WO2013009812A1

WO2013009812A1 - Methods of treatment

Info

Publication number: WO2013009812A1
Application number: PCT/US2012/046173
Authority: WO
Inventors: Shomir Ghosh; Mercedes Lobera
Original assignee: Tempero Pharmaceuticals, Inc
Priority date: 2011-07-13
Filing date: 2012-07-11
Publication date: 2013-01-17

Abstract

Disclosed is a method of treating a neurodegenerative disease or disorder or a B- cell lymphoma by administering a compound having the formula:(I) wherein X1; X2, X3, R1, R2, R3, R4, Y, A, n and L are as defined herein.

Description

METHODS OF TREATMENT

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to a method of treating neurodegenerative diseases or disorders, particularly neurodegenerative diseases and disorder associated with deacetylases, such as, Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NMD), and polyglutamine disorders, such as Huntington's disease and spinocerebellar ataxia (SCA), among others, by administering to a patient in need thereof a compound that inhibits HDAC activity

The present invention also relates to a method of treating a B-cell lymphoma, particularly B-cell lymphomas associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B- lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma), by administering to a patient in need thereof a compound that inhibits HDAC activity.

Background of the Invention

Chromatin organization involves DNA wound around histone octamers that form nucleosomes. Core histones with N-terminal tails extending from compact nucleosomal core particles can be acetylated or deacetylated at epsilon lysine residues affecting histone-DNA and histone-non-histone protein interactions. Histone deacetylases

(HDACs) catalyze the deacetylation of histone and non-histone proteins and play an important role in epigenetic regulation. There are currently 18 known HDACs that are organized into three classes: class I HDACs (HDAC1 , HDAC2, HDAC3, HDAC8 and HDAC1 1 ) are mainly localized to the nucleus; class II HDACs (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10), which shuttle between the nucleus and the cytoplasm; and class III HDACs (SIRT1-7), whose cellular localization includes various organelles.

Class II HDACs are further characterized as class lla HDACs and class lib

HDACs.

HDAC4, HDAC5 and HDAC9 are highly expressed in the brain. HDAC4 has been linked to a variety of neurodegenerative disorders: it is a downstream target of Parkin (associating it to Parkinson's disease), it's is a major component of intranuclear inclusions produced in NIIND. HDAC4 also contains a conserved glutamine rich domain, such domain has been observed to increase susceptibility to amyloid formation associated with Alzheimer's disease (Majdzadeh et al. Front. Biosci., 2009, p. 1072). Heterozygotes of HDAC4 knockouts crossed to R6/2 mice (Huntington's disease model) led to improved motor/behavior and reduced aggregation

(http://bmi.epfl.ch/files/content/sites/bmi/files/shared/Abstract Gillian Bates.pdD. HDAC4 and HDAC5 localization are regulated by neuronal activity, and HDAC5 nuclear import is increased in diseased neurons of Huntington's disease patients.

HDAC7, another class lla HDAC, has been implicated in regulating ataxin-7 turnover in a SCA-7 model (Mookerjee S et al., J Neurosci., 2009, p. 15134).

HDAC6, a class lib HDAC, is expressed in most neurons and most abundantly in cerebellar Purkinje cells, the degeneration of this type of neurons is observed in patients with spinocerebellar ataxia type 1 (SCA1 ) or SCA7. HDAC6 is involved in regulating microtubule dynamics and protein degradation and a defect in microtubule-based transport may contribute to the neuronal toxicity observed in Huntington's disease (Kazantsev et al. Nature Reviews Drug Discovery, 2008, p. 854). Additionally, HDAC6 activity has been shown to be required for autophagic degradation of aggregated huntingtin, suggesting a role in protecting cells from polyQ toxicity (Iwata, et al., J. Biol. Chem., 2005, p. 40282).

HDAC9 is a class lla histone deacetylase highly expressed in human B cells. Relative to normal B cells, expression of HDAC9 is deregulated in cell lines derived from B cell tumours and HDAC9 is highly overexpressed in cells derived from patients with non- Hodgkin's lymphoma

(http://icr.ac.uk/research/team leaders/Zelent Arthur/Zelent Arthur Rl/index.shtml). HDAC4 and HDAC9 have booth been reported to be overexpressed in CD19+ cells from patients with Waldenstrom Macroglobulinemia (Sun et al., Clinical Lymphoma, Myeloma & Leukemia, 201 1 , p. 152)

Class lla HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) have been reported to associate with Bcl-6, a transcription factor implicated in the pathogenesis of B-cell malignancies (Lemercier et al, Journal of Biological Chemistry, 2002, p. 22045, and Petrie et al, Journal of Biological Chemistry, 2003, p. 16059). Due to these interactions class lla HDACs have been suggested to modulate the transcriptional repression of BCL6 and participate in its role in B-cell activation and differentiation, inflammation, and cell-cycle regulation (Verdin et al. TRENDS in Genetics, 2003, p. 286) .

HDAC6, a class lib HDAC, has been reported to play an important role in aggresomal protein degradation, making it a target for the treatment of B cell malignancies (Simms-Waldrip et al., Molecular Genetics and Metabolism, 2008, p. 283) Based on the above evidence, a small molecule selective inhibitor of HDAC activity (more specifically, an inhibitor of HDAC4 and/or HDAC5 and/or HDAC6 and/or HDAC7 and/or HDAC8 and/or HDAC9 activity) is expected to be beneficial in the treatment of neurodegenerative diseases and in the treatment of B-cell malignancies by targeting one or several of the above enzymes.

SUMMARY OF THE INVENTION

The invention is directed to a method of treatment of a neurodegenerative disease or disorder and is further directed to a method of treatment of B-cell lymphoma, wherein each of said methods comprise administering, to a patient in need of treatment of a

neurodegenerative disease or disorder or in need of treatment of a B-cell

lymphoma, respectively, a compound of Formula I:

wherein:

R¹ is halo(CrC₄)alkyl, wherein said halo(Ci-C₄)alkyl contains at least 2 halo groups (R¹ is di-halo(C₁-C₄)alkyl);

Y is a bond and is O, X₂ is N or CH and X₃ is N or NH,

or Y is -C(O)- and X^ and X₂ are CH or N, X₃ is O or S,

or Y is -C(O)- and X^ is O, X₂ is CH or N, and X₃ is CH or N;

n is 0-4;

A is -C(=0)NR^x-, -((CrC₆)alkyl)C(=0)NR^x-, -((C C₆)alkyl)NR^xC(=0)NR^x,

-((CrC₆)alkyl)NR^xC(=0)-, -((C C₆)alkyl)S0₂-, -S0₂NR^x-, -((Ci-C₆)alkyl)S0₂NR^x-,

-((CrC₆)alkyl)NR^xS0₂-, -((Ci-C₆)alkyl)NHCH(CF₃)-, -CH(CF₃)NH-,

-((CrC₆)alkyl)CH(CF₃)NH-, -CH(CF₃)-, -((Ci-C₆)alkyl)CH(CF₃)-, or -((C C₆)alkyl)NR^x-; when n is 0, R² and R³ are independently selected from H and optionally

substituted (C C₄)alkyl, aryl(C C₄)alkyl-, and (C₃-C₇)cycloalkyl(C C₄)alkyl-,

when n is 1-4, R² and R³ are independently selected from H, fluoro, and optionally substituted (Ci-C₄)alkyl, aryl(Ci-C₄)alkyl-, and (C₃-C₇)cycloalkyl(Ci-C₄)alkyl-, wherein, when n is 1 , R² is F and R³ is H, then Z is -C(=0)NR^x-, -NR^xC(=0)NR^x, -S0₂NR^x-,

-NHCH(CF₃)-, -CH(CF₃)NH-, -CH(CF₃)-, -(C C₄)alkyl-, -NR^X-, or -(C C₃)alkyl-NR^x-, and when n is 1 -4, R² is selected from -NR^AR^B, -(C C₄)alkyl-NR^AR^B, -CONR^AR^B, -(C C₄)alkyl-CONR^AR^B, -C0₂H, -(C₁-C₄)alkyl-C0₂H, hydroxyl, hydroxy(C C₄)alkyl-, (C₁-C₃)alkoxy, and (C₁-C₃)alkoxy(C₁-C₄)alkyl-, and R³ is selected from H and optionally substituted (C C₄)alkyl, aryl(C C₄)alkyl-, and (C₃-C₇)cycloalkyl(Ci-C₄)alkyl-,

wherein the aryl, cycloalkyi and each of the (CrC₄)alkyl moieties of said optionally substituted (CrC₄)alkyl, aryl(CrC₄)alkyl-, and (C₃-C₇)cycloalkyl(CrC₄)alkyl- of any R² and R³ are optionally substituted by 1 , 2 or 3 groups independently selected from halogen, cyano, (C C₄)alkyl, halo(Ci-C₄)alkyl, (C C₄)alkoxy, halo(Ci-C₄)alkoxy, -NR^AR^A,

-((Ci-C₄)alkyl)NR^AR^A, and hydroxyl;

or R² and R³ taken together with the atom to which they are connected form an optionally substituted 4, 5, 6, or 7 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 or 2 heteroatoms independently selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by 1 , 2 or 3 substituents independently selected from (CrC₄)alkyl,

halo(C C₄)alkyl, halogen, cyano, aryl(Ci-C₄)alkyl-, (C₃-C₇)cycloalkyl(C C₄)alkyl-, -OR^Y, -NR^YR^Y, -C(=0)OR^Y, -C(=0)NR^YR^Y, -NR^YC(=0)R^Y, -S0₂NR^YR^Y, -NR^YS0₂R^Y,

-OC(=0)NR^YR^Y, -NR^YC(=0)OR^Y, and -NR^YC(=0)NR^YR^Y; and

L is 5-6 membered heteroaryl or phenyl which is substituted by R⁴ and is optionally further substituted,

wherein when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and (C₁-C₄)alkyl;

R⁴ is H, (C C₄)alkyl, halo, halo(Ci-C₄)alkyl, (C C₄)alkoxy,

((Ci-C₄)alkyl)((CrC₄)alkyl)N(Ci-C₄)alkoxy, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)N(C C₄)alkyl-, (Ci-C₄)haloalkoxy-, (Ci-C₄)alkylamino, optionally substituted (C₃-C₆)cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyi, or optionally substituted 5-6 membered heteroaryl,

wherein said optionally substituted cycloalkyi, phenyl, heterocycloalkyi or heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C₄)alkyl, halogen, cyano, halo(CrC₄)alkyl, (CrC₄)alkoxy, (Ci-C₄)alkylthio-, halo(Ci-C₄)alkoxy, hydroxyl, -NR^AR^C and -((Ci-C₄)alkyl)NR^AR^c;

or L-R⁴ , taken together, form a 1 ,3-benzodioxolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group wherein said benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group is optionally substituted by 1 , 2 or 3 groups independently selected from (CrC₄)alkyl, halogen, cyano, halo(CrC₄)alkyl, (Ci-C₄)alkoxy, (d-C₄)alkylthio-, halo(C C₄)alkoxy, hydroxyl, -NR^AR^C and -((C C₄)alkyl)NR^AR^c;

wherein each R^A is independently selected from H and (C₁-C₄)alkyl; R is H, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, -C(=0)(C₁-C₄)alkyl, -C(=0)0(C C₄)alkyl, -C(=0)NH₂, -C(=0)NH(d-C₄)alkyl, -C(=0)N((C₁-C₄)alkyl)((C₁-C₄)alkyl), -SC^d-C^alkyl, or R^A and R^B taken together with the atom to which they are attached form a 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (Ci-C₄)alkyl;

R^c is H, (Ci-C₄)alkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, or R^A and R^c taken together with the atom to which they are attached form a 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (Ci-C₄)alkyl;

each R^x is independently selected from H, (CrC₆)alkyl, and optionally substituted

(C₂-C₆)alkyl, where said optionally substituted (C₂-C₆)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C₄)alkoxy, (Ci-C₄)alkyl)NH-, or ((Ci-C₄)alkyl)((C C₄)alkyl)N-; and

each R^Y is independently selected from H, (Ci-C₄)alkyl, phenyl, and

-(Ci-C₄)alkylphenyl;

provided that when Y is -C(O)- and A is -C(=0)NR^x- or -S0₂NR^x-, then at least one of R² and R³ is not H (either one or both of R² and R³ is/are not H);

or a salt thereof, particularly a pharmaceutically acceptable salt thereof.

The invention is further directed to the use of a compound of Formula I, or a salt thereof, particularly a pharmaceutically acceptable salt, thereof in therapy, particularly the use of a compound of Formula I, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to treat a neurodegenerative disease or disorder, particularly a neurodegenerative disease or disorder associated with deacetylases, such as,

Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NMD), and polyglutamine disorders, such as Huntington's disease and spinocerebellar ataxia (SCA).

The invention is still further directed to the use of a compound of Formula I, or a salt thereof, particularly a pharmaceutically acceptable salt, thereof in therapy, particularly the use of a compound of Formula I, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to treat a B-cell lymphoma, particularly a B-cell lymphoma associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma). The invention is further directed to the manufacture of a medicament containing a compound of Formula I, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for use in therapy, particularly for use to treat a neurodegenerative disease or disorder, wherein the neurodegenerative disease or disorder is as defined above.

The invention is still further directed to the manufacture of a medicament containing a compound of Formula I, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for use in therapy, particularly for use to treat a B-cell lymphoma, particularly a B-cell lymphoma associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma).

DETAILED DESCRIPTION OF THE INVENTION

The alternative definitions for the various groups and substituent groups of

Formula I provided throughout the specification are intended to particularly describe each compound species disclosed herein, individually, as well as groups of one or more compound species. The scope of the definition of the compound of Formula I, or a salt thereof, includes any combination of these group and substituent group definitions.

In one embodiment of the compound or salt of Formula I, R¹ is a fluoro- alkyl group containing at least 2 fluoro groups (atoms). In another embodiment, R¹ is a (C₁-C₂)alkyl group containing at least 2 fluoro groups. In a specific embodiment, R¹ is CHF₂ or CF₃; more specifically, R¹ is CF₃

In selected embodiments of the compound or salt of Formula I, when Y is a bond, X-i, X₂, and X₃, taken together with the atoms to which they are attached, form an oxadiazolyl (Xi is O, X₂ and X₃ are N) or and oxazolyl (Xi is O, X₂ is CH, X₃ is N) ring moiety. In specific embodiments, when Y is a bond, X-i, X₂, and X₃, taken together with the atoms to which they are attached form an oxadiazolyl ring moiety.

In selected embodiments of the compound or salt of Formula I, when Y is -C(O)-, X-i, X₂, and X₃, taken together with the atoms to which they are attached, form an thiazolyl (X₃ is S, Xi is CH and X₂ is N or X₃ is S, Xi is N and X₂ is CH), oxazolyl (X₃ is O, Xi is CH and X₂ is N or X₃ is O, Xi is N and X₂ is CH), thienyl (X^ and X₂ are CH, X₃ is S) or furanyl (X-i and X₂ are CH, X₃ is O) ring moiety. In specific embodiments, when Y is -C(O)-, X-i, X₂, and X₃, taken together with the atoms to which they are attached form a thienyl, thiazolyl or oxazolyl ring moiety, more specifically a thienyl moiety. In selected embodiments of the compound or salt of Formula I, when Y is -C(O)-, X-i, X₂, and X₃, taken together with the atoms to which they are attached, form a furanyl or furyl (Xi is O, X₂ and X₃ are CH), oxazolyl (X-i is O, X₂ is CH, and X₃ is N), isoxazolyl (X-i is O, X₂ is N, and X₃ is CH), or oxadiazolyl (Xi is O, X₂ and X₃ are N) ring moiety. In specific embodiments, when Y is -C(O)-, X-i, X₂, and X₃, taken together with the atoms to which they are attached form a furanyl (furyl) ring moiety.

The invention is further directed to methods of treatment and uses of a compound of Formula (l-a):

wherein R¹, R², R³,R⁴, A, n and L are as defined herein.

The invention is still further directed to methods of treatment and uses of a compound of Formula (l-

wherein R¹, R², R³,R⁴, A, Z, n and L are as defined herein.

The invention is further directed to methods of treatment and uses of a compound of Formula (l-c):

wherein R¹, R², R³,R⁴, A, n and L are as defined herein.

The invention is still further directed to methods of treatment and uses of a compound of Formula (l- -e), (l-f), (l-g) or (l-h):

wherein R¹, R², R³,R⁴, A, n and L are as defined herein.

The invention is still further directed to methods of treatment and uses of a compound of Formula (l-i), (l-j), (l-k), or (l-l):

In another embodiment of the compound or salt of Formula I, A is -((C C₆)alkyl)C(=0)NR^x-, -((C₁-C₆)alkyl)S0₂NR^x-, -((C₁-C₆)alkyl)NR^xC(=0)NR^x-, or -((C C₆)alkyl)NR^xC(=0)-; particularly -((C₁-C₆)alkyl)C(=0)NR^x-, -((C₁-C₆)alkyl)S0₂NR^x-, or -(C C₆)alkyl)NR^xC(=0)-. In another embodiment, A is -((CrC₄alkyl)C(=0)NR^x-, -((CrC₄)alkyl)S0₂NR^x-, -((Ci-C₄)alkyl)NR^xC(=0)NR^x- or

particularly -((C₂-C₄)alkyl)C(=0)NR^x-, -((C₂-C₄)alkyl)S0₂NR^x-, or

-((C₂-C₄)alkyl)NR^xC(=0)-. In specific embodiments of the compound or salt of Formula I, A is -CH₂CH₂C(=0)NH-, -CH₂CH₂CH₂C(=0)NH-, -CH₂CH₂CH₂S0₂NH-,

-CH₂CH₂C(CH₃)₂C(=0)NH-, -CH₂CH₂C(CH₃)₂S0₂NH- or -CH₂CH₂CH₂CH₂C(=0)NH-.

In another embodiment of the compound or salt of Formula I, each R^x is independently selected from H, (Ci-C₄)alkyl, or optionally substituted (C₂-C₄)alkyl, where said optionally substituted (C₂-C₄)alkyl is optionally substituted by hydroxyl, cyano, amino, (Ci-C₄)alkoxy, (C C₄)alkyl)NH-, or ((Ci-C₂)alkyl)((C C₂)alkyl)N-. In other embodiments, each R^x is independently selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N-methylaminoethyl- or dimethylaminoethyl-. In particular embodiments, each R^x is independently H or methyl. In specific embodiments, R^x is H.

In another embodiment of the compound or salt of Formula I, n is 0-4; particularly 0-3. In specific embodiments, n is 1.

In another embodiment of the compound or salt of Formula I, R² and R³ taken together with the atom to which they are connected form an optionally substituted 4, 5, or 6 membered cycloalkyi or heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 heteroatom selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyl group is optionally substituted by a substituent selected from

(Ci-C₄)alkyl, halo(Ci-C₄)alkyl, halogen, cyano, aryl(Ci-C₂)alkyl-,

(C₃-C₆)cycloalkyl(Ci-C₂)alkyl-, -OR^Ya, -NR^YaR^Yb, -C(=0)OR^Ya, -C(=0)NR^YaR^Yb,

-NR^YbC(=0)R^Ya, -S0₂NR^YaR^Yb, -NR^YbS0₂R^Ya, -OC(=0)NR^YaR^Yb, -NR^YbC(=0)OR^Ya, -NR^YbC(=0)NR^YaR^Yb, where R^Ya is selected from H, (C C₄)alkyl and -(C C₄)alkylphenyl and each R^Yb is independently selected from H and (CrC₄)alkyl.

In specific embodiments of the compound or salt of Formula I, R² and R³ taken together with the atom to which they are connected form an optionally substituted 4, 5 or 6 membered cycloalkyi or heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 heteroatom selected from N and O and said optionally substituted cycloalkyi or heterocycloalkyl group is optionally substituted by a substituent selected from (Ci-C₄)alkyl, aryl(Ci-C₂)alkyl- and (C₃-C₆)cycloalkyl(Ci-C₂)alkyk

In specific embodiments of the compound or salt of Formula I, R² and R³ taken together with the atom to which they are connected form a tetrahydropyranyl or a piperidinyl group, which tetrahydropyranyl or piperidinyl may be optionally substituted by a (C₁-C₂)alkyl or benzyl group. In a more specific embodiment, R² and R³ taken together with the atom to which they are connected form a tetrahydropyranyl or an N-methyl- piperidinyl group.

In another embodiment of the compound or salt of Formula I, (for any value of n)

R² and R³ are independently selected from H and optionally substituted (CrC₄)alkyl, phenyl(Ci-C₂)alkyl-, and (C₃-C₆)cycloalkyl(Ci-C₂)alkyl-, provided that when Y is -C(O)- A is not -C(=0)NR^x- or -S0₂NR^x-.

In an further embodiment, (for any value of n) R² and R³ are not H; that is, R² and R³ are independently selected from optionally substituted (Ci-C₄)alkyl, phenyl(Ci-C₂)alkyl-, and (C₃-C₆)cycloalkyl(Ci-C₂)alkyk

In a still further embodiment, (for any value of n) one of R² and R³ is H, and the other of R² and R³ is selected from optionally substituted (CrC₄)alkyl, phenyl(Ci-C₂)alkyl-, and (C₃-C₆)cycloalkyl(Ci-C₂)alkyl-, provided that when Y is -C(O)- A is not -C(=0)NR^x- or -S0₂NR^x-.

In another embodiment of the compound or salt of Formula I, (for any value of n) R² is selected from H and optionally substituted (Ci-C₄)alkyl, phenyl(Ci-C₂)alkyl-, and (C₃-C₆)cycloalkyl(C₁-C₂)alkyl- and R³ is selected from H and methyl, provided that when Y is -C(O)- and A is -C(=0)NR^x- or -S0₂NR^x-, then at least one of R² and R³ is not H, that is, both of R² and R³ are not H or one of R² and R³ is not H. In a further embodiment, (for any value of n) R² is selected from optionally substituted (Ci-C₄)alkyl, phenyl(C₁-C₂)alkyl-, and (C₃-C₆)cycloalkyl(Ci-C₂)alkyl- and R³ is methyl. In a still further embodiment, (for any value of n) R² is selected from optionally substituted (Ci-C₄)alkyl, phenyl(Ci-C₂)alkyl-, and (C₃-C₆)cycloalkyl(CrC₂)alkyl- and R³ is H or methyl (provided that when Y is -C(O), A is not -C(=0)NR^x- or -S0₂NR^x-). In specific embodiments of the compound or salt of

Formula I, R² and R³ are independently selected from H and methyl (provided that when Y is -C(O), A is not -C(=0)NR^x- or -S0₂NR^x-). In more specific embodiments, both R² and R³ are methyl.

In another embodiment of the compound or salt of Formula I, when n is 1-4, R² is selected from amino, (Ci-C₄)alkylamino, ((Ci-C₃)alkyl)((Ci-C₃)alkyl)amino,

amino(Ci-C₄)alkyl, (Ci-C₃)alkylamino(Ci-C₄)alkyl,

((Ci-C₃)alkyl)((Ci-C₃)alkyl)amino(Ci-C₄)alkyl,

(substituted(Ci-C₃)alkyl)((Ci-C₃)alkyl)amino(Ci-C₄)alkyl (where said (substituted

(Ci-C₃)alkyl moiety is substituted by -C(=0)OH, -C(=0)0(C C₄)alkyl, or 1-8 fluoro groups), aminocarbonyl(C₁-C₄)alkyl, (C₁-C₃)alkylaminocarbonyl(C₁-C₄)alkyl,

((C₁-C₃)alkyl)((C₁-C₃)alkyl)aminocarbonyl(C₁-C₄)alkyl, hydroxyl, hydroxy(CrC₄)alkyl-, (C₁-C₄)alkoxy, and (C₁-C₄)alkoxy(C₁-C₄)alkyl- and R³ is selected from H and optionally substituted (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl-, and (C₃-C₇)cycloalkyl(C₁-C₄)alkyl-, when A is -((C C₆)alkyl)C(=0)NR^x-, -((C C₆)alkyl)NR^xC(=0)NR^x, -((C C₆)alkyl)NR^xC(=0)-, -SO2-, -((Ci-C₆)alkyl)S0₂- -((CrC₆)alkyl)S0₂NR^x-, -((Ci-C₆)alkyl)NR^xS0₂-,

-((CrC₆)alkyl)NHCH(CF₃)-, -CH(CF₃)NH-, -((Ci-C₆)alkyl)CH(CF₃)NH-, -CH(CF₃)-, -((CrC₆)alkyl)CH(CF₃)-, or -((Ci-C₆)alkyl)NR^x-.

In yet another embodiment of the compound or salt of Formula I, when n is 1-4, R² is selected from amino, hydroxyl, and (CrC₄)alkoxy, and R³ is selected from H and optionally substituted (CrC₄)alkyl, phenyl(CrC₂)alkyl-, and (C₃-C₆)cycloalkyl(d-C₂)alkyl-,

-((CrC₆)alkyl)NR^xC(=0)-, -S0₂- -((C C₆)alkyl)S0₂-, -((C C₆)alkyl)S0₂NR^x-,

-((CrC₆)alkyl)NR^xS0₂-, -((Ci-C₆)alkyl)NHCH(CF₃)-, -CH(CF₃)NH-,

-((CrC₆)alkyl)CH(CF₃)NH-, -CH(CF₃)-, -((Ci-C₆)alkyl)CH(CF₃)-, or -((C C₆)alkyl)NR^x-.

In another embodiment, n is 1-3, R² is hydroxyl and R³ is H or methyl; more specifically, n is 1 , R² is hydroxyl and R³ is H or methyl, when A is -

((CrC₆)alkyl)C(=0)NR^x-, -((C C₆)alkyl)NR^xC(=0)NR^x, -((C C₆)alkyl)NR^xC(=0)-, -S0₂- -((C C₆)alkyl)S0₂-, -((C₁-C₆)alkyl)S0₂NR^x-, -((C C₆)alkyl)NR^xS0₂-,

-((C C₆)alkyl)NHCH(CF₃)-, -CH(CF₃)NH-, -((Ci-C₆)alkyl)CH(CF₃)NH-, -CH(CF₃)-, -((C C₆)alkyl)CH(CF₃)-, or -((C₁-C₆)alkyl)NR^x-.

In a further embodiment of the compound or salt of Formula I, when n is 1-4, and A is -C(=0)NR^x- or -S0₂NR^x-, -R² is selected from amino, (C C₄)alkylamino,

((Ci-C₃)alkyl)((Ci-C₃)alkyl)amino, amino(C C₄)alkyl, (Ci-C₃)alkylamino(C C₄)alkyl, ((Ci-C₃)alkyl)((Ci-C₃)alkyl)amino(Ci-C₄)alkyl,

(Ci-C₃)alkyl moiety is substituted by -C(=0)OH, -C(=0)0(C C₄)alkyl, or 1-8 fluoro groups), aminocarbonyl(Ci-C₄)alkyl, (Ci-C₃)alkylaminocarbonyl(Ci-C₄)alkyl,

((Ci-C₃)alkyl)((Ci-C₃)alkyl)aminocarbonyl(Ci-C₄)alkyl, hydroxyl, hydroxy(CrC₄)alkyl-, (Ci-C₄)alkoxy, and (Ci-C₄)alkoxy(CrC₄)alkyl- and R³ is selected from optionally substituted (C C₄)alkyl, aryl(C C₄)alkyl-, and (C₃-C₇)cycloalkyl(C C₄)alkyl-.

In another embodiment of the compound or salt of Formula I, when A is -

C(=0)NR^x- or -S0₂NR^x-, n is 1 -3, R² is hydroxyl and R³ is methyl. In yet another embodiment, when A is -C(=0)NR^x- or -S0₂NR^x-, n is 1 , R² is hydroxyl and R³ is methyl.

In another embodiment of the compound or salt of Formula I, L is 5-6 membered heteroaryl or phenyl group which is substituted by R⁴ and is optionally further substituted by 1 substituent selected from halogen, cyano and (C₁-C₄)alkyl. In another embodiment, L is thiazolyl, thienyl, triazolyl, oxazolyl, or phenyl which is substituted by R⁴ and is optionally further substituted by a methyl group. In specific embodiments, L is thiazolyl or oxazolyl substituted only by R⁴.

In other embodiments, R⁴ is H, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)N(Ci-C₄)alkoxy, (Ci-C₄)alkylamino, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl. In another embodiment of the compound or salt of Formula I , R⁴ is H, methyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 4-cyanophenyl, 4-methoxyphenyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl. In specific embodiments, R⁴ is phenyl, 4-chlorophenyl, or 4-fluorophenyl.

As used herein, the term "alkyl" represents a saturated, straight or branched hydrocarbon moiety, which may be unsubstituted or substituted by one, or more of the substituents defined herein. Exemplary alkyls include, but are not limited to methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, f-butyl, n-pentyl, iso-pentyl (3- methyl-butyl), neo-pentyl (2,2-dimethylpropyl), etc. The term "CrC₄" refers to an alkyl containing from 1 to 4 carbon atoms.

When the term "alkyl" is used in combination with other substituent groups, such as "haloalkyl" or "cycloalkyl-alkyl" or "arylalkyl", the term "alkyl" is intended to encompass a divalent straight or branched-chain hydrocarbon radical. For example, "arylalkyl" is intended to mean the radical -alkylaryl, wherein the alkyl moiety thereof is a divalent straight or branched-chain carbon radical and the aryl moiety thereof is as defined herein, and is represented by the bonding arrangement present in a benzyl group (-CH₂-phenyl).

In addition, the term "alkyl" may be used to define a divalent substituent, such as a group bonded to two other groups. In this instance, the term "alkyl" is intended to encompass a divalent straight or branched-chain hydrocarbon radical. For example, "pentyl" is intended to represent a pentylene diradical -wherein the pentyl moiety is any one of a divalent straight (-CH2CH2CH2CH2CH2-) or branched (-CH₂CH(CH3)CH₂CH2-, -CH2CH₂CH(CH₂CH3)-, -CH₂CH₂C(CH₃)2-) chain 5-carbon radical.

As used herein, the term "cycloalkyl" refers to a non-aromatic, saturated, cyclic hydrocarbon ring. The term "(C₃-C₈)cycloalkyl" refers to a non-aromatic cyclic

hydrocarbon ring having from three to eight ring carbon atoms. Exemplary

"(C₃-C₈)cycloalkyl" groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

"Alkoxy" refers to a group containing an alkyl radical attached through an oxygen linking atom. The term "(d-C₄)alkoxy" refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom. Exemplary "(CrC₄)alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and f-butoxy. "Aryl" represents a group or moiety comprising an aromatic, monovalent monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms, which may be unsubstituted or substituted by one or more of the substituents defined herein, and to which may be fused one or more cycloalkyl rings, which may be

unsubstituted or substituted by one or more substituents defined herein.

Generally, in the compounds of Formula I, aryl is phenyl.

Heterocyclic groups may be heteroaryl or heterocycloalkyl groups.

"Heterocycloalkyl" represents a group or moiety comprising a stable, non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more of the substituents defined herein. The heterocycloalkyl may be attached by any atom of the monocyclic or bicyclic radical which results in the creation of a stable structure. This term encompasses bicyclic heterocycloalkyl moieties where the rings are joined at two atoms per ring, as exemplified by the bonding arrangement in 2,5-diazabicyclo[2.2.1]heptyl, 2- azabicyclo[2.2.1 ]heptyl, 2-oxa-5-azabicyclo[2.2.1 ]heptyl, 7-oxa-2-azabicyclo[2.2.1 ]heptyl, 2-thia-5-azabicyclo[2.2.1]heptyl,7-azabicyclo[2.2.1 ]heptyl, 2,6- diazatricyclo[3.3.1 .13,7]decyl, 2-azatricyclo[3.3.1.13,7]decyl, 2,4,9- triazatricyclo[3.3.1.13,7]decyl, 8-azabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.2]octyl, 2- azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1 ]octyl, 8-azabicyclo[3.2.1]octyl, octahydro-1 H- pyrrolo[3,2-6]pyridyl group. This term specifically excludes bicyclic heterocycloalkyl moieties where the rings are joined at a single atom per ring (spiro), as exemplified by the bonding arrangement in a 1-oxa-2-azaspiro[4.5]dec-2-en-3-yl group. Illustrative examples of heterocycloalkyls include, but are not limited to, azetidinyl, pyrrolidyl (or pyrrolidinyl), piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-1 ,4-thiazinyl, tetrahydrofuryl (or tetrahydrofuranyl), dihydrofuryl, oxazolinyl, thiazolinyl, pyrazolinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1 ]heptyl and 1 ,5,9-triazacyclododecyl.

Generally, in the compounds of Formula I, heterocycloalkyl groups are

5-membered and/or 6-membered heterocycloalkyl groups, such as pyrrolidyl (or pyrrolidinyl), tetrahydrofuryl (or tetrahydrofuranyl), tetrahydrothienyl, dihydrofuryl, oxazolinyl, thiazolinyl or pyrazolinyl, piperidyl (or piperidinyl), piperazinyl, morpholinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxanyl, tetrahydro-2H-1 ,4-thiazinyl, 1 ,4-dioxanyl, 1 ,3-oxathianyl, and 1 ,3-dithianyl. "Heteroaryl" represents a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein. This term also encompasses bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyi ring moiety, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein. Illustrative examples of heteroaryls include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl (or furanyl), isothiazolyl, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl (or pyridinyl), pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, benzo[b]thienyl, isobenzofuryl, 2,3- dihydrobenzofuryl, chromenyl, chromanyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthridinyl, quinzolinyl, benzothiazolyl,

benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, isothiazolyl.

Some of the heteroaryl groups present in the compounds of Formula I are 5-6 membered monocyclic heteroaryl groups. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain 1 , 2 or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1 , 2, 3 or 4 nitrogen ring heteroatoms. Selected 5- or 6-membered heteroaryl groups include thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, and tetrazolyl or pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and thiadiazolyl.

The terms "halogen" and "halo" represent chloro, fluoro, bromo or iodo substituents. "Hydroxy" or "hydroxyl" is intended to mean the radical -OH.

The compounds of Formula I are only those which are contemplated to be

"chemically stable" as will be appreciated by those skilled in the art.

Accordingly, the invention is further directed to a method of treatment or use of a compound according to Formula I, wherein A is -((Ci-C₆)alkyl)C(=0)NR^x-,

-((CrC₆)alkyl)S0₂NR^x- -((C C₆)alkyl)NR^xC(=0)NR^x-, or -((C C₆)alkyl)NR^xC(=0)-;

particularly -((CrC₆)alkyl)C(=0)NR^x-, -((CrC₆)alkyl)S0₂NR^x- or

-(CrC₆)alkyl)NR^xC(=0)-;

each R^x is independently selected from H, (CrC₄)alkyl, or optionally substituted (C₂-C₄)alkyl, where said optionally substituted (C₂-C₄)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C₄)alkoxy, (Ci-C₄)alkyl)NH-, or ((Ci-C₂)alkyl)((C C₂)alkyl)N-; R² and R³ taken together with the atom to which they are connected form an optionally substituted 4, 5, or 6 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 heteroatom selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by a substituent selected from (d-C₄)alkyl, halo(CrC₄)alkyl, halogen, cyano, aryl(Ci-C₂)alkyl-, (C₃-C₆)cycloalkyl(Ci-C₂)alkyl-, -OR^Ya, -NR^YaR^Yb, -C(=0)OR^Ya, -C(=0)NR^YaR^Yb,

-NR^YbC(=0)R^Ya, -S0₂NR^YaR^Yb, -NR^YbS0₂R^Ya, -OC(=0)NR^YaR^Yb, -NR^YbC(=0)OR^Ya, -NR^YbC(=0)NR^YaR^Yb, where R^Ya is selected from H, (C C₄)alkyl and -(C C₄)alkylphenyl and each R^Yb is independently selected from H and (CrC₄)alkyl;

or R² and R³ are independently selected from H and optionally substituted

(Ci-C₄)alkyl, phenyl(C C₂)alkyl-, and (C₃-C₆)cycloalkyl(Ci-C₂)alkyl-,

or R² is (Ci-C₄)alkylamino, ((Ci-C₃)alkyl)((Ci-C₃)alkyl)amino, amino(Ci-C₄)alkyl, (Ci-C₃)alkylamino(Ci-C₄)alkyl, or ((Ci-C₃)alkyl)((Ci-C₃)alkyl)amino(Ci-C₄)alkyl, and R³ is H or (Ci-C₃)alkyl,

or R² is hydroxyl and R³ is H or methyl;

L is 5-6 membered heteroaryl or phenyl group which is substituted by R⁴ and is optionally further substituted by 1 substituent selected from halogen, cyano and

(d-C₄)alkyl;

R⁴ is H, (C C₄)alkyl, (d-d)haloalkyl, (d-d)alkoxy,

((C₁-d)alkyl)((C₁-d)alkyl)N(C₁-d)alkoxy, (d-d)alkylamino, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

The invention is still further directed to a method of treatment or use of a compound according to Formula I, wherein A is -((d-C₄alkyl)C(=0)NR^x-,

-((d-C₄)alkyl)S0₂NR^x-, -((d-C₄)alkyl)NR^xC(=0)NR^x- or -((d-C₄)alkyl)NR^xC(=0)-; particularly -((d-d)alkyl)C(=0)NR^x-, -((C₂-C₄)alkyl)S0₂NR^x- or

-((C₂-C₄)alkyl)NR^xC(=0)-;

n is 1 -3;

R² and R³ taken together with the atom to which they are connected form an optionally substituted 4, 5 or 6 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 heteroatom selected from N and O and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by a substituent selected from (d-d)alkyl, aryl(d-d)alkyl-, and (C₃-C₆)cycloalkyl(d-C₂)alkyl-; or R² is selected from H and optionally substituted (C₁-C₄)alkyl,

phenyl(C₁-C₂)alkyl-, and (C₃-C₆)cycloalkyl(C₁-C₂)alkyl- and R³ is selected from H and methyl,

or R² is (Ci-C₂)alkylamino, ((Ci-C2)alkyl)((Ci-C₂)alkyl)amino, amino(Ci-C₃)alkyl, (Ci-C₂)alkylamino(Ci-C₃)alkyl, or ((Ci-C₂)alkyl)((Ci-C₂)alkyl)amino(Ci-C₃)alkyl, and R³ is H or (Ci-C₂)alkyl,

or R² is hydroxyl and R³ is H or methyl;

L is thiazolyl, thienyl, triazolyl, oxazolyl, isoxazolyl or phenyl which is substituted by R⁴ and is optionally further substituted by a methyl group;

R⁴ is H, methyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 4- cyanophenyl, 4-methoxyphenyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

Specifically, the invention is directed to a method of treatment or use of a compound according to Formula I, wherein:

A is -CH₂CH₂C(=0)NH-, -CH₂CH₂CH₂C(=0)NH-, -CH₂CH₂CH₂S0₂NH-,

-CH₂CH₂C(CH₃)₂C(=0)NH-, -CH₂CH₂C(CH₃)₂S0₂NH- or -CH₂CH₂CH₂CH₂C(=0)NH-;

R^x is H;

n is 1 ;

R² and R³ taken together with the atom to which they are connected form a tetrahydropyranyl group or R² and R³ are methyl, or R² is -CH₂CH₂N(CH₃)₂ and R³ is H, or R² is hydroxyl and R³ is methyl;

L is thiazolyl or oxazolyl substituted only by R⁴, where R⁴ is phenyl, 4-chlorophenyl, or 4-fluorophenyl;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

More specifically, the invention is directed to a method of treatment or use of a compound according to Formula I, wherein A is -CH₂CH₂CH₂C(=0)NH-,

-CH₂CH₂C(CH₃)₂C(=0)NH-, -CH₂CH₂CH₂S0₂NH-or -CH₂CH₂C(CH₃)₂S0₂NH-;

n is 1 ;

R² and R³ taken together with the atom to which they are connected form an N- methyl-piperidinyl group or R² and R³ are methyl, or R² and R³ are H, or R² is

-CH₂CH₂N(CH₃)₂ and R³ is H, or R² is hydroxyl and R³ is H or methyl;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

Specifically, the compound of Formula I is a compound according to Formula (l-a):

R¹ is -CF₃;

n is 0-4;

A is -((CrC₆)alkyl)C(=0)NR^x-, -((C C₆)alkyl)NR^xC(=0)NR^x,

-((CrC₆)alkyl)NR^xC(=0)-, -((C C₆)alkyl)S0₂-, -S0₂NR^x-, -((Ci-C₆)alkyl)S0₂NR^x-, -((CrC₆)alkyl)NR^xS0₂-, -((Ci-C₆)alkyl)NHCH(CF₃)-, -CH(CF₃)NH-,

-((Ci-C₆)alkyl)CH(CF₃)NH-, -CH(CF₃)-, -((Ci-C₆)alkyl)CH(CF₃)-, or -((C C₆)alkyl)NR^x-; when n is 0, R² and R³ are independently selected from H and optionally substituted (C C₄)alkyl, aryl(C C₄)alkyl-, and (C₃-C₇)cycloalkyl(CrC₄)alkyl-,

when n is 1 -4, R² and R³ are independently selected from H, fluoro, and optionally substituted (CrC₄)alkyl, aryl(d-C₄)alkyl-, and (C₃-C₇)cycloalkyl(CrC₄)alkyl-, wherein, when n is 1 , R² is F and R³ is H, then A is -C(=0)NR^x-, -((CrC₆)alkyl)C(=0)NR^x-, -((CrC₆)alkyl)NR^xC(=0)NR^x, -S0₂NR^x-, -((CrC₆)alkyl)S0₂NR^x-,

-((CrC₆)alkyl)NHCH(CF₃)-, -CH(CF₃)NH-, -((Ci-C₆)alkyl)CH(CF₃)NH-, -CH(CF₃)-, -((CrC₆)alkyl)CH(CF₃)-, -(C C₄)alkyl-, or -((Ci-C₆)alkyl)NR^x-, and

when n is 1 -4, R² is selected from amino, hydroxyl, (Ci-C₄)alkoxy, and R³ is selected from H and optionally substituted (Ci-C₄)alkyl, aryl(Ci-C₄)alkyl-, and

(C₃-C₇)cycloalkyl(C C₄)alkyl-,

wherein the aryl, cycloalkyi and each of the (CrC₄)alkyl moieties of said optionally substituted (CrC₄)alkyl, aryl(CrC₄)alkyl-, and (C₃-C₇)cycloalkyl(CrC₄)alkyl- of any R² and R³ are optionally substituted by 1 , 2 or 3 groups independently selected from halogen, cyano, (CrC₄)alkyl, halo(C₁-C₄)alkyl, (C C₄)alkoxy, halo(C₁-C₄)alkoxy, halogen, NR^AR^A, -((C C₄)alkyl)NR^AR^A, (C C₄)alkoxy, hydroxyl, cyano, halo(d-C₄)alkyl, and

halo(C C₄)alkoxy;

or R² and R³ taken together with the atom to which they are connected form an optionally substituted 4, 5, 6, or 7 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 or 2 heteroatoms independently selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by 1 , 2 or 3 substituents independently selected from (CrC₄)alkyl, halo(CrC₄)alkyl, halogen, cyano, aryl(Ci-C₄)alkyl-, (C₃-C₇)cycloalkyl(CrC₄)alkyl-, -OR^Y, -NR^YR^Y, -C(=0)OR^Y, -C(=0)NR^YR^Y, -NR^YC(=0)R^Y, -S0₂NR^YR^Y, -NR^YS0₂R^Y,

-OC(=0)NR^YR^Y, -NR^YC(=0)OR^Y, -NR^YC(=0)NR^YR^Y; and

wherein when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and (CrC₄)alkyl;

R⁴ is H, (C C₄)alkyl, halo(C C₄)alkyl, (C C₄)alkoxy,

((Ci-C4)alkyl)((Ci-C₄)alkyl)N(Ci-C₄)alkoxy, (C C₄)haloalkyl, (Ci-C₄)alkylamino, optionally substituted (C₃-C₆)cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, or optionally substituted 5-6 membered heteroaryl,

wherein said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C₄)alkyl, halogen, cyano, halo(CrC₄)alkyl, (d-C₄)alkoxy, halo(CrC₄)alkoxy, hydroxyl, -NR^AR^A and -((Ci-C₄)alkyl)NR^AR^A;

or L-R⁴ , taken together, form a 1 ,3-benzodioxolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group wherein said benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group is optionally substituted by 1 , 2 or 3 groups independently selected from halogen, (C₁-C₄)alkyl, cyano, halo(C₁-C₄)alkoxy,

(C₁-C₄)alkoxy, and halo(C₁-C₄)alkyl;

wherein each R^A is independently selected from H and (C₁-C₄)alkyl;

each R^x is independently selected from H, (C₁-C₆)alkyl, or optionally substituted (C₂-C₆)alkyl, where said optionally substituted (C₂-C₆)alkyl is optionally substituted by hydroxyl, cyano, amino, (Ci-C₄)alkoxy, ((Ci-C₄)alkyl)NH-, or ((Ci-C₄)alkyl)((Ci-C₄)alkyl)N-; and

each R^Y is independently selected from H, (CrC₄)alkyl, phenyl, and

-(CrC₄)alkylphenyl;

or a salt, particularly a pharmaceutically acceptable salt, thereof.

In one embodiment of this invention, the method excludes treatment with the following compounds 2,2,2-trifluoro-1 -[5-[[methyl(phenylmethyl)amino]methyl]-2-thienyl]- ethanone or 2,2,2-trifluoro-1 -[5-[[[(1 R)-1-phenylethyl]amino]methyl]-2-thienyl]-ethanone, or a salt thereof.

As used herein, the term "optionally substituted" means unsubstituted groups or rings (e.g., cycloalkyl, heterocycle, and heteroaryl rings) and groups or rings substituted with one or more specified substituents. The compounds of Formula I that are useful in the method of this invention (as well as methods for the preparation of such compounds) are described in WO201 1/088187, the disclosure of which is incorporated herein by reference.

A specific compound of Formula I is the compound 1 , A/-[4-(4-phenyl-thiazol-2-yl)- tetrahydro-pyran-4-ylmethyl]-4-(5-trifluoromethyl-[1 ,2,4]oxadiazol-3-yl)-butyramide.

Compounds that may be prepared using the methods described herein include:

A/-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-4-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)butanamide,

4-(5-(difluoromethyl)-1 ,2,4-oxadiazol-3-yl)-/\/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2- methylpropyl)butanamide,

A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-4-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)butanamide,

A/-(4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-4-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)butanamide,

A/-((4-(2-(4-fluorophenyl)oxazol-4-yl)-1 -methylpiperidin-4-yl)methyl)-4-(5-

(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)butanamide,

A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-2,2-dimethyl-4-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)butanamide,

A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-4-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)butanamide,

A/-((4-(2-(4-chlorophenyl)thiazol-4-yl)-1 -methylpiperidin-4-yl)methyl)-4-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)butanamide,

A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyethyl)-4-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)butanamide,

4-(5-(difluoromethyl)-1 ,2,4-oxadiazol-3-yl)-/\/-(4-(dimethylamino)-2-(2-(4- fluorophenyl)oxazol-4-yl)butyl)butanamide,

A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)propane-1 -sulfonamide,

A/-(3-(2-(4-fluorophenyl)oxazol-4-yl)-3-hydroxypropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)propanamide,

A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-4-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)butanamide,

A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-4-(5-(2,2,2-trifluoroacetyl)thiophen-2- yl)butanamide,

A/-(2-(3-(4-fluorophenyl)-1 H-1 ,2,4-triazol-5-yl)-2-methylpropyl)-4-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)butanamide, 3-(2-(4-fluorophenyl)oxazol-4-yl)-/\/-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)propyl)propanamide,

A/-(2-(3-(4-fluorophenyl)-1 H-1 ,2,4-triazol-5-yl)ethyl)-4-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)butanamide,

/V-(4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-4-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)butanamide,

/V-((4-(2-(4-fluorophenyl)oxazol-4-yl)-1 -methylpiperidin-4-yl)methyl)-4-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)butanamide,

and a salt, particularly a pharmaceutically acceptable salt, thereof.

Particular compounds of Formula I are:

N-(4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-4-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)butanamide,

N-((4-(2-(4-fluorophenyl)oxazol-4-yl)-1 -methylpiperidin-4-yl)methyl)-4-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)butanamide,

N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-2,2-dimethyl-4-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)butanamide,

N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-4-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)butanamide,

N-(2-(3-(4-fluorophenyl)-1 H-1 ,2,4-triazol-5-yl)ethyl)-4-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)butanamide,

N-(4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-4-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)butanamide,

N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyethyl)-4-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)butanamide,

and a salt, particularly a pharmaceutically acceptable salt, thereof.

As used herein, the term "compound(s) of Formula I " means a compound of Formula I, including any stereoisomer thereof (e.g., including any enantiomer or diastereomer of a compound recited above), in any form, for example, any salt or non-salt form (e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof), any solvate form (particularly a hydrate thereof (including mono-, di- and hemi- hydrates and including any hydrate of a salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms of any of the above)), and mixtures of various forms. Compound names were generated using the software naming program ChemDraw 1 1 .0 available from CambridgeSoft Corporation., 100 CambridgePark Drive, Cambridge, MA 02140, USA (http://www.cambridgesoft.com).

The invention also includes the use of various deuterated forms of the compounds of Formula I. Each available hydrogen atom attached to a carbon atom may be

independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formula I. The invention further includes the use of various radio-labelled or other isotopically enriched forms of the compounds of Formula I, such as compounds that contain a ²H, ³H, ¹⁴C, ¹¹C, or ¹⁸F atom. Similarly, a person of ordinary skill in the art will know how to synthesize such radio- labelled or isotopically enriched forms of the compounds of Formula I.

In one embodiment, the present invention is directed to a method of treating an HDAC-mediated neurodegenerative disease or disorder which comprises administering to a patient in need thereof, a compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof. This invention is also directed to a method of treatment of a neurodegenerative disease or disorder associated with deacetylases, such as, Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NMD), and polyglutamine disorders, such as Huntington's disease and spinocerebellar ataxia (SCA), comprising administering a therapeutically effective amount of the compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to a patient, specifically a human, in need thereof.

In another embodiment, the present invention is directed to a method of treating a B-cell lymphoma, particularly a B-cell lymphoma associated with deacetylases, which comprises administering to a patient in need thereof, a compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof. More specifically, this invention is directed to a method of treatment of Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma), comprising administering a therapeutically effective amount of the compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to a patient, specifically a human, in need thereof.

As used herein, "patient" refers to a mammal, specifically, a human. A

therapeutically "effective amount" is intended to mean that amount of a compound that, when administered to a patient in need of such treatment, is sufficient to effect treatment, as defined herein. Thus, e.g., a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is a quantity of an inventive agent that, when administered to a human in need thereof, is sufficient to inhibit the activity of HDAC such that a disease condition which is mediated by that activity is reduced, alleviated or prevented. The amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (pXC₅o), efficacy (EC₅o), and the biological half-life of the particular compound), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Likewise, the duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease or condition and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.

"Treating" or "treatment" is intended to mean at least the mitigation of a disease condition in a patient, where the disease condition is associated with, that is caused or mediated by, HDAC.

Examples of neurodegenerative diseases or disorders associated with

deacetylases that may be treated using the method of this invention include Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NMD), and polyglutamine disorders, such as Huntington's disease and spinocerebellar ataxia (SCA).

Examples of B-cell lymphomas associated with deacetylases that may be treated using the method of this invention include Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma).

In another embodiment, this invention is directed to inhibitors of HDAC and their use to stop or reduce the growth of neoplastic cells, e.g., cancer cells and tumor cells.

The methods of treatment for mitigation of a disease condition include the use of the compounds in Formula I in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy or cure of a disease.

The compounds of Formula I may be administered by any suitable route of administration, including both systemic administration and topical administration.

Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin.

The compounds of Formula I may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of Formula I depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of Formula I depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.

Treatment of a neurodegenerative disease or disorder may be achieved using the compounds of Formula I as a monotherapy, or in dual or multiple combination therapy, such as in combination with other agents, for example, in combination with one or more of the following agents: DNA methyltransferase inhibitors, acetyl transferase enhancers, proteasome or HSP90 inhibitors, , and drugs that are currently used for the treatment of Alzheimer's disease (such as a cholinesterase inhibitor (galantamine, rivastigmine, donepezil, or tacrine, or memantine), Parkinson's disease (such as levodopa, alone or combined with carbidopa or combined with benserazide, a dopamine agonist, such as pramipexole, ropinirole, or apomorphine , a MAO B inhibitor, such as selegiline or rasagiline, or a Catechol O-methyltransferase (COMT) inhibitor, such as tolcapone.

entacapone, alone or combined with carbidopa and levodopa or an anticholinergic, such as benztropine or trihexyphenidy, or a glutamate (NMDA) blocking drug, such as amantadine), neuronal intranuclear inclusion disease, Huntington's disease (such as tetrabenazine, haloperidol and clozapine, antiseizure drugs such as clonazepam and antianxiety drugs such as diazepam), and spinocerebellar ataxia, which are administered in effective amounts as is known in the art. The compounds of Formula I will normally, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, in another aspect, the invention is directed to the administration of a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically-acceptable excipient to treat a neurodegenerative disease, disorder or condition.

Treatment of a B-cell lymphoma may be achieved using the compounds of Formula I as a monotherapy, or in dual or multiple combination therapy, such as in combination with other agents, for example, in combination with one or more of the following agents:

antibodies (such as rituxumab, alone or in combination with cyclophosphamide), chemotherapeutic regimens, proteasome inhibitors (such as bortezomib), HDAC inhibitors (such as vorinostat, romidepsin, valproic acid, panobinostat, mocetinostat, givinostat, belinostat and entinostat), mTOR inhibitors (such as temsirolimus, deforolimus, everolimus,and rapamycin), DNA methyltransferase inhibitors, acetyl transferase enhancers, proteasome or HSP90 inhibitors, which are administered in effective amounts as is known in the art.

The compounds of Formula I will normally, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, in another aspect, the invention is directed to the administration of a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically-acceptable excipient to treat B cell lymphomas.

The pharmaceutical compositions useful in the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of Formula I can be extracted and then given to the patient such as with powders, syrups, and solutions for injection. Alternatively, the pharmaceutical compositions may be prepared and packaged in unit dosage form. For oral application, for example, one or more tablets or capsules may be administered. A dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of Formula I or a salt, particularly a pharmaceutically acceptable salt, thereof. When prepared in unit dosage form, the pharmaceutical compositions may contain from 1 mg to 1000 mg of a compound of Formula I.

The pharmaceutical compositions typically contain one compound of Formula I. However, in certain embodiments, the pharmaceutical compositions may contain more than one compound of Formula I. In addition, the pharmaceutical compositions may optionally further comprise one or more additional pharmaceutically active compounds.

As used herein, "pharmaceutically-acceptable excipient" means a material, composition or vehicle involved in giving form or consistency to the composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of Formula I when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically-acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.

The compounds of Formula I and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. Conventional dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of Formula I once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.

Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions useful in the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

In one aspect, the invention is directed to the use of a solid oral dosage form, such as a tablet or capsule, comprising an effective amount of a compound of Formula I and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

Pharmaceutical Compositions

Example A

Tablets are prepared using conventional methods and are formulated as follows:

Ingredient Amount per tablet

Compound 5mg

Microcrystalline cellulose 100mg

Lactose 100mg

Sodium starch glycollate 30mg

Magnesium stearate 2mg Total 237mg

Example B

Capsules are prepared using conventional methods and are formulated as follows

Inqredient Amount per tablet

Compound 15mg

Dried starch 178mg

Maqnesium stearate 2mq

Total 195mg

References:

US 20060269559, US Patent No. 7,521 ,044, WO2007084775

WO201 1/088187

"Deacetylase inhibition promotes the generation and function of regulatory T cells,"

R.Tao, E. F. de Zoeten, E. O^" zkaynak, C. Chen, L. Wang, P. M. Porrett, B. Li, L. A. Turka,

E. N. Olson, M. I. Greene, A. D. Wells, W. W. Hancock, Nature Medicine, 13 (1 1 ), 2007.

"Expression of HDAC9 by T Regulatory Cells Prevents Colitis in Mice," E. F. de

Zoeten, L. Wang, H. Sai, W. H. Dillmann, W. W. Hancock, Gastroenterology. 2009 Oct 28.

"Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of

FOXP3+ regulatory T cells," L. Wang, E. F. de Zoeten, M. I. Greene and W. W. Hancock,

Nature Review Drug Discovery. 8(12):969-81 , 2009 and references therein.

"HDAC7 targeting enhances FOXP3+ Treg function and induces long-term allograft survival," L. Wang, et al., Am. J. Transplant 9, S621 (2009).

"Selective class II HDAC inhibitors impair myogenesis by modulating the stability and activity of HDAC-MEF2 complexes," A. Nebbioso, F. Manzo, M. Miceli, M. Conte, L.

Manente, A. Baldi, A. De Luca, D. Rotili, S. Valente, A. Mai, A. Usiello, H. Gronemeyer, L.

Altucci, EMBO reports 10 (7) , 776-782, 2009. and references therein.

"Myocyte Enhancer Factor 2 and Class II Histone Deacetylases Control a Gender- Specific Pathway of Cardioprotection Mediated by the Estrogen Receptor," E. van Rooij,

J. Fielitz, L. B. Sutherland, V. L. Thijssen, H. J. Crijns, M. J. Dimaio, J. Shelton, L. J. De

Windt, J. A. Hill, E.N. Olson, Circulation Research, Jan 2010.

Claims

What is claimed is:

1. A method of treatment of a neurodegenerative disease or disorder associated with deacetylases, comprising administering, to a patient in need thereof, a compound of

Formula I:

wherein:

R¹ is halo(CrC₄)alkyl, wherein said halo(Ci-C₄)alkyl contains at least 2 halo groups (R¹ is di-halo(C C₄)alkyl);

Y is a bond and Xi is O, X₂ is N or CH and X₃ is N or NH,

or Y is -C(O)- and Xi and X₂ are CH or N, X₃ is O or S,

or Y is -C(O)- and Xi is O, X₂ is CH or N, and X₃ is CH or N;

n is 0-4;

A is -C(=0)NR^x-, -((C C₆)alkyl)C(=0)NR^x-, -((C C₆)alkyl)NR^xC(=0)NR^x,

-((C C₆)alkyl)NR^xC(=0)-, -((C C₆)alkyl)S0₂-, -S0₂NR^x-, -((C₁-C₆)alkyl)S0₂NR^x-,

-((C C₆)alkyl)NR^xS0₂-, -((d-Q alky NHCHtCFa)-, -CH(CF₃)NH-,

-((C C₆)alkyl)CH(CF₃)NH-, -CH(CF₃)-, -((d-Q alky CHtCFa)-, or -((C C₆)alkyl)NR^x-; when n is 0, R² and R³ are independently selected from H and optionally

substituted (C C₄)alkyl, aryl(C C₄)alkyl-, and (C₃-C₇)cycloalkyl(Ci-C₄)alkyl-,

when n is 1 -4, R² and R³ are independently selected from H, fluoro, and optionally substituted (Ci-C₄)alkyl, aryl(Ci-C₄)alkyl-, and (C₃-C₇)cycloalkyl(Ci-C₄)alkyl-, wherein, when n is 1 , R² is F and R³ is H, then Z is -C(=0)NR^x-, -NR^xC(=0)NR^x, -S0₂NR^x-,

-NHCH(CF₃)-, -CH(CF₃)NH-, -CH(CF₃)-, -(C C₄)alkyl-, -NR^X-, or -(C C₃)alkyl-NR^x-, and when n is 1 -4, R² is selected from -NR^AR^B, -(C C₄)alkyl-NR^AR^B, -CONR^AR^B,

-(Ci-C₄)alkyl-CONR^AR^B, -C0₂H, -(Ci-C₄)alkyl-C0₂H, hydroxyl, hydroxy(C C₄)alkyl-,

(Ci-C₃)alkoxy, and (Ci-C₃)alkoxy(Ci-C₄)alkyl-, and R³ is selected from H and optionally substituted (C C₄)alkyl, aryl(C C₄)alkyl-, and (C₃-C₇)cycloalkyl(C C₄)alkyl-,

wherein the aryl, cycloalkyl and each of the (CrC₄)alkyl moieties of said optionally substituted (C C₄)alkyl, aryl(C C₄)alkyl-, and (C₃-C₇)cycloalkyl(C C₄)alkyl- of any R² and R³ are optionally substituted by 1 , 2 or 3 groups independently selected from halogen, cyano, (C C₄)alkyl, halo(d-C₄)alkyl, (C C₄)alkoxy, halo(d-C₄)alkoxy, -NR^AR^A,

-((C C₄)alkyl)NR^AR^A, and hydroxyl;

halo(CrC₄)alkyl, halogen, cyano, aryl(Ci-C₄)alkyl-, (C₃-C₇)cycloalkyl(Ci-C₄)alkyl-, -OR^Y, -NR^YR^Y, -C(=0)OR^Y, -C(=0)NR^YR^Y, -NR^YC(=0)R^Y, -S0₂NR^YR^Y, -NR^YS0₂R^Y,

-OC(=0)NR^YR^Y, -NR^YC(=0)OR^Y, and -NR^YC(=0)NR^YR^Y; and

R⁴ is H, (C C₄)alkyl, halo, halo(Ci-C₄)alkyl, (C C₄)alkoxy,

wherein said optionally substituted cycloalkyi, phenyl, heterocycloalkyi or heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from

(Ci-C₄)alkyl, halogen, cyano, halo(CrC₄)alkyl, (CrC₄)alkoxy, (Ci-C₄)alkylthio-,

halo(Ci-C₄)alkoxy, hydroxyl, -NR^AR^C and -((Ci-C₄)alkyl)NR^AR^c;

or L-R⁴ , taken together, form a 1 ,3-benzodioxolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group wherein said benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group is optionally substituted by 1 , 2 or 3 groups independently selected from (CrC₄)alkyl, halogen, cyano, halo(CrC₄)alkyl, (Ci-C₄)alkoxy, (Ci-C₄)alkylthio-, halo(C C₄)alkoxy, hydroxyl, -NR^AR^C and -((C C₄)alkyl)NR^AR^c;

wherein each R^A is independently selected from H and (CrC₄)alkyl;

R^B is H, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl,

-C(=0)NH₂,

-S0₂(Ci-C₄)alkyl, or R^A and R^B taken together with the atom to which they are attached form a 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (Ci-C₄)alkyl;

R^c is H, (CrC₄)alkyl, phenyl, 5-6 membered heterocycloalkyi, or 5-6 membered heteroaryl, or R^A and R^c taken together with the atom to which they are attached form a 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (C₁-C₄)alkyl;

each R^x is independently selected from H, (C₁-C₆)alkyl, and optionally substituted (C₂-C₆)alkyl, where said optionally substituted (C₂-C₆)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C₄)alkoxy, (Ci-C₄)alkyl)NH-, or ((Ci-C₄)alkyl)((C C₄)alkyl)N-; and

each R^Y is independently selected from H, (Ci-C₄)alkyl, phenyl, and

-(Ci-C₄)alkylphenyl;

provided that when Y is -C(O)- and A is -C(=0)NR^x- or -S0₂NR^x-, then at least one of R² and R³ is not H;

or a salt thereof.

2. A method of treatment of a B-cell lymphoma associated with deacetylases comprising administering, to a patient in need thereof, a compound of Formula I:

wherein:

R¹ is halo(C₁-C₄)alkyl, wherein said halo(C₁-C₄)alkyl contains at least 2 halo groups (R¹ is di-halo(CrC₄)alkyl);

Y is a bond and is O, X₂ is N or CH and X₃ is N or NH,

or Y is -C(O)- and X^ and X₂ are CH or N, X₃ is O or S,

or Y is -C(O)- and Xi is O, X₂ is CH or N, and X₃ is CH or N;

n is 0-4;

A is -C(=0)NR^x-, -((CrC₆)alkyl)C(=0)NR^x-, -((C C₆)alkyl)NR^xC(=0)NR^x, -((CrC₆)alkyl)NR^xC(=0)-, -((C C₆)alkyl)S0₂-, -S0₂NR^x-, -((Ci-C₆)alkyl)S0₂NR^x-, -((CrC₆)alkyl)NR^xS0₂-, -((Ci-C₆)alkyl)NHCH(CF₃)-, -CH(CF₃)NH-,

-((CrC₆)alkyl)CH(CF₃)NH-, -CH(CF₃)-, -((Ci-C₆)alkyl)CH(CF₃)-, or -((C C₆)alkyl)NR^x-; when n is 0, R² and R³ are independently selected from H and optionally substituted (C C₄)alkyl, aryl(C C₄)alkyl-, and (C₃-C₇)cycloalkyl(C C₄)alkyl-,

when n is 1 -4, R² and R³ are independently selected from H, fluoro, and optionall; substituted (Ci-C₄)alkyl, aryl(Ci-C₄)alkyl-, and (C₃-C₇)cycloalkyl(Ci-C₄)alkyl-, wherein, when n is 1 , R² is F and R³ is H, then Z is -C(=0)NR^x-, -NR^xC(=0)NR^x, -S0₂NR^x-, -NHCH(CF₃)-, -CH(CF₃)NH-, -CH(CF₃)-, -(C C₄)alkyl-, -NR^X-, or -(C C₃)alkyl-NR^x-, and when n is 1 -4, R² is selected from -NR^AR^B, -(C C₄)alkyl-NR^AR^B, -CONR^AR^B, -(C C₄)alkyl-CONR^AR^B, -C0₂H, -(C₁-C₄)alkyl-C0₂H, hydroxyl, hydroxy(C C₄)alkyl-, (C₁-C₃)alkoxy, and (C₁-C₃)alkoxy(C₁-C₄)alkyl-, and R³ is selected from H and optionally substituted (C C₄)alkyl, aryl(C C₄)alkyl-, and (C₃-C₇)cycloalkyl(Ci-C₄)alkyl-,

-((Ci-C₄)alkyl)NR^AR^A, and hydroxyl;

-OC(=0)NR^YR^Y, -NR^YC(=0)OR^Y, and -NR^YC(=0)NR^YR^Y; and

R⁴ is H, (C C₄)alkyl, halo, halo(Ci-C₄)alkyl, (C C₄)alkoxy,

wherein each R^A is independently selected from H and (C₁-C₄)alkyl; R is H, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, -C(=0)(C₁-C₄)alkyl, -C(=0)0(C C₄)alkyl, -C(=0)NH₂, -C(=0)NH(d-C₄)alkyl, -C(=0)N((C₁-C₄)alkyl)((C₁-C₄)alkyl), -SO^d-C^alkyl, or R^A and R^B taken together with the atom to which they are attached form a 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (Ci-C₄)alkyl;

each R^Y is independently selected from H, (Ci-C₄)alkyl, phenyl, and

-(Ci-C₄)alkylphenyl;

or a salt thereof.

3. The method according to claim 1 or claim 2, wherein R¹ is CHF₂ or CF₃.

4. The method according to claim 1 or claim 2, wherein R¹ is CF₃.

5. The method according to any one of claims 1 -4, wherein when Y is a bond, Xi is O, X₂ and X₃ are N, or X^ is O, X₂ is CH, X₃ is N.

6. The method according to any one of claims 1 -4, wherein when Y is a bond, Xi is O, and X₂ and X₃ are N.

7. The method according to any one of claims 1 -4, wherein when Y is -C(O)-, X₃ is

S, Xi is CH and X₂ is N, or X₃ is S, Xi is N and X₂ is CH, or X₃ is O, Xi is CH and X₂ is N, or X₃ is O, Xi is N and X₂ is CH, or X^ and X₂ are CH, X₃ is S or X^ and X₂ are CH, X₃ is O.

8. The method according to any one of claims 1 -4, wherein when Y is -C(O)-, X₃ is S, Xi is CH and X₂ is N, or X₃ is S, Xi is N and X₂ is CH, or X₃ is O, Xi is CH and X₂ is N, or X₃ is O, X is N and X₂ is CH, or Xi and X₂ are CH, X₃ is S.

9. The method according to any one of claims 1 -4, wherein when Y is -C(O)-, X-i and X₂ are CH, X₃ is S.

10. The method according to any one of claims 1-4, wherein when Y is -C(O)-, Xi is O, X₂ and X₃ are CH, or is O, X₂ is CH, and X₃ is N, or is O, X₂ is N, and X₃ is CH,

1 1 . The method according to any one of claims 1-4, wherein when Y is -C(O)-, Xi is O, X₂ and X₃ are CH.

12. The method according to any one of claims 1-1 1 , wherein A is

-((CrC₆)alkyl)C(=0)NR^x-, -((C C₆)alkyl)S0₂NR^x-,

or -((CrC₆)alkyl)NR^xC(=0)-.

13. The method according to any one of claims 1-1 1 , wherein A is

-((CrC₄alkyl)C(=0)NR^x-, -((C C₄)alkyl)S0₂NR^x-, -((C C₄)alkyl)NR^xC(=0)NR^x- or -((C C₄)alkyl)NR^xC(=0)-.

14. The method according to any one of claims 1-1 1 , wherein A is

-((C₂-C₄)alkyl)C(=0)NR^x-, -((C₂-C₄)alkyl)S0₂NR^x-, or -((C₂-C₄)alkyl)NR^xC(=0)-.

15. The method according to any one of claims 1-1 1 , wherein A is

-CH₂CH₂C(=0)NH-, -CH₂CH₂CH₂C(=0)NH-, -CH₂CH₂CH₂S0₂NH-or

-CH₂CH₂CH₂CH₂C(=0)NH-.

16. The method according to any one of claims 1 -14, wherein each R^x is independently selected from H, (d-C₄)alkyl, or optionally substituted (C₂-C₄)alkyl, where said optionally substituted (C₂-C₄)alkyl is optionally substituted by hydroxyl, cyano, amino, (Ci-C₄)alkoxy, (C C₄)alkyl)NH-, or ((Ci-C₂)alkyl)((C C₂)alkyl)N-.

17. The method according to any one of claims 1 -14, wherein each R^x is independently selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N-methylaminoethyl- or dimethylaminoethyk

18. The method according to any one of claims 1 -14, wherein each R is independently H or methyl.

19. The method according to any one of claims 1-14, wherein R is H.

20 The method according to any one of claims 1 -19, wherein n is 0-3.

21 The method according to any one of claims 1 -19, wherein n is 0 or 1 .

22 The method according to any one of claims 1 -19, wherein n is 1.

23. The method according to any one of claims 1-22, wherein R² and R³ taken together with the atom to which they are connected form an optionally substituted 4, 5, or 6 membered cycloalkyi or heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 heteroatom selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyl group is optionally substituted by a substituent selected from

(Ci-C₄)alkyl, halo(Ci-C₄)alkyl, halogen, cyano, aryl(Ci-C₂)alkyl-,

(C₃-C₆)cycloalkyl(C₁-C₂)alkyl-, — OR^Ya, -NR^YaR^Yb, -C(=0)OR^Ya, -C(=0)NR^YaR^Yb,

-NR^YbC(=0)R^Ya, -S0₂NR^YaR^Yb, -NR^YbS0₂R^Ya, -OC(=0)NR^YaR^Yb, -NR^YbC(=0)OR^Ya, -N R^YbC(=0)N R^YaR^Yb, where R^Ya is selected from H, (C C₄)alkyl and -(C C₄)alkylphenyl and each R^Yb is independently selected from H and (C₁-C₄)alkyl.

24. The method according to any one of claims 1-22, wherein R² and R³ taken together with the atom to which they are connected form an optionally substituted 4, 5 or 6 membered cycloalkyi or heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 heteroatom selected from N and O and said optionally substituted cycloalkyi or heterocycloalkyl group is optionally substituted by a substituent selected from (Ci-C₄)alkyl, aryl(Ci-C₂)alkyl-, and (C₃-C₆)cycloalkyl(Ci-C₂)alkyk

25. The method according to any one of claims 1-22, wherein R² and R³ taken together with the atom to which they are connected form a tetrahydropyranyl or an N- methyl-piperidinyl group.

26. The method according to any one of claims 1-22, wherein R² and R³ are independently selected from optionally substituted (Ci-C₄)alkyl, phenyl(Ci-C₂)alkyl-, and (C₃-C₆)cycloalkyl(C₁-C₂)alkyl-.

27. The method according to any one of claims 1-22, wherein R² and R³ are each methyl.

28. The method according to any one of claims 1 -22, wherein one of R² and R³ is

H, and the other of R² and R³ is selected from optionally substituted (CrC₄)alkyl, phenyl(Ci-C₂)alkyl-, and (C₃-C₆)cycloalkyl(Ci-C₂)alkyl-, provided that when Y is -C(O)- A is not -C(=0)NR^x- or -S0₂NR^x-.

29. The method according to any one of claims 1 -19, wherein when n is 1-4, R² is selected from amino, (Ci-C₄)alkylamino, ((Ci-C₃)alkyl)((Ci-C₃)alkyl)amino,

amino(Ci-C₄)alkyl, (Ci-C₃)alkylamino(Ci-C₄)alkyl,

((Ci-C₃)alkyl)((Ci-C₃)alkyl)amino(Ci-C₄)alkyl,

(substituted(Ci-C₃)alkyl)((Ci-C₃)alkyl)amino(Ci-C₄)alkyl (where said substituted

((Ci-C₃)alkyl)((Ci-C₃)alkyl)aminocarbonyl(Ci-C₄)alkyl, hydroxyl, hydroxy(CrC₄)alkyl-, (C₁-C₄)alkoxy, and (C₁-C₄)alkoxy(C₁-C₄)alkyl- and R³ is selected from H and optionally substituted (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl-, and (C₃-C₇)cycloalkyl(C₁-C₄)alkyl-, and A is -((C C₆)alkyl)C(=0)NR^x-, -((C C₆)alkyl)NR^xC(=0)NR^x, -((C C₆)alkyl)NR^xC(=0)-, -((C C₆)alkyl)S0₂-, -((C₁-C₆)alkyl)S0₂NR^x-, -((C C₆)alkyl)NR^xS0₂-,

-((CrC₆)alkyl)NHCH(CF₃)-, -CH(CF₃)NH-, -((Ci-C₆)alkyl)CH(CF₃)NH-, -CH(CF₃)-, -((CrC₆)alkyl)CH(CF₃)-, or -((C C₆)alkyl)NR^x-.

30. The method according to any one of claims 1 -19, wherein when n is 1-4, R² is selected from amino, hydroxyl, and (CrC₄)alkoxy, and R³ is selected from H and optionally substituted (CrC₄)alkyl, phenyl(Ci-C₂)alkyl-, and (C₃-C₆)cycloalkyl(d-C₂)alkyl-, and A is -((C C₆)alkyl)C(=0)NR^x-, -((C C₆)alkyl)NR^xC(=0)NR^x,

-((CrC₆)alkyl)NR^xC(=0)-, -((C C₆)alkyl)S0₂-, -((C C₆)alkyl)S0₂NR^x-,

-((CrC₆)alkyl)NR^xS0₂-, -((Ci-C₆)alkyl)NHCH(CF₃)-, -CH(CF₃)NH-,

31 . The method according to any one of claims 1 -19, wherein n is 1 , R² is hydroxyl and R³ is H or methyl, when A is -((Ci-C₆)alkyl)C(=0)NR^x-,

-((CrC₆)alkyl)NR^xC(=0)NR^x,

-((Ci-C₆)alkyl)S0₂-,

-((C₁-C₆)alkyl)S0₂NR^x-, -((d-Q^alky NR^C , -((C C₆)alkyl)NHCH(CF₃)-, -CH(CF₃)NH-, -((Ci-C₆)alkyl)CH(CF₃)NH-, -CH(CF₃)-, -((Ci-C₆)alkyl)CH(CF₃)-, or -((C C₆)alkyl)NR^x-.

32. The method according to any one of claims 1 -19, wherein when n is 1-4 and A is -C(=0)NR^x- or -S0₂NR^x-, -R² is selected from amino, (C C₄)alkylamino,

((Ci-C₃)alkyl)((Ci-C₃)alkyl)aminocarbonyl(Ci-C₄)alkyl, hydroxyl, hydroxy(CrC₄)alkyl-, (Ci-C₄)alkoxy, and (Ci-C₄)alkoxy(CrC₄)alkyl- and R³ is selected from optionally substituted (C C₄)alkyl, aryl(C C₄)alkyl-, and (C₃-C₇)cycloalkyl(CrC₄)alkyl-.

33. The method according to any one of claims 1-19, wherein when A is

-C(=0)NR^x- or -S0₂NR^x-, n is 1-3, R² is hydroxyl and R³ is methyl.

34. The method according to any one of claims 1-19, wherein when A is

-C(=0)NR^x- or -S0₂NR^x-, n is 1 , R² is hydroxyl and R³ is methyl.

35. The method according to any one of claims 1-34, wherein L is 5-6 membered heteroaryl or phenyl group which is substituted by R⁴ and is optionally further substituted by 1 substituent selected from halogen, cyano and (CrC₄)alkyl.

36. The method according to any one of claims 1-34, wherein L is thiazolyl, thienyl, triazolyl, oxazolyl, isoxazolyl or phenyl which is substituted by R⁴ and is optionally further substituted by a methyl group.

37. The method according to any one of claims 1-34, wherein L is thiazolyl or oxazolyl substituted only by R⁴.

38. The method according to any one of claims 1 -34, wherein L is thiazolyl substituted only by R⁴.

39. The method according to any one of claims 1-38, wherein R⁴ is H,

(d-C₄)alkyl, (C C₄)haloalkyl, (C C₄)alkoxy, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)N(C₁-C₄)alkoxy, (C₁-C₄)alkylamino, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl.

40. The method according to any one of claims 1-38, wherein R⁴ is, , phenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 4-cyanophenyl, 4-methoxyphenyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl.

41 . The method according to any one of claims 1-38, wherein R⁴ is phenyl, 4-chlorophenyl, or 4-fluorophenyl.

42. The method according to claim 1 or claim 2, wherein:

A is -((CrC₆)alkyl)C(=0)NR^x- or -(C C₆)alkyl)NR^xC(=0)-;

each R^x is independently selected from H, (d-C₄)alkyl, or optionally substituted (C₂-C₄)alkyl, where said optionally substituted (C₂-C₄)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C₄)alkoxy, (Ci-C₄)alkyl)NH-, or ((Ci-C₂)alkyl)((Ci-C₂)alkyl)N-; n is 1 -4;

R² and R³ taken together with the atom to which they are connected form an optionally substituted 4, 5, or 6 membered cycloalkyl or heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 heteroatom selected from N, O and S and said optionally substituted cycloalkyl or heterocycloalkyl group is optionally substituted by a substituent selected from (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, halogen, cyano, aryl(C₁-C₂)alkyl-, (C₃-C₆)cycloalkyl(Ci-C₂)alkyl-, -OR^Ya, -NR^YaR^Yb, -C(=0)OR^Ya, -C(=0)NR^YaR^Yb, -NR^YbC(=0)R^Ya, -S0₂NR^YaR^Yb, -NR^YbS0₂R^Ya, -OC(=0)NR^YaR^Yb, -NR^YbC(=0)OR^Ya, -NR^YbC(=0)NR^YaR^Yb, where R^Ya is selected from H, (C C₄)alkyl and -(C C₄)alkylphenyl and each R^Yb is independently selected from H and (CrC₄)alkyl;

or R² and R³ are independently selected from H and optionally substituted (Ci-C₄)alkyl, phenyl(C C₂)alkyl-, and (C₃-C₆)cycloalkyl(Ci-C₂)alkyl-,

or R² is hydroxyl and R³ is H or methyl;

(Ci-C₄)alkyl; and R⁴ is H, (d-C₄)alkyl, (d-C₄)haloalkyl, (C C₄)alkoxy,

((C₁-C₄)alkyl)((C₁-C₄)alkyl)N(C₁-C₄)alkoxy, (C₁-C₄)alkylamino, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl.

43. The method according to claim 1 or claim 2, wherein

A is -((C₂-C₄)alkyl)C(=0)NR^x- or -((C₂-C₄)alkyl)NR^xC(=0)-;

n is 1 -3;

R² and R³ taken together with the atom to which they are connected form an optionally substituted 4, 5 or 6 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 heteroatom selected from N and O and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by a substituent selected from (Ci-C₄)alkyl, aryl(CrC₂)alkyl-, and (C3-C₆)cycloalkyl(Ci-C₂)alkyl-; or R² is selected from H and optionally substituted (Ci-C₄)alkyl,

phenyl(Ci-C₂)alkyl-, and (C₃-C₆)cycloalkyl(CrC₂)alkyl- and R³ is selected from H and methyl,

or R² is (Ci-C₂)alkylamino, ((Ci-C₂)alkyl)((Ci-C₂)alkyl)amino, amino(Ci-C₃)alkyl, (Ci-C₂)alkylamino(Ci-C₃)alkyl, or ((Ci-C₂)alkyl)((Ci-C₂)alkyl)amino(Ci-C₃)alkyl, and R³ is H or (C C₂)alkyl,

or R² is hydroxyl and R³ is H or methyl;

L is thiazolyl, thienyl, triazolyl, oxazolyl or phenyl which is substituted by R⁴ and is optionally further substituted by a methyl group; and

R⁴ is H, methyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 4- cyanophenyl, 4-methoxyphenyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl.

44. The method according to claim 1 or claim 2, wherein

A is -CH₂CH₂C(=0)NH-, -CH₂CH₂CH₂C(=0)NH-, -CH₂CH₂CH₂S0₂NH-,

R^x is H;

n is 1 ;

R² and R³ taken together with the atom to which they are connected form a tetrahydropyranyl or an N-methyl-piperidinyl group or R² and R³ are methyl or R² is -CH₂CH₂N(CH₃)₂ and R³ is H, or R² is hydroxyl and R³ is H or methyl; and

L is thiazolyl or oxazolyl substituted only by R⁴, where R⁴ is phenyl, 4-chlorophenyl, or 4-fluorophenyl.

45. The method according to claim 1 or claim 2, wherein the compound of Formula I is selected from:

A/-((4-(2-(4-fluorophenyl)oxazol-4-yl)-1 -methylpiperidin-4-yl)methyl)-4-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)butanamide,

A/-(2-(3-(4-fluorophenyl)-1 H-1 ,2,4-triazol-5-yl)-2-methylpropyl)-4-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)butanamide,

3-(2-(4-fluorophenyl)oxazol-4-yl)-/\/-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)propyl)propanamide,

A/-(2-(3-(4-fluorophenyl)-1 H-1 ,2,4-triazol-5-yl)ethyl)-4-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)butanamide, /V-(4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-4-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)butanamide,

or a pharmaceutically acceptable salt thereof.

46. The method according to any one of claims 1 or 3-45, wherein the neurodegenerative disease or disorder associated with deacetylases is Alzheimer's disease, Parkinson's disease, or neuronal intranuclear inclusion disease.

47. The method according to any one of claims 1 or 3-45, wherein the neurodegenerative disease or disorder associated with deacetylases is a polyglutamine disorder, wherein the polyglutamine disorder is Huntington's disease or spinocerebellar ataxia.

48. The method according to any one of claims 1 or 3-47, wherein the neurodegenerative disease or disorder associated with deacetylases is Huntington's disease.

49. The method according to any one of claims 2-45, wherein the B-cell lymphoma is Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma or Waldenstrom Macroglobulinemia.