be a group such as alkyl, aryl, etc., which may be substituted), carbamates (-NHC (O) -OR , wherein R may be a group such as alkyl, aryl, etc., which may be substituted), sulfonamides (-NHS (0) 2R, where R may be a group such as alkyl, aryl, etc., which may be star substituted), alkylsulfonyl (which may be substituted), aryl (which may be substituted), cycloalkyl (which may be substituted) alkylaryl (which may be substituted), alkylheterocyclyl (which may be substituted), alkylcycloalkyl (which may be substituted) , and aryloxy. In one embodiment, A is CR12, NR1 a or O. In one embodiment, B is CR12, NR1 a or C (O). In one embodiment, D is CR12 or NR1a. In one mode, E is a link, CR12 or C (O). In a further mode, E is CR12 or C (O). In one embodiment of Formula I or II, one of A, B and D is NR1, and the other two are both CR12; E is CR12 or a link. In one embodiment of the present invention, it is pyridyl, phenyl, benzothiophene or thiazolyl. In one embodiment of the present invention, z) is phenyl or pyrazolyl. In one embodiment, R is NH2.

In one modality, X is CH. In one embodiment, X is N. In one embodiment, L 1 is a bond, C C β alkyl, -C (O) -, - NR 5 C (0) - or -C (0) NR 5 -. In another embodiment, L1 is a bond or C6 alkyl. In another modality, L1 is a link. In one embodiment, R3 is H, unsubstituted or substituted d6alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

In one embodiment, R3 is H, unsubstituted or substituted phenyl or unsubstituted or substituted thienyl. In one embodiment, R3 is phenyl or thienyl, optionally substituted with halo. In one embodiment, R4 is independently selected from H, d-Cß alkyl, aryl and heterocyclyl, wherein the alkyl, aryl or heterocyclyl may be optionally substituted with one or more of R 10, In one embodiment, R 10 is independently selected from aryl and heterocyclyl, which may be optionally substituted with C-alkyl C6, CF3, halo or OR11. In another embodiment, R10 is phenyl, pyridyl, pyrimidinyl, quinolinyl, thiazolyl, naphthyl or benzimidazolyl, wherein said phenyl, pyridyl, pyrimidinyl, quinolinyl, thiazolyl, naphthyl or benzimidazolyl is optionally substituted with d-C6 alkyl, CF3, halo or OR11. In one embodiment, variable q is 1. In a modality of Formula I, A is CR12, NR1a or O; B is CR12 > NR1a or C (O); D is CR12 or NR1a; E is a link, CR12 or C (O); (w) is pyridyl, phenyl, benzothiophene or thiazolyl; ÍZj is phenyl or pyrazolyl riable s is 0, In one embodiment of Formula I, A is CR 2, NR 1a or O; B is CR12, NR1a or C (O); D is CR12 or NR1a; E is a link, CR12 or C (O); (w) is pyridyl, phenyl, benzothiophene or thiazolyl; I Z j? S phenyl or pyrazolyl; and the variable s is 1. In a modality of Formula I, A is CR12, NR1a or O; B is CR12, NR1a or C (O); D is CR12 or NR1a; E is a link; (vv) is pyridyl, phenyl, benzothiophene or thiazolyl; ÍZj is phenyl or pyrazolyl; and the variable s is 0. In a modality of Formula I, A is CR12, NR1a or O; B is CR 2, NR 1a or C (O); D is CR12 or NR1a; E is CR12 or C (O); w) is pyridyl, phenyl, benzothiophene or thiazolyl; (Z is phenyl or pyrazolyl, and the variable s is 1. In one embodiment of Formula II, A is CR12, NR1a or O; B is CR12, NR1a or C (O); D is CR12 or NR1a; E is a link, CR12 or C (O); (w) is pyridyl, phenyl, benzothiophene or thiazolyl; and is phenyl or pyrazolyl. In one embodiment of Formula II, A is NR1a2 or O, B is C (O) or CR12, D is NR1a2 or CR12, and E is CR12. In another embodiment of Formula II, A is NR1a2, B is C (O), D is NR12 and E is CR12. In one embodiment of Formula II, A is O, B is NR1a2, D is CR12, there is a double bond between B and D, and E is CR12. In another embodiment of Formula II, A is O, B is C (O) or CR12, D is CR12 and E is CR12. In one more mode. A is O. B is C (O). D is NR1a2 and E is CR12. In a modality of Formula I or II, p = 0 and m = 1.

In a modality of Formula I or II, p = 1 and m = 1. In a modality of Formula I or II, p = 0 and m = 2. In a modality of Formula I or II, E is a bond.

Stereochemistry Many organic compounds exist in optically active forms that have the ability to rotate the plane of polarized light in the plane. In the description of an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center (s). The prefixes d and 1 or (+) and (-) are used to designate the sign of rotation of the polarized light in the plane by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images not superimposable on one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of said isomers is often referred to as an enantiomeric mixture. A mixture of 50:50 enantiomers is called a racemic mixture. Many of the compounds described herein may have one or more chiral centers and therefore may exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When the bonds to the chiral carbon are represented as straight lines in the Formulas of the invention, it is understood that the (R) and (S) configurations of the chiral carbon, and therefore the enantiomers and mixtures thereof, are encompassed within the formula. As used in the art, when it is desired to specify the absolute configuration around a chiral carbon, one of the bonds to the chiral carbon can be represented as a wedge (bonds to atoms above the plane) and the other can be represented as a series or wedge of short parallel lines (links to atoms below the plane). The Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon. When the HDCA inhibitors of the present invention contain a chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as the 50:50 specific mixture called racemic mixture. The enantiomers can be resolved by methods known to those skilled in the art, such as the formation of diastereomeric salts that can be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001 )); the formation of diastereoisomeric derivatives or complexes that can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of an enantiomer with a specific enantiomer reagent, for example enzymatic esterification; or gas-liquid chromatography or liquids in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be understood that where the desired enantiomer is converted to another chemical entity by one of the separation methods described above, a further step is required to release the desired enetiomeric form Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using reagents, substrates, catalysts or optically active solvents, or converting one enantiomer into the other by asymmetric transformation It is understood that the designation of a specific absolute configuration on a chiral carbon of the compounds of the invention means that the designated enantiomeric form of the compounds is in excess enantiomepco (ee) or in other words is substantially free of the other enantiomer. For example, the "R" forms of the compounds are substantially free of the "S" forms of the compounds and are, therefore, in enantiomeric excess of the "S" forms. Conversely, the "S" forms of the compounds are substantially free of "R" forms of the compounds and are, therefore, in excess enantiomepco of the "R" form. The enantiomeric excess, as used herein, is the presence of a particular enantiomer in more than 50% In a particular embodiment when a specific absolute configuration is designated, the enantiomeric excess of the represented compounds is at least about 90%. When a compound of the present invention has two or more chiral carbons it can have more than two optical isomers and can exist in diastereomeric forms. For example, when there are two chiral carbons, the compound can have up to 4 optical isomers and 2 pairs of enantiomers (( S, S) / (R, R) and (R, S) / (S, R)). The pairs of enantiomers (e.g., (S, S) / (R, R)) are mirror image stereoisomers of one another. Stereoisomers that are not mirror images (e.g., (S, S) and (R, S)) are diastereomers. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair can be separated as described above. The present invention includes each diastereomer of said compounds and mixtures thereof. This invention is also intended to encompass pro-drugs of the compounds of the present invention described herein. A prodrug of any of the compounds can be prepared using well-known pharmacological techniques. This invention, in addition to the compounds listed above, is intended to encompass the use of homologs and analogues of said compounds. In this context, homologs are molecules that have important structural similarities to the compounds described above and analogs are molecules that have important biological similarities without taking into account structural similarities.

Pharmaceutically acceptable salts The compounds of the present invention described herein can, as indicated above, be prepared in the form of their pharmaceutically acceptable salts. The pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not transmit undesirable toxicological effects. Examples of said salts are addition salts of acids, organic and inorganic acids, for example, acid addition salts which can be, for example, hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acid acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid, trifluoroacetic acid, formic acid, phosphoric acid and the like. The pharmaceutically acceptable salts can also be prepared by treatment with inorganic bases, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and organic bases such as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like. The pharmaceutically acceptable salts can also be salts formed from elemental anions such as chlorine, bromine and iodine. The described active compounds can also be prepared, as indicated above, in the form of their hydrates. The term "hydrate" includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like. The described active compounds can also be prepared, as indicated above, in the form of a solvate with any organic or inorganic solvent, for example alcohols such as methanol, ethanol, propanol and isopropanol, ketones such as acetone, aromatic solvents and the like. The described active compounds can also be prepared in any solid or liquid physical form. For example, the compound may be in crystalline form, in amorphous form, and have any particle size. In addition, the particles of the compound can be micronized, or they can be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical form. The compounds of the present invention may also show polymorphism. This invention also includes different polymorphs of the compounds of the present invention. The term "polymorph" refers to a particular crystalline state of a substance, which has physical properties such as X-ray diffraction, IR spectra, melting point, and the like.

PROCESSES OF TREATMENT The invention also relates to methods of using the compounds of the present invention. As demonstrated in this document, the compounds of the present invention are useful for the treatment of cancer. In addition, there is a wide range of other diseases for which substituted nicotinamides may be useful. Non-limiting examples are diseases mediated by thioredoxin (TRX) as described herein, and diseases of the central nervous system (CNS) as described herein. 1. - Cancer Treatment As demonstrated herein, the compounds of the present invention are useful for the treatment of cancer. Accordingly, in one embodiment, the invention relates to a method of treating cancer in a subject in need of treatment comprising administering to said subject a therapeutically effective amount of the compounds of the present invention. The term "cancer" refers to any cancer caused by the proliferation of neoplastic cells, such as solid tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like. In particular, cancers that can be treated by the compounds, compositions and methods of the invention include, but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated microcytic, undifferentiated macrocytic, adenocarcinoma), alveolar carcinoma (bronchiolar), bronchial adenoma, sarcoma, lymphoma, chondromatosis hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small intestine (adenocarcinoma, lymphoma, tumors carcinoids, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transient cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminoma, teratoma, carcinoma) embryonal, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bones: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, chondroid malignant giant cell tumor, osteochondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), neurofibroam of the spinal cord, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumoral cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucosal cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli cell tumors -Leydig, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (carcinoma) ); Hematology: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, carcinoma of basal cells, squamous cell carcinoma, Karposi's sarcoma, moles of dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In this manner, the expression "cancer cell" as provided herein, includes a cell affected by any of the conditions mentioned above. In one embodiment, the present compounds are useful in the treatment of cancers including, but not limited to: leukemias including acute leukemias and chronic leukemias such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) , chronic myelogenous leukemia (CML) and capillary cell leukemia; lymphomas such as cutaneous T-cell lymphomas (CTCL), peripheral non-cutaneous T-cell lymphomas, lymphomas associated with human T-cell lifelike virus (HTLV) such as adult T-cell leukemia / lymphoma (ATLL), Hodgkin and non-Hodgkins lymphoma, large cell lymphomas, diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma; mesothelioma, primary lymphoma of the central nervous system (CNS); multiple myeloma; juvenile solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilm's tumor, bone tumors, and soft tissue sarcomas, solid tumors common to adults such as head and neck cancers (e.g., oral, laryngeal, and esophageal), genito cancers urinary (for exa, prostate, bladder, kidney, uterine, ovarian, testicular, rectal and colon), lung cancer, breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, cancer liver and thyroid cancer. 2. - Treatment of diseases mediated by thioredoxin IRX) In another embodiment, the compounds of the present invention are used in a method for treating a disease or disorder mediated by thioredoxin (TRX) in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of one or more of the compounds of the present invention. Examples of TRX-mediated diseases include, but are not limited to, acute and chronic inflammatory diseases, autoimmune diseases, allergic diseases, diseases associated with oxidative stress, and diseases characterized by cellular hyperproliferation. Non-limiting examples are inflammatory conditions of a joint including rheumatoid arthritis (RA) and psoriatic arthritis; inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including P-mediated T-cell psoriasis) and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (eg, necrotizing, cutaneous, and hypersensitive vasculitis); eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyte infiltration of the skin organs, ischemic injury, including cerebral ischemia (for example, brain injury as a result of trauma, epilepsy, hemorrhage or stroke, each of which can lead to neurodegeneration); HIV, heart failure, chronic liver disease, acute or malignant, autoimmune thyroiditis; systemic lupus erythematosus, Sjorgren's syndrome, pulmonary diseases (eg, ARDS); acute pancreatitis; Amyotrophic lateral sclerosis (ALS); Alzheimer disease; cachexia / anorexia; asthma; atherosclerosis; chronic fatigue syndrome, fever; diabetes (for example, insulin diabetes or juvenile onset diabetes); glomerulonephritis; rejection of graft versus host (for example, in transplants); hemorrhagic shock; hyperalgesia: inflammatory bowel disease; multiple sclerosis; myopathies (eg, metabolism of muscle proteins, esp in sepsis); osteoporosis; Parkinson's disease; pain; premature birth; psoriasis; reperfusion injury; cytokine-induced toxicity (eg, septic shock, endotoxic shock); side effects of radiation therapy, disease of the temporal joint of the jaw, tumor metastasis; or an inflammatory condition resulting from tension, twisting, damage to the cartilage, trauma such as burns, orthopedic surgery, infection or other disease processes. Allergic diseases and conditions, include but are not limited to allergic respiratory diseases such as asthma, allergic rhinitis, pulmonary hypersensitivity diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffier's syndrome, chronic eosinophilic pneumonia), delayed-type hypersensitivity, diseases interstitial lung disease (ILD) (eg, idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis, or dermatomyositis); sistinemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), allergies to insect bites, and the like. 3. - Treatment of diseases of the central nervous system (CNS) In another embodiment, the compounds of the present invention are used in a method for treating a disease of the central nervous system in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any one or more of the compounds of the present invention. In a particular embodiment, CNS disease is a neurodegenerative disease. In a further embodiment, neurodegenerative disease is a hereditary neurodegenerative disease, such as hereditary neurodegenerative diseases that are polyglutamine expansion diseases. Generally, neurodegenerative diseases can be grouped as follows: I. Disorders characterized by progressive dementia in the absence of other prominent neurological signs, such as Alzheimer's; Senile dementia of the Alzheimer type; and Pick's disease (lobar atrophy). II. Syndromes that combine progressive dementia with other prominent neurological abnormalities such as A) syndromes that appear mainly in adults (eg, Huntington's disease, Multiple systemic atrophy combining dementia with ataxia and / or manifestations of Parkinson's disease, Progressive supranuclear palsy (Steel -Richardson-Olszewski), diffuse Lewy disease, and corticodentatonigral degeneration); and B) syndromes that appear mainly in children or young adults (eg, Hallervorden-Spatz disease and progressive familial myoclonic epilepsy). III. Syndromes that gradually develop postural and movement abnormalities such as agitans paralysis (Parkinson's disease), striatonigral degeneration, progressive supranuclear palsy, torsion dystonia (torsion spasms, dystonia musculorum deformans), spasmodic torticollis and other dyskinesias, familial tremor, and syndrome of Gilíes de la Tourette. IV. Progressive ataxia syndromes such as cerebellar degenerations (eg, cortical cerebellar degeneration and olivopontocerebellar atrophy (OPCA)); and spinocerebellar degeneration (Friedreich's ataxia and related disorders). V. Syndrome of failure of the central autonomic nervous system (Shy-Drager syndrome). SAW. Syndromes of muscle weakness and loss without sensory changes (motor neuron disease such as amyotrophic lateral sclerosis, spinal muscular atrophy (eg, childhood spinal muscular atrophy (Werdnig-Hoffman), juvenile spinal muscular atrophy (Wohlfart-Kugelberg-Welander) and other forms of familial spinal muscular atrophy), primary lateral sclerosis, and hereditary spastic paraplegia, syndromes that combine weakness and muscle loss with sensory changes (progressive neural muscle atrophy, chronic familial polyneuropathies) such as peroneal muscle atrophy (Charcot-Marie-Tooth), Hypertrophic interstitial polyneuropathy (Dejerine-Sottas), and miscellaneous forms of chronic progressive neuropathy VIII Syndromes of progressive visual loss such as pigeon-hole degeneration of the retina (retinitis pigmentosa), and hereditary optic atrophy (Leber's disease).

Definitions: The term "treating" in its various grammatical forms in relation to the present invention refers to preventing (ie, chemoprevention), curing, reversing, attenuating, alleviating, minimizing, suppressing or arresting the detrimental effects of a disease state. , the development of the disease, causative agent of the disease (eg, bacteria or virus) or other abnormal condition. For example, the treatment may involve alleviating a symptom (ie, not necessarily all symptoms) of a disease or attenuating the progression of a disease. Since some of the methods of the invention involve the physical removal of the etiologic agent, the skilled artisan will appreciate that they are equally effective in situations where the compound of the invention is administered prior to, or simultaneously with, exposure to the etiologic agent (treatment prophylactic) and situations where the compounds of the invention are administered after (even much later) exposure to the etiologic agent. Cancer treatment, as used herein, refers to partially or totally inhibiting, delaying or preventing the progression of cancer including cancerous metastasis; inhibit, delay or prevent the recurrence of cancer including cancerous metastasis; or preventing the onset or development of cancer (chemoprevention) in a mammal, for example a human being.

As used herein, the term "therapeutically effective amount" is intended to encompass any amount that will achieve the desired therapeutic or biological effect. The therapeutic effect depends on the disease or disorder treated or the desired biological effect. As such, the therapeutic effect may be a decrease in the severity of the symptoms associated with the disease or disorder and / or inhibition (partial or complete) of the development of the disease. The amount needed to elicit the therapeutic response can be determined based on the age, health, size and sex of the subject. The optimal amounts can also be determined based on the control of the response of the subject to the treatment. In the present invention, when the compounds are used to treat or prevent cancer, the desired biological response is partial or total inhibition, retardation or prevention of cancer progression including cancer metastasis; inhibition, delay or prevention of cancer recurrence including cancerous metastasis; or the prevention of the appearance or development of cancer (chemoprevention) in a mammal, for example a human being. Further, in the present invention, when the compounds are used to treat and / or prevent diseases and conditions mediated by thioredoxin (TRX), a therapeutically effective amount is a regulating amount, for example, it increases, decreases, or maintains a physiologically level. of TRX in the subject in need of treatment to elicit the desired therapeutic effect. The therapeutic effect depends on the disease or condition mediated by specific TRX treated. As such, the therapeutic effect may be a decrease in the severity of the symptoms associated with the disease or disorder and / or inhibition (partial or complete) of the development of the disease or diseases. In addition, a therapeutically effective amount may be an amount that inhibits histone deacetylase. In addition, a therapeutically effective amount may be an amount that selectively induces terminal differentiation, arrest of cell growth and / or apoptosis of neoplastic cells, or an amount that induces terminal differentiation of tumor cells. The method of the present invention is intended for the treatment or chemoprevention of human patients with cancer. However, it is also likely that the treatment was effective in the treatment of cancer in other subjects. "Subject," as used herein, refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice or other bovine, ovine, equine, canine, feline, rodent or murine species.

Histone deacetylases and histone deacetylase inhibitors As demonstrated herein, the compounds of the present invention show improved activity as inhibitors of histone deacetylase (HDCA). Accordingly, in one embodiment, the invention relates to a method for inhibiting histone deacetylase activity comprising contacting the histone deacetylase with an effective amount of one or more of the compounds of the present invention. Histone deacetylases (HDAC), as this term is used herein, are enzymes that catalyze the removal of acetyl groups from lysine residues at the amino terminal ends of the histones of the nucleosomal nucleus. As such, HDAC together with histone acetyl transferases (HAT) regulate the histone acetylation state. Acetylation of histone acetilation affects gene expression and HDAC inhibitors, such as hybrid poar compound based on hydroxamic acid suberoylanilide hydroxamic acid (SAHA) induce growth arrest, differentiation and / or apoptosis of cells transformed in vitro and inhibit tumor growth in vivo. HDACs can be divided into three classes based on structural homology. HDAC class I (HDAC 1, 2, 3 and 8) have similarity with the yeast RPD3 protein, are located in the nucleus and are found in complexes associated with transcriptional co-repressors. The HDAC class II (HDAC 4, 5, 6, 7 and 9) are similar to the HDA1 protein of yeast, and have both nuclear and subcellular cytoplasmic localization. The HDACs of the two classes I and II are inhibited by HDCA inhibitors based on hydroxamic acid, such as SAHA. Class III HDACs form a class of structurally distant NAD-dependent enzymes that are related to yeast SIR2 proteins and are not inhibited by HDCA inhibitors based on hydroxamic acid.

Histone deacetylase inhibitors or HDCA inhibitors, as this expression is used herein, are compounds that are capable of inhibiting histone deacetylation in vivo, in vitro, or both. As such, HDCA inhibitors inhibit the activity of at least one histone deacetylase. As a result of inhibiting the deacetylation of at least one histone, an increase in the acetylated histone occurs and the accumulation of acetylated histone is a suitable biological marker to evaluate the activity of the HDCA inhibitors. Therefore, procedures that evaluate the accumulation of acetylated histones can be used to determine the HDCA inhibitory activity of the compounds of interest. It is understood that compounds that can inhibit the activity of histone deacetylase can also bind to other substrates and as such can inhibit other biologically active molecules such as enzymes. It will also be understood that the compounds of the present invention are capable of inhibiting any of the histone deacetylases shown above, or any other histone deacetylase. For example, in patients receiving HDCA inhibitors, the accumulation of acetylated histones in peripheral mononuclear cells as well as in tissue treated with HDCA inhibitors can be determined against adequate control. The HDAC inhibitory activity of a particular compound can be determined in vitro using, for example, an enzyme assay showing the inhibition of at least one histone deacetylase. In addition, the determination of the accumulation of acetylated histones in cells treated with a particular composition can be determinant of the HDCA inhibitory activity of a compound. Assays for the accumulation of acetylated histones are well known in the literature. See, for example, Marks, P.A. et al., J. Nati. Cancer Inst., 92: 1210-1215, 2000, Butler, L.M. et al., Cancer Res. 60: 5165-5170 (2000), Richon, V. M. et al., Proc. Nati Acad. Sci., USA, 95: 3003-3007, 1998, and Yoshida, M. et al., J. Biol. Chem., 265: 17174-17179, 1990. For example, an enzymatic assay for determining the activity of an HDAC inhibitor compound can be carried out in the following manner. In summary, the effect of an HDAC inhibitor compound on HDAC1 labeled with a purified affinity human epitope (Flag) can be assayed by incubating the enzyme preparation in the absence of substrate on ice for about 20 minutes with the indicated amount of inhibitor compound. The substrate (histone obtained from [3 H] acetyl-labeled mouse erythroleukemic cells) can be added and the sample can be incubated for 20 minutes at 37 ° C in a total volume of 30 μl. The reaction can then be stopped and the released acetate can be extracted and the amount of radioactivity release can be determined by scintillation counting. An alternative assay useful for determining the activity of an HDAC inhibitor compound is the "HDAC Fluorescence Activity Assay"; Drug Discovery Kit-AK-500"available from BIOMOL Research Laboratories, Inc., Plymouth Meeting, Pa. In vivo studies can be carried out in the following manner: Animals, for example, mice, can be injected intraperitoneally with an HDAC inhibitor compound The selected tissues, for example, brain, spleen, liver, etc., can be isolated at predetermined times after administration.The histones can be isolated from tissues essentially as described by Yoshida et al. , J. Biol. Chem. 265: 17174-17179, 1990. Equal amounts of histones (approximately 1 μg) can be electrophoresed on 15% SDS-polyacrylamide gels and can be transferred to Hybond-P filters (available from Amersham The filters can be blocked with 3% milk and can be probed with an anti-histone acetylated rabbit polyclonal purified antibody H4 (aAc-H4) and acetylated anti-histone antibody H3 (aAc-H3) (Upstate Biotechnology, Inc. Acetylated histone levels can be visualized using a goat anti-rabbit antibody conjugated with horseradish peroxidase (1: 5000) and the SuperSignal chemiluminescent substrate (Pierce). Parallel gels can be run as a control load for the histone protein, and stained with Coomassie Blue (CB). In addition, HDCA inhibitors based on hydroxamic acid have been shown to positively regulate the expression of the p21WAF1 gene. The p21WAF1 protein is induced in 2 hours of culture with HDCA inhibitors in various transformed cells using conventional methods. Induction of the p21W? M gene is associated with accumulation of acetylated histones in the chromatin region of this gene. The induction of p21WAF1 can therefore be recognized as being involved in the arrest of the G1 cell cycle caused by HDCA inhibitors in transformed cells Combination Therapy The compounds of the present invention can be administered alone or together with other therapies suitable for the treated disease or disorder. When separate dosage formulations are used, the compounds of the present invention and the other therapeutic agent can be administered essentially at the same time. (concurrently) or at separate times stepwise (sequentially) It is understood that the pharmaceutical combination includes all of these regimens Administration in these various forms is suitable for the present invention as long as the patient notices the beneficial therapeutic effect of the compounds of the present invention invention and the other therapeutic agent substantially at the same time In one embodiment, said beneficial effect is achieved when the target concentrations in blood of each active drug are substantially maintained at the same time. The present compounds may also be useful together with Therapeutic compounds known and anti-cancer agents. For example, the present compounds are useful in conjunction with known anti-cancer agents. Combinations of the compounds described herein with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by VT Devita and S. Hellman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person skilled in the art would be able to distinguish which combinations of agents would be useful based on the particular characteristics of the drugs and cancer involved. Such anti-cancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic / cytostatic agents, antiproliferative agents, prenyl protein transferase inhibitors, HMG inhibitors -CoA reductase and other inhibitors of angiogenesis, inhibitors of cell proliferation and survival signaling, apoptosis-inducing agents, agents that alter the control points of the cell cycle, agents that alter tyrosine kinase (RTK) receptors and cancer vaccines. The present compounds are particularly useful when co-administered with radiation therapy. In one embodiment, the present compounds may also be useful in conjunction with known anti-cancer agents including the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl inhibitors transferase protein, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors. "Estrogen receptor modulators" refers to compounds that prevent or inhibit the binding of estrogens to the receptor, regardless of the mechanism. Examples of estrogen receptor modulators include, but are not limited to, diethylstibestral, tamoxifen, raloxifene, idoxifen, LY353381, LY117081, toremifene, fluoximester, ifulvestrant, 4- [7- (2,2-dimethyl-1-oxopropoxy-4-methyl. -2- [4- [2- (1-piperidinyl) ethoxy] phenyl] -2H-1-benzopyran-3-yl] -phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl -hydrazone, and SH646. Other hormonal agents include: aromatase inhibitors (eg, aminoglutethimide, anastrozole, and tetrazole), luteinizing hormone-releasing hormone (LHRH) analogs, ketoconazole, goserelin acetate, leuprolide, megestrol acetate, and mifepristone "androgen receptor modulators" refers to compounds that prevent or inhibit the binding of androgens to the receptor, regardless of the mechanism Examples of androgen receptor modulators include finasteride and other 5a-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate. "Retinoid receptor modulators" refers to compounds that prevent or inhibit the binding of retinoids to the receptor, regardless of the mechanism. Examples of said retinoid receptor modulators include bexarotene, tretinoin, 13-c / s-retinoic acid, 9-cis-retinoic acid, α-difluoromethyl-ornithine, ILX23-7553, frans-N- (4'-hydroxyphenyl) ) retinamide, and N-4-carboxyphenyl retinamide. "Cytotoxic / cytostatic agents" refers to compounds that cause cell death or inhibit cell proliferation mainly by directly preventing cell function or inhibit or prevent cellular mitosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia-activatable compounds, agents microtubule inhibitors / microtubule stabilizers, inhibitors of mitotic kinetics, histone deacetylase inhibitors, inhibitors of kinases involved in mitotic development, antimetabolites; biological response modifiers; hormonal / anti-hormonal therapeutic agents, hematopoietic growth factors, therapeutic agents directed by monoclonal antibodies, topoisomerase inhibitors, proteasome inhibitors and ubiquitin ligase inhibitors. Examples of cytotoxic agents include, but are not limited to, sertenef, cachectin, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine, streptozocin, tasonermin, lonidamine, carboplatin, altretamine, dacarbazine, procarbazine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosylate, trofosfamide, nimustine, dibrospide chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulvene, dexiphosphamide, c / s-aminadichloro ( 2-methyl-pyridine) platinum, benzylguanine, glufosfamide, GPX100, tetrachloride (trans, trans, frans) -b / s-n7- (hexane-1,6-diamine) -n7í7- [diamine-platinum (ll)] b / s [diamine (chloro) platinum (II)], diarizidinilspermina, arsenic trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3,7-dimethylxanthine, zorubicin, doxorubicin, daunorubicin, idarubicin, anthracenedione, bleomycin,mitomycin C, dactinomycin, plicatomicina, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN10755, and 4- demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see WO 00/50032). An example of a compound that can be activated by hypoxia is tirapazamine. Examples of proteasome inhibitors include but are not limited to lactacystin and bortezomib. Examples of microtubule inhibitors / microtubule stabilizers include vincristine, vinblastine, vindesine, vinzolidine, vinorelbine, vindesine sulfate, 3 ', 4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, podophyllotoxins (e.g., etoposide ( VP-16) and teniposide (VM-26)), paclitaxel, docet, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, criptofycina, 2,3,4,5,6-pentafluoro-? / - (3-fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrovinblastine,? /,? / - dimethyl- / _- valyl- _ -valon -? / - methyl-L-valyl-L-prolyl-L-proline t-butylamide, TDX258, the epothilones (see for example U.S. Patent Nos. 6,284,781 and 6,288,237) and BMS188797. Some examples of topoisomerase inhibitors topotecan, hicaptamina, irinotecan, rubitecano, 6-etoxipropionil-3 ', 4'-0-exo-benzylidene-chartreusina, 9-methoxy -? /,? / - dimethyl-5-nitropyrazole [3 , 4,5-kl] acridin-2- (6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzotde piranß ' BJJ-indolizinp ^^ ^ blquinolin-I O. I SÍTH.I SHJdiona, lurtotecan, 7- [2 - (/ - isopropylamino) ethyl] - (20S) camptothecin, BNP 350, BNPI1100, BN80915, BN80942, etoposide phosphate , teniposide, sobuzoxane, 2'-dimethylamino-2'-deoxy-etoposide, GL331,? / - [2- (dimethylamino) ethyl] -9-hydroxy-5,6-dimethyl-6H-pyrido [4, 3-b] carbazole-1-carboxamide, asulacrine, (5a, 5aB, 8aa, 9b) -9- [2 - [? / - [2- (dimethylamino) ethyl] -? / - methylamino] ethyl] -5- [4-hydroxy-3,5-dimethoxyphenyl] -5,5a, 6,8,8a, 9-hexohydrofuro (3 ', 4': 6,7) naphtho (2,3-d) -1, 3-dioxol -6-one, 2,3- (methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenzo [c] -phenanthridinium, 6,9- £ > / s [(2-aminoethyl) amino] benzo [g] isoguinolin-5,10-dione, 5- (3-aminopropylamino) -7,10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazole [4, 5,1-de] acridin-6-one,? / - [1- [2 (diethylamino) ethylamino] -7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl] formamide, N- (2- ( dimethylamino) ethyl) acridin-4-carboxamide, 6 - [[2- (dimethylamino) ethyl] amino] -3-hydroxy-7H-inden [2,1-c] quinolin-7-one, and dimesne. Examples of inhibitors of mitotic kinetics, and in particular human mitotic kinesin KSP, are described in PCT Publications WO 01/30768, WO 01/98278, WO 03/050,064, WO 03/050122, WO 03/049,527, WO 03 / 049,679, WO 03/049,678 and WO 03/39460 and PCT Outstanding Applications No. US03 / 06403 (filed March 4, 2003), US03 / 15861 (filed May 19, 2003), US03 / 15810 (filed on March 19, 2003) May 2003), US03 / 18482 (filed on June 12, 2003) and US03 / 18694 (filed on June 12, 2003). In one embodiment, inhibitors of mitotic kinetics include, but are not limited to, KSP inhibitors, MKLP1 inhibitors, CENP-E inhibitors, MCAK inhibitors, inhibitors of Kif14, Mfosfl inhibitors and Rab6-KIFL inhibitors. Examples of "histone deacetylase inhibitors" include, but are not limited to, SAHA, TSA, oxamflatine, PXD101, MG98, valproic acid, and scriptaid. Further references to other histone deacetylase inhibitors can be found in the following documents; Miller, T.A. and col. J. Med. Chem. 46 (24): 5097-51 16 (2003). "Inhibitors of kinases involved in mitotic development" include, but are not limited to, aurora kinase inhibitors, inhibitors of Polo-like kinases (PLK, in particular PLK-1 inhibitors), bub-1 inhibitors and bub-R1 inhibitors. An example of an "Aurora kinase inhibitor" is VX-680, "Antiproliferative agents" includes RNA oligonucleotides and Antisense DNAs such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocythabin, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocphosphate, phosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, thiazofurine, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenocytidine, 2'-fluoromethylene-2'-deoxycytidine,? / - [5- (2,3-dihydro-benzofupl) sulfonyl] - ? / '- (3,4-dichlorophenyl) urea,? / 6- [4-deoxy-4- [? / 2- [2 (E), 4 (£) -tetradecadienoyl] glycylamino] -L-glycero-β -L-hand-heptopyranosyl] adenine, aplidine, ecteinascidin, troxacitabine, 4- [2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pipmidin [5,4-b] [1, 4] thiazin-6-yl- (S) -ethyl] -2,5-thienoyl- -glutamic acid, aminopterin, 5-flurouracil, floxuridine, methotrexate, leucovarin, hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP) ), cytarabine, pentostatin, fludarabine phosphate, cladribine (2-CDA), asparaginase, gemcitabine, ala nosine, 1- 1 -acetyl-8- (carbamoyloxy-methyl) -4-formyl-6-methoxy-14-oxa-1,1,1-diazatetracycle (7,4,1, 0,0) -tetradeca- ester 2,4,6-trien-9-yl acetic acid, swainsonin, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-1-BD-arabinofuranosyl cytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone . Examples of therapeutic agents directed by monoclonal antibodies include therapeutic agents that have cytotoxic agents or radioisotopes attached to a cancer cell-specific or target cell-specific monoclonal antibody. Examples include Bexxar. "Prenyl protein transferase inhibitor" refers to a compound that inhibits any one of any combination of the prenyl protein transferase enzymes, including farnesyl protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-1), and geranylgeranil-protein transferase type-ll (GGPTase-ll, also called Rab GGPTase). "Inhibitors of angiogenesis" refers to compounds that inhibit the formation of new blood vessels, regardless of the mechanism. Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1 / KDR (VEGFR2), inhibitors of growth factors obtained from the epidermis , obtained from fibroblasts, or obtained from platelets, inhibitors of MMP (metalloproteinases of hue), integrin blockers, interferon-a, interleukin-12, erythropoietin (epoietin-a), granulocyte-CSF (filgrastin), granulocyte, macrophage-CSF (sargramostima), pentosan polysulfate, cyclooxygenase inhibitors, including non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, as well as selective inhibitors of cyclooxygenase 2 such as celecoxib and rofecoxib (PNAS, Vol. 89, p.7384 (1992); JNCI, Vol. 69, p.475 (1982), Arch. Opthalmol., Vol. 108, p.573 (1990), Anat. Rec, Vol. 238, p.68 (1994), FEBS Letters, Vol. 372 , p.83 (1995), Clin, Orthop., Vol. 313, p.76 (1995), J. Mol. Endocrino!., Vol. 16, p. 107 (1996); Jpn. J. Pharmacol., Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol. Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatories (such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxyamidotriazole, combretastatin A-4, squalamine, 6-0-chloroacetyl-carbonyl) -fumagilol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab. Clin. Med. 105: 141-145 (1985)), and antibodies to VEGF (see, Nature Biotechnology, Vol. 17, p. .963-968 (October 1999), Kim et al., Nature, 362, 841-844 (1993), WO 00/44777, and WO 00/61186). Other therapeutic agents that modulate or inhibit angiogenesis and may also be used in conjunction with the compounds of the present invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem. La. Med. 38: 679-692 ( 2000)). Examples of such agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb, Haemost, 80: 10-23 (1998)), low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of activatable fibrinolysis inhibitor by active thrombin [TAFIa]) (see Thrombosis Res. 101: 329-354 (2001)). TAFIa inhibitors have been described in PCT Publication WO 03/013526 and U.S. Serial No. 60 / 349,925 (filed on January 18, 2002). "Agents that alter cell cycle control points" refers to compounds that inhibit protein kinases that transduce signals from cell cycle checkpoints, thereby sensitizing the cancer cell to agents that damage DNA. Such agents include inhibitors of ATR, ATM, inhibitors of Chk1 and Chk2 kinases and cdk and cdc kinases and are specifically exemplified by 7-hydroxistaurosporin, flavopiridol, CYC202 (Ciclacel) and BMS-387032. "Agents that alter tyrosine kinase receptors (RTK)" refers to compounds that inhibit RTK and therefore mechanisms involved in oncogenesis and tumor development. Such agents include inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met. Other agents include RTK inhibitors shown as those described by Bume-Jensen and Hunter, Nature, 411: 355-365, 2001.

"Cell proliferation inhibitors and survival signaling pathway" refers to pharmaceutical agents that inhibit cell surface receptors and signal transduction cascades downstream from those surface receptors. Such agents include inhibitors of EGFR inhibitors (for example gefitinib and erlotinib), ERB-2 inhibitors (for example trastuzumab), IGFR inhibitors, CD20 inhibitors (rituximab), inhibitors of cytokine receptors, MET inhibitors, inhibitors of PI3K (for example LY294002), serine / threonine kinases (including but not limited to Akt inhibitors such as those described in the documents (WO 03/086404, WO 03/086403, WO 03/086394, WO 03/086279, WO 02 / 083675, WO 02/083139, WO 02/083140 and WO 02/083138), Raf kinase inhibitors (for example BAY-43-9006), MEK inhibitors (for example CI-1040 and PD-098059) and mTOR inhibitors. (eg Wyeth CCI-779 and Ariad AP23573) Such agents include small molecule inhibitory compounds and antibody antagonists. "Apoptosis inducing agents" include activators of members of the TNF receptor family (including TRAIL receptors). Other Examples of angiog inhibitors neses include, but are not limited to, endostatin, ucraine, ranpirnase, IM862, 5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) oxiranyl] -1-oxaspiro [2.5] oct- 6-yl (chloroacetyl) carbamate, acetyldinanaline, 5-amino-1 - [[3,5-dichloro-4- (4-chlorobenzoyl) phenyl] -methyl] -1 H-1, 2,3-triazole-4- carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulphated mannopentase phosphate, 7.7- (carbonyl-b / s [imino -? / - methyl-4,2-pyrrolocarbonylimino [? / - methyl-4.2- pyrrole] -carbonylimino] -b / s- (1,3-naphthalenedisulfonate), and 3 - [(2,4-dimethylpyrrol-5-yl) methylene] -2-indolinone (SU5416). As previously used, "integrin blockers" refers to compounds that selectively antagonize, inhibit, or counteract the binding of a physiological ligand to the β3 integrin, to compounds that selectively antagonize, inhibit, or counteract the binding of a physiological ligand to the avß5 integrin, to compounds that antagonize, inhibit or counteract the binding of a physiological ligand to the integrin avß3 and the integrin ayßs, and to compounds that antagonize, inhibit or counteract the activity of the integrin (s) particular (s) expressed in capillary endothelial cells. The expression also refers to integrin antagonists avßd, otvßd. a.l ßi, 2ßl, adßl, a? ßl and < 6β4 The expression also refers to antagonists of any combination of the integrins avß3, ayßs, to ßd.

«Vß8,« l ßl, a2ßl, adßl, ad l and a6β4- Some specific examples of tyrosine kinase inhibitors include? / - (trifluoromethylphenyl) -5-methylisoxazole-4-carboxamide, 3 - [(2,4-dimethylpyrrole-5 -yl) methylidenyl) indolin-2-one, 17- (allylamino) -17-demethoxygelandanemycin, 4- (3-chloro-4-fluorophenylamino) -7-methoxy-6- [3- (4-morpholinyl) propoxyl] quinazoline , / V- (3-ethynylphenyl) -6,7-b / 's (2-methoxyethoxy) -4-quinazolinamine, BIBX1382, 2,3,9,10,11, 12-hexahydro-10- (hydroxymethyl) ) -10- hydroxy-9-methyl-9,12-epoxy-1 H-diindole [1, 2,3-fg: 3 ', 2', r-kl] pyrrole [3,4-i] [1 , 6] benzodiazocin-1-one, SH268, genistein, imatinib (STI571), CEP2563, 4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrole [2,3-d] pyrimidinemethane sulfonate, 4- (3-bromo-4-hydroxyphenyl) amino-6,7-dimethoxyquinazoline, 4- (4'-hydroxyphenyl) amino-6,7-dimethoxyquinazoline, SU6668, STI571A,? / - 4-chlorophenyl-4- (4-pyridylmethyl) ) -1-phthalazinamine, and EMD121974. Combinations with different compounds of anticancer compounds are also encompassed in the present methods. For example, combinations of the compounds claimed herein with PPAR-? Agonists. (ie, PPAR-gamma) and PPAR-d agonists (ie, PPAR-delta) are useful in the treatment of certain malignancies. PPAR-? and PPAR-d are the receptors? and d activated by the nuclear peroxisome proliferator. The expression of PPAR-? in endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc Pharmacol.; 31: 909-913; J. Biol. Chem. 1999; 274: 9116-9121; Invest. Oftalmol Vis. Sci. 2000; 41: 2309-2317). More recently, PPAR- agonists? have been shown to inhibit the angiogenic response to VEGF in vitro; troglitazone maleate and rosiglitazone inhibit the development of retinal neovascularization in mice. (Arch. Oftamol, 2001; 119: 709-717). Examples of PPAR-? Agonists and PPAR-? / a agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2 - [(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl) oxy] ] -2-methylpropionic acid (described in USSN 09 / 782,856), and 2 (R) -7- (3- (2-chloro-4- (4-fluorophenoxy) phenoxy) propoxy) -2-ethylchroman-2 acid -carboxylic (described in documents USSN 60 / 235,708 and 60 / 244,697). Another embodiment of the present invention is the use of the compounds described herein in conjunction with gene therapy for the treatment of cancer. For an overview of genetic strategies to treat cancer see Hall et al. (Am J Hum Genet 61: 785-789, 1997) and Kufe et al (Cancer Medicine, 5th Ed, pp. 876-889, BC Decker, Hamilton 2000). Gene therapy can be used to deliver any tumor suppressor gene. Examples of such genes include, but are not limited to, p53, which can be delivered by gene transfer mediated by recombinant virus (see U.S. Patent No. 6,069,134, for example), Duc-4, NF-1, NF-2, RB , WT1, BRCA1, BRCA2, a uPA / uPAR antagonist ("Adenovirus-Mediated Delivery of uPA / uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August 1998; 5 (8) 1105-13 ), and gamma interferon (J. Immunol., 2000; 164: 217-222). The compounds of the present invention may also be administered in conjunction with a multi-drug intrinsic resistance (MDR) inhibitor, in particular MDR associated with high levels of transporter protein expression. Such MDR inhibitors include glycoprotein-p (P-gp) inhibitors, such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar). A compound of the present invention can be used in conjunction with anti-emetic agents to treat nausea or emesis, including acute, delayed, delayed phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy. For the prevention or treatment of emesis, a compound of the present invention may be used in conjunction with other anti-emetic agents, especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadrona (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorteno or others such as those described in U.S. Patent Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, an antidopaminergic, such as phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol. In one embodiment, an anti-emesis agent selected from a neurokinin 1 receptor agonist, a 5HT 3 receptor agonist and a corticosteroid is administered as an adjuvant for the treatment or prevention of emesis that may result from the administration of the present compounds. A compound of the present invention can also be administered with an agent useful in the treatment of anemia. Said anemia treatment agent is, for example, a continuous activator of the erythropoiesis receptor (such as epoetin alfa). A compound of the present invention can also be administered with an agent useful in the treatment of neutropenia. Said neutropenia treatment agent is, for example, a hematopoietic growth factor that regulates the production and function of neutrophils such as a human factor stimulating the granulocyte colony, (G-CSF). Examples of a G-CSF include filgrastim. A compound of the present invention can also be administered with an immunological enhancing drug, such as levamisole, bacillus Calmette-Guerin, octreotide, isoprinosine and Zadaxin. A compound of the present invention may also be useful for treating or preventing cancer, including bone cancer, together with bisphosphonates (understood to include bisphosphonates, bisphosphonates, bisphosphonic acids and diphosphonic acids). Examples of bisphosphonates include but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, pyridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof. A compound of the present invention may also be useful for treating or preventing breast cancer together with aromatase inhibitors. Examples of aromatase inhibitors include but are not limited to anastrozole, letrozole and exemestane. A compound of the present invention may also be useful for treating or preventing cancer along with therapeutic siRNAs. Also included in the scope of the claims is a method of treating cancer comprising administering a therapeutically effective amount of a compound of Formula I in conjunction with radiation therapy and / or together with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic / cytostatic agent, an antiproliferative agent, a prenyl protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, an inhibitor of reverse transcriptase, an angiogenesis inhibitor, PPAR-? agonist, PPAR-d agonists, an inhibitor of intrinsic multi-drug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunological enhancing drug, an inhibitor of cell proliferation and survival signaling, a bis osfonate, an aromatase inhibitor, a therapeutic siRNA, y-secretase inhibitors, agents that alter tyrosine kinase receptors (RTK) and an agent that alters a cell cycle checkpoint. The use of all these approaches together with the compounds of Formula I and II, as described herein, are within the scope of the present invention.

Dosages and Dosage Programs The dosage regimen using the compounds of the present invention can be selected according to various factors including type, species, age, weight, sex and the type of cancer treated; the severity (ie, stage) of the disease to be treated; the route of administration; the renal and hepatic function of the patient of the patient; and the particular compound or salt thereof employed. A physician or veterinarian skilled in the art can easily determine and prescribe the effective amount of the drug required to treat, for example, to prevent, inhibit (totally or partially) or arrest the development of the disease. For oral administration, suitable daily dosages are for example between about 5-4,000 mg / m2 administered orally once a day, twice a day or three times a day, continuous (every day) or intermittently (eg, 3 times a day). -5 days per week). For example, when used to treat the desired disease, the dose of the compounds of the present invention may vary between about 2 mg and about 2000 mg per day. The compound of the present invention can be administered once a day (QD), or divided into multiple daily doses such as twice a day (BID), and three times a day (TID). For administration once a day, a properly prepared medication would therefore contain all the necessary daily dose. For administration twice a day, a drug prepared properly would therefore contain half the daily dose needed. For administration three times a day, a properly prepared drug would therefore contain one third of the daily dose needed. In addition, the administration can be continuous, that is, every day, or intermittently. The terms "intermittent" or "intermittently" as used herein mean stopping and starting at regular or irregular intervals. For example, intermittent administration of an HDAC inhibitor may be administration one to six days per week or may mean administration in cycles (eg, daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week). week) or may mean administration on alternate days. Typically, an intravenous formulation containing a concentration of the compounds of the present invention of between about 1.0 mg / ml to about 10 mg / ml can be prepared. In one example, a sufficient volume of intravenous formulation can be administered to a patient on a day so that the total dose for the day is between about 10 and about 1500 mg / m2 Subcutaneous formulations, preferably prepared according to well-known procedures in the technique at a pH in the range between about 5 and about 12, also include suitable buffers and isotonicity agents, as described below. They can be formulated to deliver a daily dose of HDAC inhibitor in one or more daily subcutaneous administrations, for example, one, two or three times each day. It should be apparent to one skilled in the art that the various modes of administration, dosages and dosing schedules described herein show only specific embodiments and should not be construed as limiting the broad scope of the invention. Any permutations, variations and combinations of dosages and dosing schedules are included within the scope of the present invention. The term "administration" and variants thereof (eg, "administering" a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided together with one or more other active agents (e.g., a cytotoxic agent, etc.), it is understood that "administration" and each of its variants includes concurrent and sequential introduction of the compound or prodrug thereof and other agents. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from the combination of the specified ingredients in the specified amounts.

The term "therapeutically effective amount" as used herein means the amount of active compound or pharmaceutical agent that elicits the biological and medicinal response in a tissue, system, animal or human being that is expected by a researcher, veterinarian, doctor in medicine or another doctor.

Pharmaceutical Compositions The compounds of the invention, and derivatives, fragments, analogs, pharmaceutically acceptable salt homologs or hydrates thereof, can be incorporated into pharmaceutical compositions suitable for oral administration, together with a pharmaceutically acceptable carrier or excipient. Said compositions typically comprise a therapeutically effective amount of any of the above compounds, and a pharmaceutically acceptable carrier. In one embodiment, the effective amount is an amount effective to selectively induce terminal differentiation of appropriate neoplastic cells and less than an amount that causes toxicity in a patient. Any inert excipient that is commonly used as a carrier or diluent can be used in the formulations of the present invention, such as, for example, a gum, a starch, a sugar, a cellulosic material, an acrylate, or mixtures thereof. A preferred diluent is microcrystalline cellulose. The compositions may further comprise a disintegrating agent (e.g., croscarmellose sodium) and a lubricant (e.g., magnesium stearate), and may further comprise one or more additives selected from a binder, a buffer, a protease inhibitor, a surfactant , a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity enhancing agent, a sweetener, a film forming agent, or any combination thereof. In addition, the compositions of the present invention may be in the form of controlled release or immediate release formulations. In one embodiment, the pharmaceutical compositions are administered orally, and are thus formulated in a form suitable for oral administration, ie, in the form of a solid or liquid preparation. Suitable solid oral formulations include tablets, capsules, pills, granules, pellets and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like. In one embodiment of the present invention, the composition is formulated in a capsule. In accordance with this embodiment, the compositions of the present invention comprise in addition to a compound of the present invention and the inert carrier or diluent, a hard gelatin capsule. As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration, such as sterile water without pyrogens. Suitable vehicles are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils can also be used. The use of said media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional medium or agent is incompatible with the active compound, the use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. Solid vehicles / diluents include, but are not limited to, a gum, a starch (e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g., microcrystalline cellulose), an acrylate (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof same. For liquid formulations, pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions, emulsions or oils. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.

Aqueous vehicles include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Examples of oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and cod liver oil. The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and tonicity adjusting agents such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. In addition, the compositions may also comprise binders (e.g., gum arabic, corn starch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g., corn starch, starch) of potato, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium glycoate starch, Primogel), buffers (for example, tris-HCl, acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitor, surfactants (e.g., sodium lauryl sulfate), permeation enhancers, solubilizing agent ( for example, glycerol, polyethylene glycerol), a glidant (e.g., colloidal silicon dioxide), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, hydroxy butylated nisol), stabilizers (e.g., hydroxypropyl cellulose, hiroxypropylmethyl cellulose), viscosity-increasing agents (e.g., carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citric acid ), flavoring agents (e.g., peppermint, methyl salicylate, or orange flavoring), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate) ), fluidity enhancers (eg, colloidal silicon dioxide), plasticizers (eg, diethyl phthalate, triethyl citrate), emulsifiers (eg, carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g. , poloxamers or poloxamines), coating agents and film formers (for example, ethyl cellulose, acrylates, polymethacrylates) and / or adjuvants. In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. The procedures for the preparation of said formulations will be apparent to those skilled in the art. The materials can also be obtained from the market of Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes directed to cells infected with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to procedures known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811. The compounds of the present invention can be administered intravenously on the first day of treatment, with oral administration on the second day and all consecutive days thereafter. The compounds of the present invention can be administered in order to prevent the development of the disease or stabilize the tumor growth. The amount of the compound administered to the patient is less than an amount that would cause toxicity in the patient. In certain embodiments, the amount of the compound that is administered to the patient is less than the amount that causes a concentration of the compound in the patient's plasma to equal or exceed the toxic level of the compound. In one embodiment, the concentration of the compound in the patient's plasma is maintained at approximately 10 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at approximately 25 nM.

In another embodiment, the concentration of the compound in the patient's plasma is maintained at approximately 50 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at approximately 100 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at approximately 500 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at approximately 1000 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at approximately 2500 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at approximately 5000 nM. The optimum amount of the compound to be administered to the patient in the practice of the present invention will depend on the particular compound used and the type of cancer treated. The present invention also includes a pharmaceutical composition useful for treating or preventing cancer comprising a therapeutically effective amount of a compound of Formula I and a second compound selected from: a estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic / cytostatic agent, an antiproliferative agent, an inhibitor of prenyl protein transferase, an inhibitor of HMG-CoA reductase, an inhibitor of HIV protease, a reverse transcriptase inhibitor, an inhibitor of angiogenesis, a PPAR- agonist, a PPAR-d agonist, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, a therapeutic siRNA, y-secretase inhibitors, agents that alter tyrosine kinase receptors ( RTK) and an agent that alters a cell cycle control point.

In Vitro Procedures: The present invention also provides methods of using the compounds of the present invention to induce terminal differentiation, cell growth arrest and / or apoptosis of neoplastic cells thereby inhibiting the proliferation of said cells. The methods can be practiced in vivo or in vitro. In one embodiment, the present invention provides in vitro methods to selectively induce terminal differentiation, arrest of cell growth and / or apoptosis of neoplastic cells, thereby inhibiting the proliferation of said cells, contacting the cells with an effective amount of any one or more of the compounds of the present invention described herein. In a particular embodiment, the present invention relates to an in vitro method to selectively induce terminal differentiation of neoplastic cells and thereby inhibit the proliferation of said cells. The method comprises contacting the cells under suitable conditions with an effective amount of one or more of the compounds of the present invention described herein. In another embodiment, the invention relates to an in vitro method for selectively inducing the arrest of cell growth of neoplastic cells and thereby inhibiting the proliferation of said cells. The method comprises contacting the cells under suitable conditions with an effective amount of one or more of the compounds of the present invention described herein. In another embodiment, the invention relates to an in vitro method for selectively inducing apoptosis of neoplastic cells and thereby inhibiting the proliferation of said cells. The method comprises contacting the cells under suitable conditions with an effective amount of one or more of the compounds of the present invention described herein. In another embodiment, the invention relates to an in vitro method for inducing terminal differentiation of tumor cells in a tumor, comprising contacting the cells with an effective amount of any one or more of the compounds of the present invention described in this document. In one embodiment, the methods for selectively inducing terminal differentiation, arresting cell growth and / or apoptosis of neoplastic cells, and for inhibiting HDAC will comprise contacting the cells in vivo, i.e., administering the compounds to a host subject. neoplastic cells or tumor cells in need of treatment.

Thus, the present invention provides in vivo methods to selectively induce terminal differentiation, arrest of cell growth and / or apoptosis of neoplastic cells in a subject, thereby inhibiting the proliferation of said cells in the subject, by administering to the subject an effective amount of any one or more of the compounds of the present invention described herein. In a particular embodiment, the present invention relates to a method for selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting the proliferation of said cells in a subject. The method comprises administering to the subject an effective amount of one or more of the compounds of the present invention described herein. In another embodiment, the invention relates to a method for selectively inducing cell growth arrest of neoplastic cells and thereby inhibiting the proliferation of said cells in a subject. The method comprises administering to the subject an effective amount of one or more of the compounds of the present invention described herein. In another embodiment, the invention relates to a method for selectively inducing apoptosis of neoplastic cells and thereby inhibiting the proliferation of said cells in a subject. The method comprises administering to the subject an effective amount of one or more of the compounds of the present invention described herein.

In another embodiment, the invention relates to a method for treating a patient having a tumor characterized by the proliferation of neoplastic cells. The method comprises administering to the patient one or more of the compounds of the present invention described herein. The amount of compound is effective to selectively induce terminal differentiation, induce cell growth arrest and / or induce apoptosis of said neoplastic cells and thereby inhibit their proliferation. The invention is illustrated in the following generic schemes and the examples in the Experimental Details Section that follows. This section is shown to aid in the understanding of the invention but is not intended to be, and should not be construed as limiting in any way the invention as shown in the claims that follow thereafter.

SCHEME 1 R is resin or H OUTLINE 2 SCHEME 3 SCHEME 4 SCHEME 5 1) Hydrolysis of the Ester SCHEME 6 1 Addition d SCHEME 7 1) Addition of 2) Addition of 3) Deprotection of TFA SCHEME 8 1) Addition of 2) Addition of 3) Deprotection of TFA Experimental section Intermediate Synthesis Preparation of tere-butyl (2-Aminophenyl) carbamate (A) Intermediate A was prepared by the method described by Seto, CT, et al., Molecular self-assembly through hydrogen bonding: aggregation of five molecules to form at supramolecular discrete structure, J. Am. Chem. Soc, 1993, vol. 1 15, 1321.

Preparation of tere-butyl (2- {[[6-chloropyridin-3-yl) carbonipamino) phenyl) carbamate (B). To a solution of f-butyl (2-aminophenyl) carbamate A (10 g, 48.0 mmol) in CH 2 Cl 2 (200 mL) was added 6-chloronicotinoyl chloride (8.5 g, 48.0 mmol). The reaction mixture was concentrated after 2 hours of stirring at room temperature and purified by flash chromatography (10-75% EtOAc / hexanes) to give the Boc-protected nicotinamide B confirmed by MS (ESI +): cale. [M + Na] + 370.1, obs. 370.1.

Preparation of Tere-Butyl (3-Aminobiphenyl-4-yl) carbamate (C) A mixture of N-Boc 4-bromo-2-nitroaniline (39.0 g, 123 mmol), phenylboronic acid (16.5 g, 135 mmol) and K2CO3 (34.1 g, 247 mmol) in 350 ml of dioxane and 150 ml of water was degassed by bubbling nitrogen through the mixture for 30 min. Then, Pd (PPh3) 4 (4.32 g, 3.7 mmol) was added and the orange mixture was heated at 78 ° C for 18 h. It was cooled and partitioned between ether (1500 ml) and water (400 ml). The mixture was filtered through a pad of Celite (a / ether washes). The organic phase was separated, washed with brine, dried (MgSO) and concentrated, yielding 44.1 g of a reddish-orange solid. Recrystallization from EtOAc-hexanes (ca. 50 ml + 1100 ml, respectively) gave the bright orange solid N-Boc 4-phenyl-2-nitroaniline: MS (E) [M + Na] + cale. 337.2, obs. 337.2. A solution of the nitro compound (16.5 g, 52.5 mmol) in 400 mL of EtOAc was evacuated and refilled with nitrogen (2 x). 10% Pd / C (1.60 g) was added, then it was evacuated and re-charged with hydrogen (3 x). It was stirred under a hydrogen atmosphere overnight. The mixture was filtered through a pad of Celite (a / EtOAc washes and then CH 2 Cl 2) and concentrated to give a pale orange solid. It was stirred and heated with ca. 800 ml of hexanes, then cooled and the product was collected (cold a / hexane washes). The resulting solid was dissolved in CH2Cl2 and concentrated to give the off-white solid? / - BOC (3-aminobiphenyl-4-yl) amine C: 1 H NMR (600 MHz, CDCl 3) d 7.51 (d, J = 3.2 Hz, 2 H), 7.38 (t, J = . 6 Hz, 2 H), 7.31 (m, 2 H), 7.22 (s, 1 H), 7.12 (dd, J = 8.2, 2.1 Hz, 1 H), 6.45 (sa, 1 H), 1.51 (s, 9 H); MS (El) [M + Na] + cale. 285.1, obs. 285.1.

Preparation of (3- (f (6-chloropyridin-3-yl) carbamino) biphenyl-4- p-carbamate tere-butyl (D). To a solution of f-butyl (3-aminobiphenyl-4-yl) carbamate (2.06 g, 7.25 mmol) in pyridine (10 mL) was added 6-chloronicotinyl chloride (1.30 g, 7.39 mmol). After 4 hours of stirring at room temperature, the reaction mixture was filtered and the solvent was concentrated. The formation of tere-butyl (3- {[[6-chloropyridin-3-yl) carbonyl] amino} biphenyl-4-yl) carbamate (D) was confirmed by 1 H NMR (600 MHz, CD3OD) : .510.84 (s, 1 H), 9.79 (s, 1 H), 9.60 (s, 1 H), 9.19-9.16 (m, 1 H), 8.59 (s, 1 H), 8.57-8.55 (m, 2H), 8.43-8.40 (m, 2H), 8.34-8.30 (m, 1 H), 8.25-8.21 (m, 2H), 8.16-8.12 (m, 1 H), 2.22 (s, 9H).

AND Preparation of tere-butyl [2-amino-4- (2-thienyl) phenylcarbamate] (E) A mixture of tere-butyl (4-bromo-2-nitrophenyl) carbamate (19.4 g, 61.2 mmol), thiophen-2-boronic acid (9.94 g, 77.7 mmol) and K2C03 (22.2 g, 160 mmol) in 60 ml of dioxane and 60 ml of water was degassed by bubbling nitrogen through the mixture for 30 min. Then, Pd [PPh3] 4 (5.25 g, 4.53 mmol) was added and the heterogeneous mixture was heated to reflux for 20 h. The mixture was cooled and diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and concentrated. The resulting solid was dissolved in diethyl ether (500 ml) and filtered through a layer of silica. The solvents were removed under reduced pressure to yield the yellow-brown solid: 1 H NMR (600 MHz, CDCl 3): d 9.65 (s, 9 H), 8.58 (d, J = 8.8 Hz, 1 H), 8.39 (d, J = 2.1 Hz, 1 H), 7.81 (dd, J = 8.8, 1.8 Hz, 1 H), 7.32 (m, 2 H), 7.09 (dd, J = 5.3, 3.8 Hz, 1 H), 1.54 (s) 9 H); EM (IEN +): cale. [M + Na] + 343.1, obs. 343.1. A solution of? / - BOC 2-nitro-4- (2-thienyl) aniline (18.0 g) in 350 ml of EtOAc was evacuated and refilled with nitrogen (2 x). To the solution was added 10% Pd / C (4.46 g) and the reaction mixture was evacuated and re-charged with hydrogen (2 x). The black reaction mixture was stirred under a hydrogen atmosphere overnight. The mixture was filtered through a pad of celite (with EtOAc washings and then CH2Cl2) and concentrated to give a brownish-white solid. The solid was triturated with ether and filtered to provide off-white tere-butyl [2-amino-4- (2-thienyl) phenyl] carbamate (E): 1 H NMR (600 MHz, DMSO-6) d 8.31 (a , 1 H), 7.41 (dd, J = 5.0, 0.9 Hz, 1 H), 7.26 (dd, J = 3.5, 1.2 Hz, 1 H), 7.23 (day, J = 8.5 Hz, 1 H), 7.05 ( dd, J = 5.0, 3.5 Hz, 1 H), 6.94 (d, J = 2.1 Hz, 1 H), 6.81 (d, J = 8.2, 2.1 Hz, 1 H), 4.98 (s, 2 H), 1.43 (s, 9 H); EM (IEN +): cale. [M + Na] + 291.1, obs. 291.1.

Preparation of [2-. { [(6-Chloropyridin-3-yl) carbonyl-amino) -4- (2-thienyl) phenyl-carbamic acid tere-butyl ester (F). A mixture of tere-butyl [2-amino-4- (2-thienyl) phenyl] carbamate (E) (600 mg, 2.07 mmol) and 6-chloronicotinyl chloride (380 mg, 2.16 mmol) in ml of pyridine was stirred overnight, poured into EtOAc, washed with Saturated NaHC03, dried (Na2SO4) and concentrated to give the BOC-protected chloronicotinamide (F): 1 H NMR (600 MHz, CD3OD): d 8.95 (d, J = 2.3 Hz, 1 H), 8.35 (dd, J = 8.2 Hz, 2.3 Hz, 1 H), 7.85 (sa, 1 H), 7.62 (d, J = 8.5 Hz, 1 H), 7.55-7.51 (m, H), 7.37-7.35 (m, 2H), 7.07 (dd, J = 5.0 Hz, 3.5 Hz, 1 H), 4.59 (s, 1 H), 1.49 (s, H); EM (IEN +): cale. [M + Naf 452.1, obs. 452.1.

Preparation of tere-butyl [2-Amino-4- (3-thienyl) phenylcarbamate (G) and [2-. { [(6-Chloropyridin-3-yl) carbonylamino) -4- (3-thienyl) phenyl-carbamate tere-butyl ester (H) Intermediates G and H were prepared from (4-bromo-2-nitrophenyl) carbamate of tere-butyl using the procedures used for the preparation of intermediates E and F. Intermediate G: MS (IEN +): cale. [M + Na] + 291.1, obs. 291.1, Intermediate H: EM (IEN +): cale. [M + Na] + 452.1, obs. 452.1.

Preparation of Tere-Butyl (3-Amino-1-phenyl-1 / - / - pyrazol-4-yl) carbamate (I) A solution of methyl 4-nitro-1 H-pyrazole-3-carboxylate (54.0 g, 315.6 mmol), phenylboronic acid (77.0 g, 631.2 mmol), copper (II) acetate (86.0 g, 473.4 mmol) and pyridine (49.9 g, 631.2 mmol) in methylene chloride (600 mL) was stirred at room temperature open to the air for 48 hours. The reaction was evaporated in vacuo, diluted with 1000 ml of methylene chloride and filtered through a large silica pad (washing with 2 liters of methylene chloride). The solvent was evaporated in vacuo. H NMR (CDCl 3) d 8.61 (s, 1 H), 7.73 (m, 2 H), 7.50 (m, 3 H), 4.02 (s, 3H). A solution of methyl 4-nitro-1-phenyl-1 / - / - pyrazole-3-carboxylate (78.1 g, 315.9 mmol) in THF (600 mL) was treated dropwise with 4 M potassium hydroxide (79 mL, 316 mmol) and the solution was stirred at room temperature for 16 hours. The reaction was evaporated in vacuo and acidified with 6M HCl. After the addition of water (500 ml), the solids were removed by filtration and dried, giving the desired compound as a grayish solid. 1 H NMR (CD 3 OD) d 9.37 (s a, 1 H), 7.88 (m, 2 H), 7.59 (m, 2 H), 7.44 (m, 1 H). A solution of 4-nitro-1-phenyl-1 / - / - pyrazole-3-carboxylic acid (20.0 g, 85.8 mmol), triethylamine (36.0 mL, 257.3 mmol) and diphenylphosphorylazide (37.8 g, 137.2 mmol) in dioxane ( 400 ml) and tert-butanol (200 ml) was heated to reflux for 16 hours. The reaction was evaporated to dryness in vacuo, diluted with methylene chloride (400 mL) and treated with trifluoroacetic acid (128 g, 857.7 mmol). The solution was stirred at room temperature for 16 hours. The reaction was evaporated in vacuo and the resulting oil was diluted with hexanes (750 mL), ethyl acetate (150 mL) and methylene chloride (100 mL). The solids were filtered, washed with the above solvent system (75:15: 10 hexanes: ethyl acetate: methylene chloride) and dried to give the desired product as a yellow solid. 1 H NMR (CDCl 3) d 8.43 (s, 1 H), 7.62 (m, 2 H), 7.48 (m, 2 H), 7.37 (m, 1 H). A solution of 4-nitro-1-phenyl-1 H-pyrazol-3-amine (0.15 g, 0.74 mmol), di-tert-butyl dicarbonate (0.16 g, 0.74 mmol) and triethylamine (0.19 g, 1.84 mmol) in 20 ml of methanol was degassed with nitrogen and treated with platinum oxide (17 mg, 10 mol%). The solution was placed in a hydrogen atmosphere and stirred at room temperature for 2 hours. Then, the reaction was degassed with nitrogen, filtered through celite, washed with methanol and evaporated in vacuo. Flash chromatography (20-35% ethyl acetate / hexanes) gave the title compound as a somewhat purple solid. 1 H NMR (CDCl 3) d 7.85 (s, 1 H), 7.51 (m, 2 H), 7.37 (m, 2 H), 7.18 (m, 1 H), 6.40 (br s, 1 H).

Preparation of (3 - ([(6-Chloropyridin-3-yl) carbonyl-amino) -1-phenyl-1 H -pyrazol-4-yl)-tere-butylcarbamate (J) To a solution of (3-amino- 1-phenyl-1H-pyrazol-4-yl) carbamic acid / butyl ester (100 mg, 0.364 mmol) in pyridine (500 μl) was added 6-chloronicotinoyl chloride (53 mg, 0.304 mmol) in CH2Cl2 (2 ml). ). After 6 hours of stirring at room temperature, the reaction mixture was filtered and the solvent was concentrated. The formation of f-butyl (3-) -3- (6-chloropyridin-3-yl) carbonyl] amino.} - 1-phenyl-1H-pyrazol-4-yl) carbamate (J) was confirmed by MS (IEN +): cale. [M + H] + 414.1, obs. 414.1.

KL Preparation of [3-Amino-1- (3-chlorophenyl) -1H-pyrazole-4-illcarbamate tere-butyl (K) and (1- (3-chlorophenyl) -3- { [(6-chloropyridin -3-yl) carbonyl-amino) -1 / - / - pyrazol-4-yl)-tere-butylcarbamate (L) Intermediates K and L were prepared from 3-chlorophenylboronic acid in a manner analogous to the steps used for prepare intermediates I and J. Intermediate K: EM (El) cale. 309.1 (M + + H), found 309.1 (M + + H). Intermediate L: EM (El) cale. 448.1 (M + + H), found 448.1 (M + + H).

Preparation of Tere-Butyl (2-Aminophenyl) Carbamate (A1) Intermediate A1 was prepared by the procedure described by Seto, C. T .; Matías, J. P .; Whitesides, G.M. Molecular self-assembly through hydrogen bonding: aggregation of five molecules to form a discrete supramolecular structure. J. Am. Chem. Soc. 1993, 115, 1321.

Preparation of tere-butyl (2-f [(6-chloropyridin-3-yl) carbamylamino) phenyl) carbamate (B1) To a solution of f-butyl (2-aminophenyl) carbamate A1 (10 g, 48.0 mmol) in CH2Cl2 (200 mL) was added 6-chloronicotinoyl chloride (8.5 g, 48.0 mmol). The reaction mixture was concentrated after 2 hours of stirring at room temperature and purified by flash chromatography (10-75% EtOAc / hexanes) to give the Boc-protected nicotinamide B1 confirmed by MS (ESI +): cale. [M + Na] + 370.1, obs. 370.1.

Tere-butyl (3-aminobiphenyl-4-yl) carbamate (C1). A mixture of? / - Boc-4-bromo-2-nitroaniline (39.0 g, 123 mmol), phenylboronic acid (16.5 g, 135 mmol) and K2C03 (34.1 g, 247 mmol) in 350 ml of dioxane and 150 ml of Water was degassed by bubbling nitrogen through the mixture for 30 min. Then, Pd (PPh3) (4.32 g, 3.7 mmol) was added and the orange mixture was heated at 78 ° C for 18 h. It was cooled and partitioned between ether (1500 ml) and water (400 ml). The mixture was filtered through a pad of Celite (a / ether washes). The organic phase was separated, washed with brine, dried (MgSO4) and concentrated to give 44.1 g of a reddish-orange solid. Recrystallization from EtOAc-hexanes (ca. 50 ml + 1100 ml, respectively) gave the bright orange solid N-Boc-4-phenyl-2-nitroaniline: MS (E) [M + Naph. 337.2, obs. 337.2. A solution of the nitro compound (16.5 g, 52.5 mmol) in 400 mL of EtOAc was evacuated and refilled with nitrogen (2 x). 10% Pd / C (1.60 g) was added, then it was evacuated and re-charged with hydrogen (3 x). It was stirred under a hydrogen atmosphere overnight. The mixture was filtered through a pad of Celite (washes of a / EtOAc and then CH2Cl2) and concentrated to give a pale orange solid. It was stirred and heated with ca. 800 ml of hexanes, then cooled and the product was collected (cold a / hexane washes). The resulting solid was dissolved in CH2Cl2 and concentrated to give the off-white solid? / - BOC- (3-aminobiphenyl-4-yl) amine C1: 1H NMR (600 MHz, CDCl3) d 7.51 (d, J = 3.2 Hz, 2 H), 7.38 (t, J = 5.6 Hz, 2 H), 7.31 (m, 2 H), 7.22 (s, 1 H), 7.12 (dd, J = 8.2, 2.1 Hz, 1 H), 6.45 ( sa, 1 H), 1.51 (s, 9 H); MS (El) [M + Na] + cale. 285.1, obs. 285.1. (3- ({[[6-chloropyridin-3-yl) carbonyl-amino) biphenyl-4-yl) tere-butyl carbamate (DU To a solution of f-butyl (3-aminobiphenyl-4-yl) carbamate C1 (2.06 g, 7.25 mmol) in pyridine (10 mL) was added 6-chloronicotinyl chloride (1.30 g, 7.39 mmol). After 4 hours of stirring at room temperature, the reaction mixture was filtered and the solvent was concentrated. The formation of tere-butyl (3- {[[6-chloropyridin-3-yl) carbonyl] amino} biphenyl-4-yl) carbamate (D1) was confirmed by 1 H NMR (600 MHz, CD3OD) : d 10.84 (s, 1 H), 9.79 (s, 1 H), 9.60 (s, 1 H), 9.19-9.16 (m, 1 H), 8.59 (s, 1 H), 8.57-8.55 (m, 2H), 8.43-8.40 (m, 2H), 8.34-8.30 (m, 1 H), 8.25-8.21 (m, 2H), 8.16-8.12 (m, 1 H), 2.22 (s, 9H).

General procedures EXAMPLE 1 ? / - (2-Aminophenyl) -6- (4-oxo-1-phenyl-1, 3,8-triazaspiro [4.5ldec-8-Qnicotinamide A mixture of Boc-protected chloronicotinamide B (125 mg, 0.359 mmol) and 1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one (Acros Chemical Co.) (249 mg, 1.08 mmol) was heated at 85 ° C for 4 hours in DMSO / PhMe (2 ml of a 1: 1 solution). Then, the reaction mixture was diluted with EtOAc (25 mL) and washed with aq. NaHCO3. sat (1 x 5 ml) and brine (1 x 5 ml). The crude oil was purified by reverse phase flash chromatography (25% MeCN / H20 with 0.05% TFA to 100% MeCN with 0.05% TFA) and the formation of the desired Boc-protected spiro-nicotinamide was confirmed by EM (IEN +): cale. [M + H] + 543.3, esp. 543.2. The Boc-protected spiro-nicotinamide was treated with TFA (1.5 mL) in CH2Cl2 (3 mL) and after 20 minutes of stirring at room temperature, the reaction mixture was concentrated and purified by reverse phase chromatography (15% MeCN). % -75% / H2O with 0.05% TFA). The appropriate fractions were combined, diluted with EtOAc (50 mL) and washed with aq. NaHCO3. sat (1 x 10 ml) and brine (1 x 5 ml). The organic phase was dried over Na2SO4, filtered and concentrated to give the desired nicotinamide: 1 H NMR (600 MHz, CD3OD) d 8.79, (s, 1 H), 8.12 (d, J = 7.0 Hz, 1 H), 7.17 (d, J = 7.6 Hz, 1 H), 7.09-7.04 (m, 3H), 6.93-6.87 (m, 2H), 6.78-6.70 (m, 2H), 6.58 (d, J = 7.9 Hz, 2H ), 4.68 (s, 2H), 4.40-4.34 (ma, 2H), 3.80 (dt, J = 12.9 Hz, 3.2 Hz, 2H), 2.63-2.56 (m, 2H), 1.75 (d, J = 14.1 Hz 2H); EM (IEN +): cale. [M + H] + 443.2, obs. 443.2. The compounds described in the following table were prepared by procedures analogous to the synthetic procedures described above, but using the appropriate starting materials.

TABLE 1 EXAMPLE 2 ? / - (4-Am? Nob? Phen? L -3? L) -6- (4-oxo-1-phen? L-1, 3,8-tr? Azasp? Ro [4 51dec-8- ?) n? n? nam? da To a solution of 1-phenol-1, 3,8-tpazaesp? ro [4 5] decan-4-one (Acros Chemical Co) (182 mg, 0 787 mmol ) in DMSO (2 ml) was added (3- {[[6-chlorop? pd? n-3? l) carbon? l] am? no.}. b? phen? l-4? l) / -butyl carbamate D (133 mg, 0 315 mmol) The reaction mixture was heated at 85 ° C for 6 hours, cooled to room temperature, diluted with EtOAc (25 mL) and then washed with NaHCO 3. Ac sat (1 x 5 mL) and brine (1 x 5 mL) The organic phase was dried over Na 2 SO 4, filtered, concentrated and the crude residue was purified by flash chromatography (10-100% EtOAc / hexanes). of the Boc-protected biphenyl-spiro-nicotinamide was confirmed by EM (IEN +) cale [M + H] + 619 3, esp 619 3 A solution of the Boc-protected biphenyl-spiro-nicotinamide in CH 2 Cl 2 (3 ml) was added TFA (1 mL) The reaction mixture was concentrated after 20 minutes of stirring at ambient temperature The crude residue was purified by reverse phase chromatography (10-75% MeCN / H 2 O with 0 05% TFA). The appropriate fractions were combined, diluted with EtOAc (50 mL) and washed with NaHCO 3 ac sat ( 1 x 10 ml) and brine (1 x 5 ml) The organic phase was dried over Na 2 SO 4, filtered and concentrated to give the desired biphenyl spiro-nicotinamide 1 H NMR (600 MHz, CD 3 OD) d 8 81 (d, J = 2 1 Hz, 1 H), 8 16 (dd, J = 8 8 Hz, 2 3 Hz, 1 H), 7 55 (dd, J = 8 1 Hz, 1 1 Hz, 2 H), 7 48 (d, J = 2 1 Hz, 1 H), 7 38- 7 35 (m, 3H), 7 24-7 22 (m, 1 H), 7 09-7 06 (m, 2H), 6 96 (dd, J = 10 8 Hz, 8 8 Hz, 2H), 6 73 (t, J = 7 3 Hz, 1 H), 6 60 (d, J = 7 92 Hz, 2H), 4 90 (s, 2H), 4.41-4.38 (ma, 2H), 3.82 (dt, J = 12.8 Hz, 3.1 Hz, 2H), 2.64-2.58 (m, 2H), 1 77 (d, J = 14.1 Hz, 2H), EM (IEN +) - cale [M + H] + 519 3, obs. 519.3. The compounds described in the following table were prepared by procedures analogous to the synthetic procedures described above, but using the appropriate starting materials.

TABLE 2 EXAMPLE 3 ? / - f2-Amino-5- (2-thienyl) phenin-6- (2,8-diazaspiror4.51dec-8-yl) nicotinamide. 2-Thiophenyl-Boc-chloronicotinamide F (60 mg, 0.14 mmol) was dissolved in 1 mL of DMSO and treated with NEt3 (0.100 mL) and 2,8-diazaspiro [4.5] decane-2-carboxylate tere-butyl ester ( 50 mg, 0.21 mmol). The mixture was stirred at 90 ° C for 18 h, partitioned between EtOAc and saturated NaHCO 3, dried (Na 2 SO 4), filtered and concentrated. The residue was dissolved in 1 ml of 1: 1 TFA / CH 2 Cl 2, stirred for 5 h and concentrated. Reverse phase chromatography (10-100% MeCN / water with 0.05% TFA) followed by neutralization by extraction of EtOAc / sat. NaHCO 3. and dried (Na2SO4) gave the target spirocyclic compound: 1 H NMR (600 MHz, CD3OD): d 8.73 (s, 1 H), 8.06 (dd, J = 8.8, 2.1 Hz, 1 H), 7.45 (s, 1 H ), 7.33 (dd, J = 8.2, 2.1 Hz, 1 H), 7.21 (dd, J = 5.0, 1.2 Hz, 1 H), 7.19 (dd, J = 3.5, 0.9 Hz, 1 H), 7.00 (dd) , J = 5.0, 3.5 Hz, 1 H), 6.88 (d, J = 8.5 Hz, 1 H), 6.81 (d, J = 9.1 Hz, 1 H), 3.72 (m, 2 H), 3.62 (m, 2 H), 2.94 (t, J = 7.3 Hz, 2 H), 2.71 (s, 2 H), 1.68 (t, J = 7.0 Hz, 2 H), 1.60 (m, 4 H); EM (IEN +): cale. [M + H] + 434.2, obs. 434.2.

EXAMPLE 4 6- (2-Acetyl-2,7-diazaspirof4.51dec-7-yl) -? / - f2-amino-5- (2-thienyl) phenylH-nicotinamide. A mixture of tere-butyl 2,7-diazaspiro [4.5] decane-7-carboxylate (200 mg, 0.833 mmol), NEt3 (0.200 mL, 1.44 mmol) and Ac2O (0.100 mL, 1.06 mmol) in 1 mL of DMF it was stirred for 5 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO 3, the organic phase was dried (Na 2 SO 4), filtered and concentrated. The mixture was treated with 1: 1 TFA / CH 2 Cl 2, stirred for 1 h and concentrated. The oily residue was azeotropically distilled with methanol and placed under high vacuum overnight. Then, the resulting sticky residue was dissolved in 2 ml of DMSO containing [2-. { [(6-chloropyridin-3-yl) carbonyl] amino} Tere-Butyl (2-thienyl) phenyl] carbamate (100 mg, 0.233 mmol) was treated with NEt3 (0.50 mL) and stirred at 90 ° C for 12 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO3.The organic phase was dried (Na2SO4), filtered and concentrated. Finally, the residue was dissolved in 1: 1 TFA / CH 2 Cl 2, stirred for 1 h and concentrated. Reverse phase chromatography (10-100% MeCN / water with 0.05% TFA) followed by removal of TFA by EtOAc / saturated extraction and drying (Na2SO4) gave the title compound: 1 H NMR (600 MHz, CD3OD) : d 8.69 and 8.71 (2s, 1 H), 8.05 and 8.07 (2d, J = 9.1 Hz, 1 H), 7.47 (s, 1 H), 7.35 (d, J = 8.2 Hz, 1 H), 7.23 ( d, J = 5.0 Hz, 1 H), 7.20 (d, J = 3.5 Hz, 1 H), 7.01 (d, J = 5.0, 3.5 Hz, 1 H), 6.91 (d, J = 8.2 Hz, 1 H ), 6.82 (dd, J = 9.1, 6.2 Hz, 1 H), 3.75 (m, 2 H), 3.65 (m, 1 H), 3.52 (m, 3 H), 3.03 and 3.19 (2d, J = 12.3 Hz, 1 H), 2.00 and 2.04 (2s, 3 H), 1.6-1.9 (m, 6 H); EM (IEN +): cale. [M + H] + 476.2, obs. 476.2. The compounds described in the following table were prepared by procedures analogous to the synthetic procedures described above, but using the appropriate starting materials.

TABLE 3 EXAMPLE 5 N- [2-Amino-5- (2-thienyl) phenyl-6- (4-oxo-1-phenyl-1,3,8-triazaspiro [4.51dec-8-yl] nicotinamide. To a solution of 1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one (Acros Chemical Co.) (534 mg, 2.31 mmol) in DMSO (1.5 mL) was added [2-. { [(6-chloropyridin-3-yl) carbonyl] amino} -4- (2-thienyl) phenyl] carbamate of f-butyl (331 mg, 0.77 mmol) The reaction mixture was heated at 85 ° C for 10 hours, cooled to room temperature, diluted with EtOAc ( 50 ml) and then warmed with NaHCO3 ac sat. (1 x 10 ml) and brine (1 x 5 ml). The organic phase was dried over Na2SO, filtered, concentrated and the crude residue was purified by flash chromatography (10-100% EtOAc / hexanes). The formation of the Boc-protected biaryl spiro-nicotinamide was confirmed by MS (ESI +): cale. [M + H] + 625.3, esp. 625.3. To a solution of the Boc-protected biaryl spiro-nicotinamide in CH 2 Cl 2 (4 mL) was added TFA (2 mL). The reaction mixture was concentrated after 20 minutes of stirring at room temperature and the crude residue was purified by reverse phase chromatography (10-75% MeCN / H 2 O with 0.05% TFA). The appropriate fractions were combined, diluted with EtOAc (50 mL) and washed with aq. NaHCO 3. sat (1 x 10 ml) and brine (1 x 5 ml). The organic phase was dried over Na2SO4, filtered and concentrated to give the desired biaryl spiro-nicotinamide: 1 H NMR (600 MHz, DMSO-d6): d 9.56 (s, 1H), 8.78 (d, J = 2.6 Hz, 2H), 8.12 (dd, J = 9.1 Hz, 2.3 Hz, 1 H), 7.46 (d, J = 2.1 Hz, 1 H), 7.35-7.31 (m, 1 H), 7.29-7.26 (m, 1 H ), 7.24-7.22 (m, 1 H), 7.07-7.01 (m, 3H), 6.97 (d, J = 9.1 Hz, 1 H), 6.79 (d, J = 8.2 Hz, 1 H), 6.65 (t , J = 7.3 Hz, 1 H), 6.48 (d, J = 8.2 Hz, 1 H), 4.58 (s, 2H), 4.38-4.32 (ma, 2H), 3.68 (dt, J = 12.9 Hz, 3.2 Hz , 2H), 2.50-2.42 (m, 2H), 1.66 (d, J = 14.1 Hz, 2H); EM (IEN +): cale. [M + H] + 525.2, obs. 525.2. The compounds described in the following table were prepared by procedures analogous to the synthetic procedures described above, but using the appropriate starting materials.

TABLE 4 EXAMPLE 6 ? / - [2-Amino-5- (2-t-enyl) phenyl-6- (2-oxo-1-oxa-3,8-diazaspiro [4.51dec-8-yl] nicotinamide) 1-oxa- 3,8-diazaspiro [4.5] decan-2-one from Boc-piperidone as described by Smith, PW et al., New Spiropiperidines as Potent and Selective Non-Peptide Tachykinin NK2 Receptor Antagonists. J. Med. Chem. 1995, 38, 3772. A solution of 1-oxa-3,8-diazaspiro [4.5] decan-2-one (390 mg, 1.44 mmol, mono-TFA salt), NEt3 (1.00 ml, 7.19 mmol) and [2-. { [(6-chloropyridin-3-yl) carbonyl] amino} -4- (2-thienyl) phenyl] -butyl carbamate (400 mg, 0.93 mmol) in 5 mL of DMSO was stirred at 90 ° C for 21 hours. The crude reaction mixture was cooled and partitioned between CH2Cl2 and 2N HCl. Then, the organic phase was washed with water, dried (Na2SO4), filtered and concentrated. The oily residue was dissolved in CH2Cl2 / TFA 3: 1 (4 mL) and stirred for 1 hour. The mixture was concentrated and purified by reverse phase chromatography (30-100% MeCN / water containing 0.05% TFA). The product was neutralized by partitioning between CHCl3 / methanol and 2N NaOH and the organic phase was dried (Na2SO) and concentrated to give the target compound: 1 H NMR (600 MHz, DMSO-d6): d 9.53 (s, 1 H) , 8.74 (d, J = 2.3 Hz, 1 H), 8.08 (dd, J = 9.1, 2.6 Hz, 1 H), 7.54 (s, 1 H), 7.43 (d, J = 2.1 Hz, 1 H), 7.33 (dd, J = 5.0, 1.2 Hz, 1 H), 7.25 (dd, J = 8.2, 2.3 Hz, 1 H), 7.21 (dd, J = 3.8, 1.2 Hz, 1 H), 7.02 (dd, J = 5.0, 3.5 Hz, 1 H ), 6.96 (d, J = 8.8 Hz, 1 H), 6.77 (d, J = 8.2 Hz, 1 H), 5.12 (sa, 2 H), 3.92 (m, 2 H), 3.53 (m, 2 H) ), 3.27 (s, 2 H), 1.71-1.83 (m, 4 H); EM (IEN +): cale. [M + H] + 450.2, obs. 450.1. The compounds described in the following table were prepared by procedures analogous to the synthetic procedures described above, but using the appropriate starting materials.

TABLE 5 EXAMPLE 7 ? / - r2-Amino-5- (2-thienyl) phen-6- (1,8-diazaspiro [4.51dec-8-i-nicotinamide] A mixture of [2- {[[6-chloropyridin-3-yl] ) carbonyl] amino.} -4- (2-thienyl) phenyl] carbamate / butyl-butyl ester (200 mg, 0.47 mmol) and 1,8-diazaspiro [4.5] decane-1-butyl-butyl carboxylate ( 200 mg, 0.83 mmol) in 5 ml of DMSO was treated with Et3N (0.104 ml) and stirred at 90 ° C. for 12 h.The reaction mixture was partitioned between EtOAc and saturated NaHCO3 and the organic phase was dried (MgSO4). it was filtered and concentrated.Finally, the residue was dissolved in 1: 1 TFA / CH2CI2, stirred for 1 h and concentrated Reverse phase chromatography (10-100% MeCN / water with 0.05% TFA) followed by neutralization by extraction of EtOAc / satd NaHCO3 and drying (MgSO4) gave the target spirocyclic compound: 1 H NMR (600 MHz, DMSO-d 6): d 9.48 (s, 1 H), 8.72 (d, J = 1.8, Hz, 1 H), 8.05 (dd, = 8.4, 1.8 Hz, 1 H), 7.42 (d, J = 1.8 Hz, 1 H), 7.33 (d, J = 5.4 Hz, 1 H), 7.26 (dd, J = 8.4, 2.4 Hz, 1 H), 7.21 (d, J = 3 Hz, 1 H), 7.02 (t, J = 4.2 Hz, 1 H), 6.91 (d, J = 9.6, 1 H), 6.77 (d, J = 9.0, 1 H), 5.10 (s, 2 H), 3.80 (ma, 2 H), 3.57 (ma, 2 H), 2.96 (ma, 2 H), 1.79 (ma, 2 H) , 1.58 (ma, 4 H); EM (IEN +): cale. [M + H] + 434.2, obs. 434.2.

EXAMPLE 8 ? / - (4-Amino-1-phenyl-1-1 H -pyrazol-3-yn-6- (4-oxo-1-phenyl-1,3,8-triazaspiro- [4,5ldec-8-yl) nicotinamide A a solution of 1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one (Acros Chemical Co.) (159 mg, 0.688 mmol) in DMSO (1.2 mL) was added (3-. {[[(6-chloropyridin-3-yl) carbonyl] amino.} -1-phenyl-1H -butyl-4-yl) -butyl carbamate (114 mg, 0.275 mmol). The reaction mixture was heated at 85 ° C for 12 hours, cooled to room temperature, diluted with EtOAc (25 mL) and then heated with aq. NaHCO 3. sat (1 x 5 ml) and brine (1 x 5 ml). The organic phase was dried over Na2SO4, filtered, concentrated and the crude residue was purified by flash chromatography (10-100% EtOAc / hexanes). The formation of the Boc-protected pyrazole spiro-nicotinamide was confirmed by MS (ESI +): cale. [M + H] + 609.3, esp. 609.3. To a solution of the Boc-protected? / - phenyl pyrazolyl spiro-nicotinamide in CH2Cl2 (4 mL) was added TFA (2 mL). The reaction mixture was concentrated after 20 minutes of stirring at room temperature and the crude residue was purified by reverse phase chromatography (10-75% MeCN / H 2 O with 0.05% TFA). The appropriate fractions were combined, diluted with EtOAc (50 mL) and washed with aq. NaHCO 3. sat (1 x 10 ml) and brine (1 x 5 ml). The organic phase was dried over Na2SO4, filtered and concentrated to give the desired? / - phenyl pyrazolyl spiro-nicotinamide: H NMR (600 MHz, DMSO-d6) d 10.52 (s, 1 H), 8.83-8.78 (m , 2H), 8.16 (dd, J = 8.9 Hz, 2.5 Hz, 1 H), 7.77 (s, 1H), 7.65 (d, J = 7.6 Hz, 2H), 7.41 (t, 7.9 Hz, 2H), 7.16 (t, J = 7.3 Hz, 1 H), 7.02 (t, J = 7.9 Hz, 2H), 6.96 (d, J = 9.1 Hz, 1 H), 6.64 (t, J = 7.3 Hz, 1 H), 6.48 (d, J = 8.2 Hz, 2H), 4.58 (s, 2H), 4.39-4.33 (ma, 2H), 3.67 (dt, J = 12.9 Hz, 3.2 Hz, 2H), 2.48-2.41 (m, 2H) ), 1.66 (d, J = 14.1 Hz, 2H); EM (IEN +): cale. [M + H] + 509.2, obs. 509.2. The compounds described in the following table were prepared by procedures analogous to the synthetic procedures described above, but using the appropriate starting materials.

TABLE 6 EXAMPLE 9 8- (5 - ([(4-Aminobiphenl-3-yl) aminolcarbonyl) pyridin-2-yl) -? / 3-phenyl-? / 2- (2-phenylethyl) -2,8-diazaspiro [4.51decano-2,3-dicarboxamide To a stirred solution of 2- (9H-fluoren-9-ylmethyl) 3- (anilinocarbonyl) -2,8-diazaspiro [4.5] decane-2,8-dicarboxylate of 8- ferc-butyl (1500 mg, 2961 mmol), EDCI (681.2 mg, 3.553 mmol), HOBt (480.0 mg, 3.553 mmol) and DMF (4.0 mL) were added aniline (413.6 mg, 4.441 mmol). After stirring at rt for 21 h, the reaction was diluted with EtOAc (30 mL) and washed with H20 (1 x 10 mL) and brine (1 x 10 mL). Then, the organic phase was dried over Na 2 SO 4, filtered, concentrated and the crude residue was purified by column chromatography (7-60% Hexanes: EtOAc). The formation of the amide was confirmed by EM (IEN +): cale. [M + H] + 582.3, esp. 582.3. To a solution of the amide dissolved in DMF (4.0 ml) was added piperidine (504.2 mg, 5.922 mmol). The reaction was placed under N2 atmosphere and stirred at rt for 1 h. Then, the crude reaction mixture was concentrated, taken up in EtOAc, and washed with H2O (1 x 10 mL). Then, the organic phase was dried over Na2SO4, filtered, concentrated and purified by reverse phase chromatography (15-85% MeCN / H2O with 0.05% TFA). The formation of the free amine was confirmed by MS (ESI +): cale. [M + H] + 360.2, esp. 360.2. To a solution of the free amine (100 mg, 0.2782 mmol) in DMF (1.5 mL) was added phenethyl isocyanate (122.84 mg, 0.8346 mmol). The reaction was stirred at rt for 18 h. Then, the crude mixture was diluted with EtOAc (10 mL) and washed with aq. NaHCO3. sat (1 x 3 ml) and brine (3 ml). Then, the organic phase was dried over Na 2 SO 4, filtered, concentrated and purified by reverse phase chromatography (15-85% MeCN / H 2 O with 0.05% TFA). The formation of urea was confirmed by MS (ESI +): cale. [M + H] + 507.3, esp. 507.3. The purified urea was dissolved in CH CI2 (2.0 ml) and treated with TFA (1.0 ml) under N2 atmosphere. After stirring the reaction mixture at rt for 30 min, it was concentrated and purified by reverse phase chromatography.

(MeCN at 15-85% / H20 with 0.05% TFA). The formation of the free amine was confirmed by MS (ESI +): cale. [M + H] + 407.2, esp. 407.3. To a solution of the free amine in DMSO (0.5 ml) and toluene (0.25 ml) was added (3- {[[(6-chloropyridin-3-yl) carbonyl] amino} biphenyl-4-yl. ) ferric-butyl carbamate (47.2 mg, 0.111 mmol). The reaction was heated in an oil bath at 85 ° C. After being stirred at 85 ° C for 48 h, the crude reaction mixture was cooled to rt, diluted with EtOAc (20 mL) and washed with aq. NaHCO 3. sat (1 x 5 ml) and brine (1 x 3 ml). Then, the organic phase was dried over Na SO4, filtered, concentrated and purified by reverse phase chromatography (15-85% MeCN / H20 with 0.05% TFA). The formation of spiro-nicotinamide was confirmed by MS (ESI +): cale. [M + H] + 794.4, esp. 794.3. Then, a solution of the spiro-nicotinamide in CH 2 Cl 2 (2.0 ml) was treated with TFA (1.0 ml) under N 2 atmosphere and stirred at rt for 30 min. Then, the crude reaction mixture was concentrated and purified by reverse phase chromatography (10-100% MeCN / H 2 O with 0.05% TFA). The appropriate fractions were collected and concentrated. Then, the TFA salt of the desired product was dissolved in EtOAc (30 mL) and washed with aq. NaHCOs. sat (1 5 ml) and brine (1 x 5 ml). Then, the organic phase was dried over Na 2 SO 4, filtered and concentrated to give the desired biphenyl spiro-nicotinamide. EM (IEN +): cale. [M + H] + 694.3, esp. 694.3.

EXAMPLE 10 8- (5- { [(4-Aminobiphenyl-3-yl) aminolcarbonyl) pyridin-2-yl) -? / - (2-phenylethyl) -1-oxa-2,8-diazaspiro [4.5ldec-2 -3-carboxamide To a solution of 8 - (/ erc-butoxycarbonyl) -1-oxa-2,8-diazaspiro [4.5] dec-2-en-3-carboxylic acid (300 mg, 1.06 mmol), EDC (242 mg, 1. 26 mmol) and HOBt (171 mg, 1.26 mmol) in DMF (4 mL) was added phenethylamine (159 μL, 1.26 mmol). After 4 h at room temperature, the reaction mixture was diluted with EtOAc (10 mL) and washed with H2O (1 x 5 mL) and brine (1 x 5 mL). The organic phase was dried over Na 2 SO 4, filtered and concentrated. The crude oil was taken up in CH2Cl2 (4 mL) and treated with TFA (2 mL). The reaction mixture was concentrated and the crude oil was purified by reverse phase chromatography (10-75% MeCN / H 2 O with 0.05% TFA), giving the α / - (2-phenylethyl) -1-oxa-2, 8-diazaspiro [4.5] dec-2-en-3-carboxamide confirmed by MS (ESI +): cale. [M + H] + 288.2, obs. 288.2. To a solution of? / - (2-phenylethyl) -1-oxa-2,8-diazaspiro [4.5] dec-2-en-3-carboxamide (127 mg, 0.442 mmol) in DMSO (1 mL) and -Pr2NEt (250 μl) was added (3- {[[6-chloropyridin-3-yl) carbonyl] amino} biphenyl-4-yl) carbamate-butyl ester (75 mg, 0.18 mmol). The reaction mixture was heated at 85 ° C for 8 h, cooled to room temperature, diluted with EtOAc (10 mL) and then heated with NaHCO 3 (1 x 10 mL) and brine (1 x 5 mL). The organic phase was dried over Na 2 SO 4, filtered and concentrated. The crude oil was purified by flash chromatography (10-100% EtOAc / hexanes) and the Boc-protected biphenyl nicotinamide was treated with TFA (2 mL) in CH 2 Cl 2 (4 mL) for 20 minutes. The reaction mixture was concentrated and the crude residue was purified by reverse phase chromatography (10-100% MeCN / H 2 O with 0.05% TFA), giving the desired benzamide biphenyl after washing with conventional NaHCO 3 (sat. of the TFA salt confirmed by EM (IEN +): cale. [M + H] + 575.3, obs. 575.3.

EXAMPLE 11 6- (2-acetyl-2,8-diazaspiror4.51dec-8-ip -? / - 2-amino-5- (2-thienyl) phenyl-nicotinamide A mixture of 2,8-diazaspiro [4.5] decane-8 Erectile butylcarboxylate (500 mg, 1.81 mmol) and NEt 3 (1.00 mL, 7.19 mmol) in 5 mL of CH 2 Cl 2 was treated with Ac 2 O and stirred for 5 h The reaction mixture was diluted with EtOAc and washed NaHCO 3 sat, dried (Na 2 SO), filtered and concentrated The oily residue was dissolved in 1 ml of TFA and 3 ml of CH 2 Cl 2, stirred for 1 h and concentrated The excess TFA was removed azeotropically with methanol The oily material was dissolved in 2 ml of DMSO, treated with NEt3 (0.500 ml, 3.59 mmol) and chloronicotinamide F (200 mg., 0.466 mmol), stirred at 90 C for 18 h and partitioned between EtOAc and sat. NaHCO 3. The organic phase was dried (Na2SO), concentrated and the residue was purified by chromatography on Si02 (MeOH / EtOAc, 0% to 50%). Then, the intermediate was stirred in 1 mL of TFA and 3 mL of CH2Cl2 for 2 h, concentrated, poured into CH2Cl2 / methanol, washed with NaOH2N, dried (Na2SO) and concentrated to provide the title compound. 1 H NMR (600 MHz, DMSO-6) d 9 47 (s, 1 H), 8 72 (s, 1 H), 8 05 (m, 1 H), 7 43 (s, 1 H), 7 33 ( d, = 4 7 Hz, 1 H) 7 26 (d, J = 8 2 Hz, 1 H), 7 22 (d, J = 2 9 Hz, 1 H), 7 02 (t, J = 4 1 Hz , 1 H), 6 90 (dd, J = 8 8, 4 7 Hz, 1 H), 6 78 (d, = 8 2 Hz, 1 H), 5 11 (s, 2 H), 3 72 (m , 2 H), 3 62 (m, 1 H), 3 57 (m, 1 H), 3 48 (t, J = 7 0 Hz, 1 H), 3 33 (m, 2 H), 3 20 ( s, 1 H), 1 91 (s, 3 H), 1 82 (t, J = 7 0 Hz, 1 H), 1 73 (t, J = 7 0 Hz, 1 H), 1 50 (m, 4 H), MS (E) [M + H) + cale 476 1, obs 476 1 The compounds described in the following table are prepared by procedures analogous to the synthetic procedures described above, but using the appropriate starting materials TABLE 7 EXAMPLE 12 ? / - (2-aminophenyl) -6- (3- [2- (methylamino) -2-oxoetin-4-oxo-1-phenyl-1,3,8-triazaspiro [4.5ldec-8-yl] nicotinamide] The title compound was prepared from? / - methyl-2- (4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-3-yl) acetamide following the procedure indicated in Example 1. EM (IEN +): cale. [M + HJ + 514.3, Obs. 514.3. This spirocycle and the related spirocycles were prepared by the procedures described in (1) Poulain, R. Horvath, D .; Bonnet, B .; Eckhoff, C; Chapelain, B .; Bodinier, M.-C; Deprez, B. From Hit to Lead. Combining Two Complement / Methods for Focused Library Design. Application to Opiate Ligands. J. Med. Chem. 2001, 44, 3378 and (2) Mach, R. H .; Jackson, J. R. Luedtke, R. R .; Ivins, K. J .; Molinoff, P. B .; Ehrenkaufer, R. L. Effect of N-alkylation on the affinities of analogs of spiperone for dopamine D2 and serotonin 5-HT2 receptors. J. Med. Chem. 1992, 35, 423.

The compounds described in the following table were prepared by procedures analogous to the synthetic procedures described above, but using the appropriate starting materials.

TABLE 8 EXAMPLE 13 8- [5 - (([2-Amino-5- (2-thienyl) phenylamino) carbonyl) pyridin-2-yl -? / - ethyl-1,8-diazaspiro [4,5-decano-1-carboxamide A solution of 1, 8-diazaspiro [4.5] -decano-1-carboxylate of fer-butyl (600 mg, 2.5 mmol) in 5 ml of CH 2 Cl 2 was treated with CbzCl (528 μl, 3.75 mmol) and NEt 3 (697 μl, 5.0 mmol ) and stirred for 1 h at room temperature. The reaction mixture was partitioned between EtOAc and saturated NaHCO 3, the organic phase was dried (MgSO 4), filtered and concentrated. The crude residue was purified by chromatography on Si02 gel (0-100% EtOAc / CH2Cl2). The residue was stirred in 2 ml of TFA and 2 ml of CH2Cl2 for 1 h at room temperature and concentrated. The reaction mixture was neutralized by extraction of EtOAc / sat. NaHCO3, dried (MgSO4), filtered and concentrated. The formation of the Cbz-protected spirocycle was confirmed by MS (ESI +): cale. [M + H] + 275.2, esp. 275.2. To a solution of the Cbz-protected spirocycle in CH 2 Cl 2 (50 mL) were added Et 3 N (509 μL, 3.65 mmol) and ethyl isocyanate (115 μL, 1.46 mmol) and stirred at room temperature for 12 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO3, the organic phase was dried (MgSO), filtered and concentrated. A suspension of spiroamine (200 mg, 0.73 mmol) and 5% Mole / C Pd (40 mg, 0.037 mmol) in 5 mL of MeOH was deoxygenated by hydrogen exchange / vacuum. The mixture was treated with 1 atm of hydrogen for 3 days, filtered through Celite and concentrated to give? / -ethyl-1,8-diazasp? Ro [4.5] decane-1-carboxamide. A solution of intermediate F (82 mg, 0.19 mmol), β / - ethyl-1,8-diazaspiro [4.5] -decano-1-carboxamide (73 mg, 0.35 mmol), and NEt3 (43 μL, 0.31 mmol) in 5 ml of DMSO was stirred at 90 ° C for 12 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO 3, the organic phase was dried (MgSO), filtered and concentrated. The residue was stirred in 2 ml of TFA and 2 ml of CH2Cl2 for 1 h at room temperature and concentrated. Reverse phase chromatography (10 to 100% MeCN / water with 0.05% TFA) followed by neutralization by extraction of EtOAc / saturated NaHCO3 and drying with MgSO4 gave the title compound: MS (ESI +): cale. [M + H] + 505.2, obs. 505.2.

EXAMPLE 14 ? / - (4-Aminobiphenyl-3-yl) -6- (7-pyrimidin-2-yl-2,7-diazaesp? Ro [4.41non-2-yl) nicotinamide A solution of 6-chloronicotinamide D (580) mg, 1.37 mmol) in 5 ml of DMSO was treated with NEt3 (0.50 ml, 3.59 mmol) and 2-benzyl-2,7-diazaspiro [4.4] nonane (500 mg, 2.31 mmol) and heated at 90 ° C for 15 h. The mixture was cooled and partitioned between EtOAc and saturated NaHCO3, dried (Na2SO4), filtered and concentrated. Chromatography on Si02 (0 to 30% MeOH / EtOAc) gave the adduct. A suspension of this benzylamine (700 mg, 1.16 mmol) and 20% Pd (OH) 2 / C (200 mg, 0.28 mmol) in 10 ml of EtOH was deoxygenated by hydrogen exchange / vacuum. The mixture was treated with 379,211 kPa (55 psi) of hydrogen for 2 days (Parr hydrogenation apparatus), filtered through Celite and concentrated, giving the de-benzylated spirocyclic amine. A portion of this secondary amine (40 mg, 0.078 mmol) in 2 ml of DMSO was treated with NEt3 (0.050 ml) and 2-chloropyrimidine (20 mg, 0.18 mmol) and then heated at 90 ° C for 15 h. The crude mixture was partitioned between EtOAc and saturated NaHCO3, dried (Na2SO) and concentrated. The resulting residue was dissolved in 1: 1 TFA / CH2Cl2 (2 mL), stirred for 2 h and then concentrated. Reverse phase chromatography (20 to 100% MeCN / water with 0.05% TFA) followed by neutralization by extraction of EtOAc / saturated NaHC03 and drying with Na SO gave the target pyrimidine: 1 H NMR (600 MHz, CD3OD) d 8.73 (s, 1 H), 8.30 (d, J = 5.0 Hz, 2 H), 8.10 (dd, J = 8.80, 2.1 Hz, 1 H), 7.54 (d, J = 7.3 Hz, 2 H), 7.45 ( d, J = 2.1 Hz, 1 H), 7.35 (m, 3 H), 7.23 (t, J = 1.2 Hz, 1 H), 6.95 (d, J = 8.5 Hz, 1 H), 6.59 (t, J) = 5.0 Hz, 1 H), 6.57 (d, J = 9.1 Hz, 1 H), 3.60-3.70 (m, 4 H), 3.50-3.60 (m, 4 H), 2.08-2.15 (m, 4 H); MS (El) [M + H] + cale. 492.3, obs. 492.3. The compounds described in the following table were prepared by procedures analogous to the synthetic procedures described above, but using the appropriate starting materials.

TABLE 9 EXAMPLE 15 1,2-phen? Lend? Am? A 7- (5-. {[[(2-Aminophenyl) amino-1-carbonyl) pyridin-2-yl) -2,7-diazaspiro [4,41nonan-2-pyridin carboxylate] -3-ylmethyl 2-benzyl-2,7-diazaspiro [4.4] nonane was purchased from Clariant Ltd. For the synthesis and manipulation of this spirocycle, see Culbertson, TP et al., Quinolone antibacterial agents substituted at the 7-position with spiroamines. Synthesis and structure-activity relationships. J. Med. Chem. 1990, 33, 2270. A mixture of 2-benzyl-2,7-diazaspiro [4.4] nonane (1.00 g, 4.68 mmol), methyl 6-chloronicotinate (800 mg, 4.68 mmol) and K2CO3 (700 mg, 5.07 mmol) in 5 ml of DMSO was stirred with microwave irradiation for 20 min at a temperature of 150 ° C. The mixture was poured into EtOAc, washed with sat. NaHCO3, dried (Na2SO4), filtered and concentrated to give 6- (7-benzyl-2,7-diazaspiro [4.4] non-2-yl) nicotinate. methyl. A flask containing a suspension of benzylamine and 20% Pd (OH) 2 C (600 mg, 0.857 mmol) in 20 ml of EtOH was evacuated and purged three times with H2 gas. Using a Parr agitator apparatus, the suspension was stirred at 344,737 kPa (50 psi) of H2 for 20 h. The pressure was released and the mixture was filtered through a pad of Celite and concentrated to give 6- (2,7-diazaspiro [4.4] non-2-yl) methyl nicotinate: 1 H NMR (600 MHz, DMSO- d6) d 8.59 (d, J = 2.1 Hz, 1 H), 7.89 (dd, J = 9.1, 2.3 Hz, 1 H), 7.27 (d, J = 4.4 Hz, 1 H), 6.44 (d, J = 8.8 Hz, 1 H), 3.74 (s, 3 H), 3.13 ( sa, 4 H), 2.89 (t, J = 7.3 Hz, 2 H), 2.72 (AB, J = 7.6 Hz, 2 H), 1.92 (ma, 2 H), 1.69 (AB, J = 7.3 Hz, 2 H).

A mixture of pyridin-3-ylmethanol (0.050 mL, 0.51 mmol) and carbonyldiimidazole (80 mg, 0.49 mmol) in 3 mL of THF was stirred for 4 h. Then, 6- (2,7-diazaspiro [4.4] non-2-yl) methyl nicotinate (150 mg, 0.575 mmol) and DMAP (1 crystal) were added and the mixture was stirred for 15 h and then concentrated to dryness . Chromatography on S1O2 (0-20% MeOH / EtOAc) gave the intermediate methyl ester. The methyl ester was dissolved in 2 ml of 1: 1 THF / water, treated with LiOH H2O (25 mg, 0.60 mmol) and stirred for 20 hours, after which the mixture was concentrated, azeotropically dried with MeOH and put on vacuum for 3 h. A mixture of the residue in 2 ml of DMF was treated with EDC (200 mg, 1.05 mmol), HOBt (100 mg, 0.74 mmol) and phenylenediamine (100 mg, 0.93 mmol), stirred for 15 h and concentrated to dryness. Reverse phase chromatography (5-20% water / MeCN with 0.05% TFA) gave 7- (5- { [(2-Aminophenyl) amino] carbonyl, pyridin-2-yl) -2, 7-diazaspiro [4.4] nonan-2-carboxylate of pyridin-3-ylmethyl in the form of the tris-TFA salt: 1 H NMR (600 MHz, DMSO-cf 6) d 9.95 (d, J = 4.1 Hz, 1 H), 8.73 (d, J = 12.9 Hz, 1 H), 8.65-8.67 (m, 2 H), 8.17 (d, J = 9.1 Hz, 1 H), 8.10 (dd, J = 21.0, 7.9 Hz, 1 H) , 7.66 (m, 1 H), 7.25 (d, J = 7.9 Hz, 1 H), 7.13 (t, J = 7.6 Hz, 1 H), 7.05 (d, J = 7.9 Hz, 1 H), 6.96 ( m, 1 H), 6.74 (dd, J = 9.1, 3.8 Hz, 1 H), 5.15 (m, 2 H), 3.60 (m, 2 H), 3.30-3.55 (m, 6 H), 2.01 (m , 2 H), 1.91 (m, 2 H); MS (El) [M + H] + cale. 473.3, obs. 473.4.

The compounds described in the following table were prepared by procedures analogous to the synthetic procedures described above, but using the appropriate starting materials TABLE 10 EXAMPLE 16 4) TFA, CH2CI2 8- (5-ir (4-Aminobiphenyl-3-ipamino-1-carbonyl) pyridin-2-yl) -? / - (2-phenylethyl) -2,8-diazaspiro [4.51decano-2-carboxamide] To a solution of 6 methyl-chlorothonicotinate (200 mg, 1.16 mmol) in DMSO / PhMe (2 ml of a 1: 1 solution) was added with 2,8-diazaspiro [4.5] decane-2-carboxylic acid-f-butyl ester (700 mg, 2.91 mmol). The reaction mixture was heated at 85 ° C for 6 hours and then diluted with EtOAc (10 mL). The organic phase was washed with NaHC 3 (1 x 5 mL) and brine (1 x 5 mL), dried over Na 2 SO 4 and then concentrated. The crude residue was purified by flash-phase reversed-phase chromatography (10-100% MeCN / H 2 O with 0.05% TFA), giving 8- [5- (methoxycarbonyl) pyridin-2-yl] -2,8-diazaspiro [4.5 ] f-butyl decane-2-carboxylate: MS (ESI +): cale. [M + H] + 376.2obs. 376.2. Then, this intermediate was treated with TFA (3 mL) in CH2Cl2 (6 mL). The reaction mixture was concentrated after 30 minutes of stirring at room temperature and the crude residue was purified by flash-phase reversed-phase chromatography (10-75% MeCN / H 2 O with 0.05% TFA), giving 6- (2, 8-diazaspiro [4.5] dec-8-yl) methyl nicotinate: MS (ESI +): cale. [M + Hf 276.2, obs. 276.2. To a solution of methyl 6- (2,8-diazaspiro [4.5] dec-8-yl) nicotinate (245.2 mg, 0.891 mmol) in DMF (3.0 mL) was added phenethyl isocyanate (393.3 mg, 2.672 mmol) . After 23 h of stirring at room temperature, the reaction mixture was diluted with EtOAc (15 mL) and washed with saturated aqueous NaHCO 3 (1 x 4 mL) and brine (1 x 4 mL). Then, the organic phase was dried over NaSO, filtered, concentrated and the crude residue was purified by reverse phase chromatography (15-85% MeCN / H 2 O with 0.05% TFA). The formation of methyl 6- (2-. {[[(2-phenylethyl) amino] carbonyl} -2,8-diazaspiro [4.5] dec-8-yl) was confirmed by EM (IEN +): . [M + H] + 423.2, obs. 423.3. To a solution of LiOH (63.7 mg, 2.672 mmol) in H 2 O (750 μl) was added dropwise a solution of 6- (2. {[[(2-phenylethyl) amino] carbonyl] -2. 8-diazaspiro [4.5] dec-8-yl) methyl nicotinate in THF (1 ml). Then, the reaction mixture was heated to reflux and cooled to room temperature. After 22 h of stirring at room temperature, the reaction was concentrated, taken up in MeOH (5 mL) and purified by reverse phase chromatography (15-85% MeCN / H 2 O with 0.05% TFA). The formation of 6- (2-. {[[(2-phenylethyl) amino] carbonyl} -2,8-diazaspiro [4.5] dec-8-yl) nicotinic acid was confirmed by MS (ESI +): heat [ M + H] + 409.2, obs. 409.2. To a solution of 6- (2-. {[[(2-phenylethyl) amino] carbonyl} -2,8-diazaspiro [4.5] dec-8-yl) nicotinic acid in DMF (2.5 ml) were added. EDCI (512.3 mg, 2672 mmol) and HOBt (300.8 mg, 2227 mmol). The reaction mixture was allowed to stir for 10 min at room temperature. Then, f-butyl (3-aminobiphenyl-4-yl) carbamate (759.8 mg, 2.672 mmol) was added at room temperature. The reaction was heated to 50 ° C and allowed to stir for 90 h. Then, the reaction mixture was cooled to room temperature, diluted with EtOAc (15 mL) and washed with H2O (5 mL). Then, the organic phase was dried over Na2SO4, filtered, concentrated and purified by reverse phase chromatography (15-100% MeCN / H2O with 0.05% TFA). The formation of the Boc-protected biphenyl spiro-nicotinamide was confirmed by MS (ESI +): calo 675.3, obs. 675.3. To a solution of the Boc-protected biphenyl spiro-nicotinamide in CH 2 Cl 2 (4 mL) was added TFA (1.5 mL). After stirring at room temperature for 30 min the reaction mixture was concentrated and the crude residue was purified by reverse phase chromatography (15-85% MeCN / H20 with 0.05% TFA). The appropriate fractions were combined, diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (1 x 50 mL) and brine (1 x 50 mL). The organic phase was dried over Na 2 SO 4, filtered and concentrated to give the desired biphenyl-spiro-nicotinamide: 1 H NMR (600 MHz, DMSO-6) d 9.49 (s, 1 H), 8.73 (d, J = 2.3 Hz, 1 H), 8.06 (dd, J = 11.4 Hz, 2.4 Hz, 1 H), 7.52 (dd, J = 9.5 Hz, 1.1 Hz, 2H), 7.47 (d, J = 2.1 Hz, 1H), 7.36 (t , J = 7.9, 2H), 7.29-7.24 (m, 3H), 7.21 (t, J = 7.3 Hz, 1 H), 7.17-7.15 (m, 3H), 6.90 (d, J = 9.1 Hz, 1 H ), 6.83 (d, J = 8.2 Hz, 1 H), 3.76-3.72 (m, 2H), 3.56-3.52 (m, 2H), 3.30-3.25 (m, 3H), 3.21-3.17 (m, 2H) , 3.13 (sa, 2H), 2.69 (t, J = 7.5 Hz, 2H), 1.74 (t, = 7.04 Hz, 2H), 1.50-1.47 (m, 4H) EM (IEN +): cale. [M + H] + 575.3, obs. 575.3.

EXAMPLE 17 ? / - (4-Aminobiphenyl-3-yl) -4- (1, 8-diazaspirof4.51dec-8-ylmethylbenzamide) To a scintillation vial were added the FDMP stratosphere resin (1.5 mmol / g load) (67). mg, 0.10 mmol), 137 mg (0.5 mmol) of fer-butyl (3-amino-1-phenyl-1 / - / - pyrazol-4-yl) carbamate and 1 ml of 5% AcOH in DCE and the The vial was allowed to stir overnight at room temperature, 106 mg (0.5 mmol) of NaBH (OAc) 3 in 1 ml of 5% AcOH in DCE was added to the vial, the vial was capped, purged and left react for 3 days at room temperature The resin was washed 3 times with each of the following solvents and dried under vacuum: DMF, MeOH, H20, MeOH and DCM The resin from the previous step (0.1 mmol) was added to one vial of scintillation together with 2 ml of DCM and 51 mg (0.4 mmol) of DIEA The vial was shaken for 1 minute and 38 mg (0.2 mmol) of 4-chloromethylbenzoyl chloride was added The vial was capped, purged and allowed to react overnight at room temperature The resin was washed 3 times with each of the following solvents and dried under vacuum: DCM, DMF, H2O, MeOH and DCM. To a scintillation vial, the resin from the previous step (0.1 mmol) was added together with 214 mg (1.0 mmol) of proton sponge, 45 mg (0.3 mmol) of Nal, 120 mg (0.5 mmol) of 1.8. -diazapiro [4.5] decane-1-carboxylate of fer-butyl and 2 ml of DMF. The resin was washed three times with each of the following solvents and dried under vacuum: DMF, H2O, MeOH and DCM. The resin from the previous step (0.1 mmol) was cleaved with 3 ml of 1: 1 DCM: TFA for 2 hours at room temperature. The filtrate was collected and purified by HPLC to yield the product,? / - (4-aminobiphenyl-3-yl) -4- (1, 8-diazaspiro [4.5] dec-8-ylmethyl) benzamide, in the form of a solid white: MS (ESI +): cale. [M + H] + 441.3, obs. 441.3.

The compounds described in the following table were prepared by procedures analogous to the synthetic procedures described above, but using the appropriate starting materials.

TABLE 11 EXAMPLE 18 ? / - (4-aminobiphenyl-3-yl) -4- (1, 8-diazaspiror-4-ldec-8-ylcarboni-D-benzamide) To a solution of stirring terephthaloyl chloride (50 mg, 246 mmol) in 3 ml of dichloromethane was added. He added slowly (3-aminobiphenyl-4-yl) -carbamic acid ester (70 mg, 0.246 mmol) over a period of 10 minutes, followed by the addition of diisopropylethylamine (43 μL, 0.246 mmol). left under stirring for 30 min at room temperature, then 1,8-diazaspiro [4.5] decane-1-carboxylic acid-butyl ester (59 mg, 0.246 mmol) was added, followed by the addition of diisopropylethylamine (43 μl, 0.246). The reaction mixture was allowed to stir for 1 hour at room temperature, the reaction mixture turned turbid, then Carbonate Argonaut MP (255 mg, 0.738 mmol) Carbonate eliminating resin was added and stirred overnight. At room temperature, the mixture was completely dissolved by the addition of 3 ml of dimethylformamide, filtered through the scavenging resin and concentrated. Dichloromethane (1 mL) was added, the mixture was stirred to form a suspension and then treated with trifluoroacetic acid (10 mL). The reaction mixture was concentrated after 2 hours of stirring at room temperature and the crude residue was purified by reverse phase chromatography (5-75-95% acetonitrile / water with 0.1% formic acid). The appropriate fractions were combined and lyophilized. EM (IEN +): cale. [M + H] + 455.2, obs. 455.1.

EXAMPLE 19 ? / - (4-. {[[(4-aminobiphenyl-3-yl) aminolcarbonyl) phenyl) -7-benzyl-2,7-diazaspiro [4.41nonan-2-carboxamide. To a solution of stirring 4-isocyanatobenzoyl chloride (50 mg, 0.275 mmol) in 3 mL of dichloromethane was slowly added 2-benzyl-2,7-diazaspiro [4.4] nonane (60 mg, 0.275 mmol) over a period of time. 10 minutes. The reaction mixture was allowed to stir for 30 min at room temperature. Then, fer-butyl (3-aminobiphenyl-4-yl) carbamate (78.2 mg) was added., 0.275 mmol), followed by the addition of diisopropylethylamine (48 μL, 0.275 mmol). The reaction mixture was allowed to stir for 1 hour at room temperature. Then, Carbonate Argonaut MP scavenging resin (285 mg, 0.825 mmol) was added and the mixture was stirred overnight at room temperature. Then, the mixture was filtered from the eliminating resin and concentrated. Dichloromethane (1 mL) was added, the mixture was stirred and then treated with trifluoroacetic acid (10 mL). The reaction mixture was concentrated after 2 hours of stirring at room temperature and the crude residue was purified by reverse phase chromatography (5-50-95% acetonitrile / water with 0 1% formic acid). The appropriate fractions were combined. and lyophilized EM (IEN +) cale [M + H] + 546 3, obs 546 2 The compounds described in the following table were prepared by procedures analogous to the synthetic procedures described above, but using the appropriate starting materials TABLE 12 EXAMPLE 20 ? / - (4-Aminobiphenyl-3-yl) -6- (2,8-diazaspiro [4.5ldec-8-yl) -1-benzothiophen-2-carboxamide 6-bromo-1-benzothiophen-2-carboxylate was prepared ethyl acetate following the procedure: sodium hydride (60% dispersion in mineral oil, 0.73 g, 18.3 mmol) was suspended in DMSO (10 mL) and ethyl mercaptoacetate (1.11 mL, 10.1 mmol) was added portionwise using a water bath. water to moderate the exotherm. When the addition was complete, the water bath was removed and the stirring was continued for 15 minutes. A solution of 4-bromo-2-fluorobenzaldehyde (1.86 g, 9.16 mmol) in DMSO (2 mL) was added in one portion. The dark solution was stirred for 15 minutes before being poured into cold water (300 ml). The products were extracted into Et2O (2 x 200 mL). The combined organic extracts were washed with brine, dried over MgSO and concentrated in vacuo. Purification of the residue by MPLC gave the desired product (pale yellow solid). 1 H NMR (DMSO-d 6) .58.37 (d, J = 1.8 Hz, 1 H), 8.17 (s, 1 H), 7.94. (d, J = 8.4 Hz, 1 H), 7.60 (dd, J = 8.4.1.8 Hz, 1H), 4.32 (c, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H). A mixture of ethyl 6-bromo-1-benzothiophen-2-carboxylate (250 mg, 0.88 mmol), 2,8-diazaspiro [4.5] decane-2-carboxylic acid-ferric butyl ester (200 mg, 0.83 mmol) and K3PO (1.00 g, 4.72 mmol) in 2 ml of DMAc was deoxygenated by the freeze-pump-thaw procedure. The mixture was treated with Pd [P (ferc-Bu) 3] 2 (130 mg, 0.250 mmol) and stirred at 90 ° C overnight. The reaction mixture was partitioned between EtOAc and sat. NaHCO 3, the organic phase was dried (Na 2 SO 4), filtered and concentrated. The residue was dissolved in 1 ml of MeOH, 1 ml of THF and 1 ml of H2O, treated with LiOH monohydrate (100 mg, 2.40 mmol) and stirred for 12 h. The mixture was poured into EtOAc and washed with 2 N HCl and water, dried (Na 2 SO), filtered and concentrated. The oily residue was dissolved in 2 ml of DMF, treated with intermediate C (200 mg, 0.980 mmol), BOP (300 mg, 0.679 mmol) and -Pr NEt (0.250 ml, 1.41 mmol) and stirred for 1 day at room temperature followed by 5 days at 60 ° C. The mixture was partitioned between EtOAc and sat. NaHCO 3. and the organic phase was dried (Na2SO) and concentrated. Chromatography on SiO2 (0 to 100% EtOAc / CH2Cl2) gave the pure intermediate. The oil was stirred in 2 ml of 1: 1 TFA / CH2CI2 for 1 h and concentrated. The oil was dissolved in EtOAc, washed with sat. NaHCO3, dried (Na2SO4) and concentrated to give the title compound: MS (ESI +): cale. [M + H] + 483.2, obs. 483.3.

EXAMPLE 21 ? / - (4-Aminobiphenyl-3-yl) -4- (1, 8-diazaspiro [4.51dec-8-yl) benzamide. FDMP stratosphere resin (loading 1.5 mmol / g) (67 mg, 0.10 mmol), 137 mg (0.5 mmol) was added to a scintillation vial. (3-amino-1-phenyl-1 / - / - pyrazol-4-yl) -carbamic acid ester and 1 ml of 5% AcOH in DCE and the vial was allowed to stir overnight at room temperature. To the vial was added 106 mg (0.5 mmol) of NaBH (OAc) 3 in 1 ml of 5% AcOH in DCE. The vial was capped, purged and allowed to react for 3 days at room temperature. The resin was washed 3 times with each of the following solvents and dried under vacuum: DMF, MeOH, H0, MeOH and DCM. The resin from the previous step (0.1 mmol) was added to a scintillation vial together with 2 ml of DCM and 51 mg (0.4 mmol) of DIEA. The vial was stirred for 1 minute and 53 mg (0.2 mmol) of 4-iodobenzoyl chloride was added. The vial was capped, purged and allowed to react overnight at room temperature. The resin was washed 3 times with each of the following solvents and dried in vacuo: DCM, DMF, H 0, MeOH and DCM. The resin from the previous step (0.1 mmol) was added to a scintillation vial together with 120 mg (0.5 mmol) of 1,8-diazaspiro [4.5] decane-1-carboxylic acid-butyl ester, 85 mg (0.4 mmol) of K3P04, 26 mg (0.05 mmol) Pd (P (t-Bu) 3) 2 and 2 ml of DMA. The vial was flushed with Argon and heated to 90 ° C. The reaction was allowed to proceed overnight at 90 ° C. The resin was washed three times with each of the following solvents and dried under vacuum: DMF, H2O, MeOH and DCM. The resin (0.1 mmol) from the previous step was cleaved with 3 ml of DCM 1: 1: TFA for 2 hours at room temperature. The filtrate was collected and purified by HPLC to yield the product,? / - (4-aminobiphenyl-3-yl) -4- (1, 8-diazaspiro [4.5] dec-8-yl) benzamide, in the form of a solid white: MS (ESI +): cale. [M + H] + 427.2, obs. 427.2.

EXAMPLE 22 ? / - (2-Amino-5-thien-2-ylphenyl) -2- (4-oxo-1-phenyl-1,3,8-triazaspiro [4.51dec-8-yl] -1,3-thiazole- 5-carboxamide. 2-Bromo-1,3-thiazole-5-carboxylic acid ethyl ester (1.0 g, 4.2 mmol) was prepared in THF and 3 equivalents of 1-phenyl-1,3,8-triazaspiro were added to this stirring solution. [4.5] decan-4-one (2.94 g, 12.7 mmol).

The resulting mixture was heated at 100 ° C for 30 min in the microwave. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate and concentrated in vacuo to give an oily residue. The residue was purified by MPLC (50-100% EtOAc: Hex): MS (ESI +): cale. [M + H] + 387.1, obs. 387.1.

Prepared 2- (4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) -1,3-thiazole-5-carboxylic acid ethyl ester (0.75 g, 1.9 mmol) 0.25 M in 1,4-dioxane and to this stirred solution was added 3 equivalents of 3 M lithium hydroxide (1.9 ml, 5.8 mmol). The resulting mixture was microwaved at 75 ° C for 1 hour. Then, the reaction mixture was neutralized to pH = 6 with 1N aqueous HCl and a white solid appeared from the solution. The precipitate was removed by filtration and dried in vacuo to give 2- (4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) -1,3-thiazole-5- acid. carboxylic The material was then carried without further purification: MS (ESI +): cale. [M + H] + 359.1, obs. 359.1. 2- (4-Oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) -1,3-thiazole-5-carboxylic acid (60 mg, 0.16 mmol) 0.25 M was prepared in Anhydrous DCM and to this stirring solution was added catalytic DMF followed by 3 equivalents of thionyl chloride (179 mg, 1.5 mmol). The resulting solution was stirred at room temperature under a nitrogen atmosphere for 1 hour. Then, the reaction mixture was concentrated in vacuo and azeotropically distilled once with toluene to remove excess thionyl chloride. The residue was made 0.5 M in anhydrous DCM and to this stirring solution was added 3 equivalents of triethylamine (48 mg, 0.48 mmol) followed by 1 equivalent of fer-butyl 2-amino-4-thien-2-ylphenylcarbamate (30 mg). mg, 0.16 mmol). The resulting mixture was stirred at room temperature for 14 hours. Then, the reaction mixture was diluted with 4 M TFA in DCM and allowed to stir at room temperature. After one hour, the reaction mixture was concentrated in vacuo and purified by reverse phase chromatography: MS (ESI +): cale. [M + H] + 531 1, obs. 531.1.

EXAMPLE 23 EDC, HOBt, DMF 7- (5- { F (2-Aminophenyl) am? No] carbonyl | pyridin-2-yl) -217-diaza-spiro [3,51nonan-2-carboxylic acid-butyl ester. A mixture of 2,7-diazaspiro [3.5] nonane of fer-butyl (660 mg, 2.91 mmol), methyl 6-chloronicotinate (500 mg, 2.91 mmol) and Et3N (0.487 mL, 3.50 mmol) in 2 mL of? / -methylpyrrolidine was stirred with microwave irradiation for 20 min at a temperature of 180 ° C. The mixture was poured into EtOAc and washed with sat. NaHCO 3, dried (MgSO 4), filtered and concentrated to give 7- [5- (methoxycarbonyl) pyridin-2-yl] -2,7-diazaspiro [3.5] ferrous butyl nonan-2-carboxylate. The methyl ester was dissolved in 2 ml of 1: 1 THF / water, treated with LiOH H2O (26 mg, 0.62 mmol) and stirred for 20 hours. The mixture was poured into EtOAc and washed with 1M HCl followed by brine, dried (MgSO), filtered and concentrated to give 6- [2- (fer-butoxycarbonyl) -2,7-diazaspiro acid [3.5] non-7-yl] nicotinic. A mixture of the carboxylic acid in 2 ml of DMF was treated with EDC (132 mg, 0.69 mmol), HOBt (93 mg, 0.69 mmol) and phenylenediamine (125 mg, 1.15 mmol) and stirred for 15 h at room temperature. Then, the reaction mixture was diluted with EtOAc and washed with sat. NaHCO3, dried (MgSO4), filtered and concentrated. The crude oil was purified by reverse phase flash chromatography (10-100% MeCN / H 2 O with 0.05% TFA) and formation of the desired product, 7- (5-. {[[(2-aminophenyl) amino ] carbonyl.}. pyridin-2-yl) -2,7-diazaspiro [3.5] nonan-2-carboxylate of fer-butyl, which was confirmed by MS (ESI +): cale. [M + H] + 438.2, obs. 438.3.

EXAMPLE 24 7- (5-. {[[(2-Aminophenyl) aminolcarbonyl) pyridin-2-yl) -2,7-diazaspiro- [3,51nonan-2-carboxylic acid benzyl ester. 7 - [5- (Methoxycarbonyl) pyridin-2-yl] -2,7-diazaspiro [3.5] nonan-2-carboxylic acid-butyl ester (100 mg, 0.28 mmol) was treated with 1: 1 TFA / CH2Cl2, it was stirred for 1 h and concentrated. Neutralization by extraction of EtOAc / sat. NaHCO3. and drying (MgSO4) gave the intermediate spiroamine. A solution of spiroamine (100 mg, 0.28 mmol) in 5 mL of CH2Cl2 was treated with CbzCl (0.058 mL, 0.42 mmol) and Et3N (0.193 mL, 1.38 mmol) and stirred for 1 h at room temperature. The reaction mixture was partitioned between EtOAc and saturated NaHCO 3, the organic phase was dried (MgSO 4), filtered and concentrated. The formation of the Cbz-protected spirocyte was confirmed by EM (IEN +): cale. [M + H] + 396.2, esp. 396.2. 7 - [5- (Methoxycarbonyl) pyridin-2-yl] -2,7-diazaspiro [3.5] nonan-2-carboxylic acid benzyl ester was dissolved in 2 ml of 1: 1 THF / water, treated with LiOH HO ( 26 mg, 0.62 mmol) and stirred for 20 hours, after which the mixture was concentrated, azeotropically dried with MeOH and placed under vacuum for 3 h. A mixture of the residue in 2 ml of DMF was treated with EDC (752 mg, 3.9 mmol), HOBt (532 mg, 3.9 mmol) and phenylenediamine (709 mg, 6.6 mmol), stirred for 15 h and concentrated to dryness. Reverse phase chromatography (10-100% water / MeCN with 0.05% TFA) gave the desired product, 7- (5-. {[[(2-aminophenyl) amino] carbonyl} pyridin-2-yl. ) -2,7-diazaspiro [3.5] nonan-2-carboxylate benzyl, which was confirmed by MS (ESI +): cale. [M + H] + 472.2, obs. 472.2.

EXAMPLE 25 ? / - r2-Amino-5- (2-thienyl) phenyl-6- (2,7-diazaspirof3.51non-7-Qnicotinamide) [2- {[[6-chloropyridin-3-yl] was dissolved carbonyl] amino.} -4- (2-thienyl) phenyl] carbamate of fer-butyl F (20 mg, 0.088 mmol) in 1 ml of DIVISO and treated with Et 3 N (0.010 ml) and 2,7-diazaspiro [ 3.5) ferric-butyl nonan-2-carboxylate (20 mg, 0.047 mmol) The mixture was stirred at 90 ° C for 18 h, partitioned between EtOAc and saturated NaHCO3, dried (MgSO4), filtered, concentrated and the residue was purified by chromatography on Si0 (EtOAc / CH2Cl2, 0% to 100%) .The residue was dissolved in 1 ml of 1: 1 TFA / CH2CI2, stirred for 1 h and concentrated. of EtOAc / sat'd NaHC03 and drying (MgSO) gave the desired product,? / - [2-amino-5- (2-thienyl) phenyl] -6- (2,7-diazaspiro [3.5] non-7- il) nicotinamide, which was confirmed by MS (ESI +): cale [M + H] + 420.2, obs 420.1.

EXAMPLE 26 Inhibition of hdca by new compounds - HDAC1-Flaq assay The ability to inhibit histone deacetylase subtype 1 (HDAC1) in the new compounds of the present invention was tested using an in vitro deacetylation assay. The source of enzymes for this assay was an immunopurified human HDAC1 complex labeled with stable expression mammalian cell epitope. The substrate consisted of a commercial product containing an acetylated lysine side chain (BIOMOL Research Laboratories, Inc., Plymouth Meeting, PA). After deacetylation of the substrate by incubation with the purified HDAC1 complex, a fluorophore is produced which is directly proportional to the level of deacetylation. Using a substrate concentration at Km for the enzyme preparation, the deacetylation assay was performed in the presence of increasing concentrations of new compounds to determine in a semi-quantitative manner the concentration of compound required during the 50% inhibition (IC50) of the deacetylation reaction. The compounds of the present invention described in the above Examples and Tablets show histone deacetylase inhibitory activity at concentrations of less than about 1 μM.

EXAMPLE 27 Inhibition of HDAC in Cell Lines - ATP Test The ability of the new compounds of the present invention to inhibit the proliferation of human cervical cancer cells (HeLa) and colon carcinoma (HCT116) was tested. In this essay, also called Vialight assay, cell ATP levels are measured as a means to quantify cell proliferation. This assay makes use of a Cambrex bioluminescent process (ViaLight PLUS, cat # LT07-121). In the presence of ATP, luciferase converts luciferin to oxyluciferin and light. The amount of light produced (emission at 565 nm) is measured and correlated with a relative amount of proliferation. Human cervical cancer (HeLa) or colon carcinoma (HCT116) cells were incubated with vehicle or increasing concentrations of compound for 48, 72 or 96 hours. Cell proliferation was quantified by directly adding the cell lysis reagent (provided in the Vialight assay kit) to the culture wells, followed by the addition of the ATP control reagent (containing luciferase / luciferin). The amount of light produced is then measured (emission at 565 nm). The amount of light produced, as measured by absorbance at 565 nm, is directly proportional to the amount of living cells in culture. Although this invention has been particularly shown and described with references to embodiments thereof, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the meaning of the disclosed invention. Instead, the scope of the invention is defined by the claims that follow.

Claims (6)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound, represented by Formula II: wherein A, B and D are independently selected from CR12, NR1a, C (O) and O; E is selected from a bond, CR12, NR1a, C (O) and O; where at least one of A, B, D or E is CR12; and with the proviso that when A is O, then E is not O; - it is an optional double link; (\? M is an aryl or heteroaryl, optionally substituted with 1 to 3 substituents selected from R7; (ZJ is an aryl or heteroaryl; R1 is independently selected from hydrogen, C6 alkyl, (CR62) nR10, (CR62) nC ( 0) R4, (CR62) nC (O) OR4, (CR62) nC (0) NR52, (CR62) nS (0) 2R4, (CR62) nOH and halo; R1a is independently selected from hydrogen, d-C6 alkyl, (CR62) nR10, (CR62) nC (0) R4, (CR62) nC (0) OR4, (CR62) nC (0) NR52 or (CR62) nS (0) 2R4; L is selected from a link, - CR112 -, -C (0) NR5 -, -NR5C (0) - and -C (O) -; R3 is selected from H, unsubstituted or substituted d6alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl halo, CN, amide, carboxyl, C 1 -C 7 alkoxy C 1 -Chaloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 7 alkenyl, C 1 -C 7 alkynyl, C 7 -C 7 alkyl = 0) O-, C7-C7 alkyl (= O) -, hydroxyalkoxy, -NHS02, -S02NH, C7-alkyl-NHS02-, C -C7-S02NH- alkyl, CrC-sulphonyl, CrC7-amino alkyl , dialkyl (C C7) -amino and L2-R12; R4 is independently of H, C6 alkyl, aryl and heterocyclyl, wherein the alkyl, aryl or heterocyclyl may be optionally substituted; R 5 is independently selected from hydrogen, d-Cß alkyl and aryl, which may be optionally substituted with 1 to 3 substituents selected from CrC 6 alkyl, aryl, heteroaryl or halo; R 6 is independently selected from hydrogen, C 1 -C 7 alkyl, aryl, OR 1 1, halo and NR 11; wherein the alkyl or aryl may be optionally substituted with 1 to 3 substituents selected from d-Cß alkyl, aryl, heteroaryl or halo; R7 is independently selected from hydrogen, OH, NR112, nitro, CN, amide, carboxyl, CrC7 alkoxy, d-C7 alkyl, d-C7 haloalkyl, C---7 haloalkyloxy, C-- C hydroxy alkyl, C7 alkenyl, alkyl C -? - C7-C (= 0) 0-, alkyl d-C7-C (= O) -, C7 alkynyl, halo, amide, hydroxyalkoxy, -NR11S02, -SO2NR11, C7-alkyl NR11S02- , alkyl C C7-S02NR11-. C 7 -alkylsulfonyl, C 7 -alkylamino and dialkyl (CrC 7) -amino; R10 is independently selected from aryl and heterocyclyl, which may be optionally substituted; R11 is independently selected from hydrogen, unsubstituted or substituted d-C alquilo alkyl, and unsubstituted or substituted aryl; L 2 is selected from a bond, C 4 alkylene, CrC 4 alkynyl, C C 4 alkenyl, -O-, -S-, -NH-, -C (= 0) NH-, -NHC (= O) -, -NHC ( = O) NH-, -SO2NH-, -NHSO2-, -SO2-, -C (= O) - and -C (= O) 0-; R12 is selected from: substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted C3-C3 cycloalkyl; m is 0, 1 or 2; n is independently selected from 0, 1, 2, 3 and 4; p is 0, 1 or 2, with the proviso that the sum of the variables m and p is not greater than 2; q is 1, 2, 3 or 4; or a stereoisomer or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, further characterized in that it is represented by Formula III: wherein X is CH or N; and the remaining substituents are as defined in claim 1 or a stereoisomer or a pharmaceutically acceptable salt thereof.

3 - The compound according to claim 2, further characterized in that: A is CR12, C (O), NR1a or O; B is CR12, NR1a or C (O); D is CR12 or NR1a; E is a link, CR12 or C (O); or a stereoisomer or a pharmaceutically acceptable salt thereof.

4. The compound selected from? / - (2-Aminophenyl) -6- (4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) nicotinamide; ? / - (2-aminophenyl) -6- (7-benzyl-2,7-diazaspiro [4.4] non-2-yl) nicotinamide; 7- (5- { [(2-aminophenyl) amino] carbonyl} pyridin-2-yl) -? / - phenyl-1-oxa-2,7-diazaspiro [4.4] non-2-en- 3-carboxamide; ? / - (2-aminophenyl) -6- [3- (4-fluorobenzyl) -2-oxo-1-oxa-8-azaspiro [4.5] dec-8-yl] nicotinamide; ? / - (4-Aminobiphenyl-3-yl) -6- (4-oxo-1-phenyl-1,3,8-t? Azaspiro [4.5] dec-8-yl) nicotinamide; 7- (5- { [(4-aminobiphenyl-3-yl) amino] carbonyl} pyridin-2-yl) -? / - (2-phenylethyl) -1-oxa-2,7-diazaspiro [ 4.4] non-2-en-3-carboxamide; 6- (7-acetyl-2,7-diazaspiro [4.4] non-2-yl) -? / - (4-aminobiphenyl-3-yl) nicotinamide; ? / - [2-Amino-5- (2-thienyl) phenyl] -6- (2,8-diazaspiro [4.5] dec-8-yl) nicotinamide; 6- (2-Acetyl-2,7-diazaspiro [4.5] dec-7-yl) -? / - [2-amino-5- (2-thienyl) phenyl] -nicotinamide; 7- (5- { [(4-aminobiphenyl-3-yl) amino] carbonyl} pyridin-2-yl) -? / - ethyl-2,7-diazaspiro [4.5] decane-2-carboxamide; ? / - [2-Amino-5- (2-thienyl) phenyl] -6- (4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) nicotinamide; 6- (7-acetyl-2,7-diazaspiro [4.4] non-2-yl) -? / - [2-amino-5- (2-thienyl) phenyl] nicotinamide; ? / - [2-Amino-5- (2-thienyl) phenyl] -6- (2-oxo-1-oxa-3,8-diazaspiro [4.5] dec-8-yl) nicotinamide; ? / - [2-amino-5- (2-thienyl) phenyl] -6- (3-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] dec-8-yl) nicotinamide; ? / - [2-amino-5- (2-thienyl) phenyl] -6- (2-oxo-1-oxa-3,8-diazaspiro [4.5] dec-8-yl) nicotynamide; ? / - (4-aminobiphenyl-3-yl) -6- (3-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] dec-8-yl) nicotinamide; ? / - (4-aminobiphenyl-3-yl) -6- (2-oxo-1-oxa-3,8-diazaspiro [4.5] dec-8-yl) nicotinamide; ? / - [2-Amino-5- (2-thienyl) phenyl] -6- (1, 8-diazaspiro [4.5] dec-8-yl) nicotinamide; ? / - (4-Amino-1-phenyl-1- 1 / - / - pyrazol-3-yl) -6- (4-oxo-1-phenyl-1,3,8-triazaspiro- [4.5] dec- 8-yl) nicotinamide; 6- (7-acetyl-2,7-diazaspiro [4.4] non-2-yl) -? / - (4-amino-1-phenyl-1 / - / - pyrazol-3-yl) nicotinamide; ? / - [4-amino-1- (3-chlorophenyl) -1H-pyrazol-3-yl] -6- (2,8-diazaspiro [4.5] dec-8-yl) nicotinamide; 8- (5- { [(4-Aminobiphenyl-3-yl) amino] carbonyl}. Pyridin-2-yl) -? / 3-phenyl-? / 2- (2-phenylethyl) -2,8 -diazaspiro [4.5] decane-2,3-dicarboxamide; 8- (5- { [(4-Aminobiphenyl-3-yl) amino] carbonyl} pyridin-2-yl) -? / - (2-phenylethyl) -1-oxa-2,8-diazaspiro [ 4.5] dec-2-en-3-carboxamide; 6- (2-acetyl-2,8-diazaspiro [4.5] dec-8-yl) -? / - [2-amino-5- (2-thienyl) phenyl] -nicotinamide; ? / - (4-aminobiphenyl-3-yl) -6-. { 2 - [(2,4-dimethyl-1,3-thiazol-5-yl) sulfonyl] -2,8-diazaspiro [4.5] dec-8-yl} nicotinamide; 8- [5- ( { [2-amino-5- (2-thienyl) phenyl] amino.} Carbonyl) pihdin-2-yl] -N- (2-phenylethyl) -2,8-diazaspiro [ 4.5] decane-2-carboxamide; ? / - (2-aminophenyl) -6-. { 3- [2- (methylamino) -2-oxoethyl] -4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl} nicotinamide; ? / - (2-aminophenyl) -6- [3- (2-anilino-2-oxoethyl) -4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl] nicotinamide; ? / - (2-aminophenyl) -6- [3- (1 / - / - benzimidazol-2-ylmethyl) -4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-il ] nicotinamide; 8- [5- ( { [2-Amino-5- (2-thienyl) phenyl] amino} carbonyl) pyridin-2-yl] -? / - ethyl-1,8-diazaspiro [4.5] decane -1-carboxamide; ? / - (4-Aminobiphenyl-3-yl) -6- (7-pyrimidin-2-yl-2,7-diazaspiro [4.4] non-2-yl) nicotinamide; ? / - (4-aminobiphenyl-3-yl) -6- [7- (phenylsulfonyl) -2,7-diazaspiro [4.4] non-2-yl] nicotinamide; 7- (5- { [(4-aminobiphenyl-3-yl) amino] carbonyl}. Pyridin-2-yl) -? / - [(1 S) -1-phenylethyl] -2,7-diazaspiro [4.4] nonan-2-carboxamide; 7- (5- { [(2-Aminophenyl) amino] carbonyl} pyridin-2-yl) -2,7-diazaspiro [4.4] nonan-2-carboxylate of pyridin-3-ylmethyl; ? / - (2-aminophenyl) -6- (7-benzoyl-2,7-diazaspiro [4.4] non-2-yl) nicotinamide; ? / - (2-aminophenyl) -6- [7- (4-methoxybenzyl) -2,7-diazaspiro [4.4] non-2-yl] nicotinamide; 8- (5- { [(2-aminophenyl) amino] carbonyl} pyridin-2-yl) -? / - (4-fluorophenyl) -2,8-diazaspiro [4.

5] decane-2-carboxamide; ? / - (2-aminophenyl) -6- [7- (quinolin-8-? Lsulfon? L) -2,7-d? Azasp? Ro [4 4] non-2-? L] n? Cot? Nam ? da,? / - (2-am? nofen? l) -6-. { 7 - [(2,4-d? Met? L-1, 3-t? Azol-5? L) sulfon? L] -2,7-d? Azasp? Ro [4 4] non-2-? l} n? cot? nam? da, 8- (5- { [(4-Am? nob? phen? l-3-? l) am? no] carbon? l.}. p? r? d? n -2-? L) -? / - (2-fen? Let? L) -2,8-d? Azaesp? Ro [4 5] decane-2-carboxam? Da,? / - (4-Am? Nob Phenol-3-? l) -4- (1, 8-d? azasp? ro [4 5] dec-8-? lmet? l) benzamide,? / - (4-am? nob? phen-l-3-? l) -4 - [(4-oxo-1-phenol-1, 3,8-tpazasp? ro [4 5] dec-8-? l) met? l] benzam? da,? / - (4-am? nob? phen? l -3? l) -4- (1, 8-d? azasp? ro [4 5] dec-8-? lcarbon? l) benzam? da,? / - (4- { [(4-am? Nob? Phen? L -3? L) am? No] carbon? L.} Phen? L) -7-benzyl-2, 7-d? Azaesp? Ro [4 4] nonan-2-carboxamide, N- (4- { [(4-am? Nob? Phen? L -3? L) am? No] carbon? l.}. fen? l) -2,7-d? azasp? ro [3 5] nonan-7-carboxamide,? / - (4-Am? nob? phen? l -3? l) -6- (2,8-d? Azaesp? Ro [4 5] dec-8-? L) -1-benzot? Ofen-2-carboxamide,? / - (4-Am? Nob? Phen? L-3- l) -4- (1, 8-d? azasp? ro [4 5] dec-8-? l) benzamida,? / - (2-Am? no-5-t? en-2-? lfen? l) -2- (4-oxo-1-phenol-1, 3,8-tpazaesp? ro [4 5] dec-8-? l) -1, 3-t? azol-5-carboxam ? da, 7- (5- { [(2- Am? nofen? l) am? no] carbon? l.}. p? r? d? n-2-? l) -2,7-d [3 5] nonan-2-carboxylic acid ferr-butyl, 7- (5- { [(2-Am? nofen? l) am? no] carbon? l.}. p? r? d? n-2-?) -2,7-d? azasp? ro- [3 5] nonan-2-carboxylic acid benzyl,? / - [2-Am? no-5- (2-t? In? L) phen? L] -6- (2,7-d? Azasp? Ro [3 5] non-7-? L) n? Cot? Nam? Da, or a stereoisomer or a Pharmaceutically acceptable salt thereof - A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of any one of claims 1 to 4, and a pharmaceutically effective pharmaceutically acceptable vehicle

6. The use of the compound of any of claims 1 to 4 for the preparation of a medicament useful in the treatment or prevention of cancer in a mammal.