Inhibitors of histone deacetylase

• US 20050222410A1
• Filed: 04/17/2003
• Published: 10/06/2005
• Est. Priority Date: 04/27/2002
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Stokes, Elaine Sophie Elizabeth, Roberts, Craig Anthony
• Application Number:
  US10/512,808
• Publication Number:
  US 20050222410A1
• Time in Patent Office: Days
• US Class Current: 544/124
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 241/26 : with nitrogen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

The invention concerns a compound of the formula (I); wherein Ring A is heterocyclyl; m is 0-4 and each R¹ is a group such as hydroxy, halo, trifluoromethyl and cyano; Ring B is ring such as thienyl, thiadiazolyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl and pyridyl; R² is halo and n is 0-2; and each R⁴ is a group such as hydroxy, halo, trifluoromethyl and cyano; p is 0-4; and R³ is amino or hydroxy; or pharmaceutically-acceptable salts or in-vivo-hydrolysable ester or amide thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by histone deacetylase.

Claims

1. A compound of the formula (I):

wherein;

Ring A is a heterocyclyl, wherein if said heterocyclyl contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from G;

R¹ is a substituent on carbon and is selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkylS(O)_a wherein a is 0 to 2, C_1-6alkoxycarbonyl, N-(C_1-6alkyl)sulphamoyl, N,N-(C_1-6alkyl)₂sulphamoyl, aryl, aryloxy, arylC_1-6alkyl, heterocyclic group, (heterocyclic group)C_1-6alkyl or a group (D-E-);

wherein R¹, including group (D-E-), may be optionally substituted on carbon by one or more V; and

wherein, if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from J;

V is halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkylS(O)_a wherein a is 0 to 2, C_1-6alkoxycarbonyl, N-(C_1-6alkyl)sulphamoyl, N,N-(C_1-6alkyl)₂sulphamoyl or a group (D′

-E′

-);

wherein V, including group (D′

-E′

-), may be optionally substituted on carbon by one or more W;

W and Z are independently selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkylS(O)_a wherein a is 0 to 2, C_1-6alkoxycarbonyl, N-(C_1-6alkyl)sulphamoyl or N,N-(C_1-6alkyl)₂sulphamoyl;

G, J and K are independently selected from C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-8alkanoyl, C_1-8alkylsulphonyl, C_1-6alkoxycarbonyl, carbamoyl, N-(C_1-8alkyl)carbamoyl, N,N-(C_1-8alkyl)carbamoyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl, aryl, arylC_1-6alkyl or (heterocyclic group)C_1-6alkyl;

wherein G, J and K may be optionally substituted on carbon by one or more Q; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from hydrogen or C_1-6alkyl;

Q is halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkylS(O)_a wherein a is 0 to 2, C_1-6alkoxycarbonyl, C_1-6alkoxycarbonylamino, N-(C_1-6alkyl)sulphamoyl, N,N-(C_1-6alkyl)₂sulphamoyl, aryl, aryloxy, arylC_1-6alkyl, arylC_1-6alkoxy, heterocyclic group, (heterocyclic group)C_1-6alkyl, (heterocyclic group)C_1-6alkoxy, or a group (D″

-E″

-);

wherein Q, including group (D″

-E″

-), may be optionally substituted on carbon by one or more Z;

D, D′ and

D″

are independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, C_3-8cycloalkylC_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic group, (heterocyclic group)C_1-6alkyl;

wherein D, D′ and

D″

may be optionally substituted on carbon by one or more F′

; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from K;

E, E′ and

E″

are independently selected from —

N(R^a)—

, —

O—

, —

C(O)O—

, —

OC(O)—

, —

C(O)—

, —

N(R^a)C(O)—

, —

N(R^a)C(O)N(R^b)—

, —

N(R^a)C(O)O—

, —

OC(O)N(R^a)—

, —

C(O)N(R^a)—

, —

S(O)_r—

, —

SO₂N(R^a)_, —

N(R^a)SO₂—

;

wherein R^a and R^b are independently selected from hydrogen or C_1-6alkyl optionally substituted by one or more F and r is 0-2;

F and F′

are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkylS(O)_a wherein a is 0 to 2, C_1-6alkoxycarbonyl, N-(C_1-6alkyl)sulphamoyl and N,N-(C_1-6alkyl)₂sulphamoyl;

m is 0, 1, 2, 3 or 4;

wherein the values of R¹ may be the same or different;

Ring B is a ring selected from

wherein,

X¹ and X² are selected from CH or N, and

Y¹, Y², Y³ and Y⁴ are selected from CH or N provided that at least one of Y¹, Y², Y³ and Y⁴ is N;

R² is halo;

n is 0, 1 or 2;

wherein the values of R² may be the same or different;

R³ is amino or hydroxy;

R⁴ is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-3alkyl, C_2-3alkenyl, C_2-3alkynyl, C_1-3alkoxy, C_1-3alkanoyl, C_1-3alkanoyloxy, N-(C_1-3alkyl)amino, N,N-(C_1-3alkyl)₂amino, C_1-3alkanoylamino, N-(C_1-3alkyl)carbamoyl, N,N-(C_1-3alkyl)₂carbamoyl, C_1-3alkylS(O)_a wherein a is 0 to 2, C_1-3alkoxycarbonyl, N-(C_1-3alkyl)sulphamoyl, N,N-(C_1-3alkyl)₂sulphamoyl; and

p is 0, 1 or 2;

wherein the values of R⁴ may be the same or different;

or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof.

2. A compound of the formula (I) according to claim 1 wherein:

Ring A is a pyridyl, quinolyl, indolyl, pyrimidinyl, morpholinyl, piperidinyl, piperazinyl, pyridazinyl, pyrazinyl, thiazolyl, thienyl, thienopyrimidinyl, thienopyridinyl, purinyl, 1′

,2′

,3′

,6′

-tetrahydropyridinyl, triazinyl, oxazolyl, pyrazolyl, or furanyl;

wherein if Ring A contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from G;

or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof.

3. A compound of the formula (I) according to claim 1 wherein:

Ring A is pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, morpholin-4-yl, piperidin-4-yl, piperidin-3-yl, piperdin-2-yl, piperazin-4-yl, thiazol-2-yl, thien-2-yl, furan-3-yl, pyrrolidin-1-yl, piperidin-1-yl, triazol-1-yl or 1′

,2′

,3′

,6′

-tetrahydropyridin-4-yl wherein if Ring A contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from G;

or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof.

4. A compound of the formula (I) according to claim 1 wherein:

Ring B is thienyl, thiadiazolyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl;

or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof.

5. A compound of the formula (I) according to claim 1 wherein:

R¹ is a substituent on carbon and is selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkylS(O)_a wherein a is 0 to 2, C_1-6alkoxycarbonyl, N-(C_1-6alkyl)sulphamoyl, N,N-(C_1-6alkyl)₂sulphamoyl, aryl, aryloxy, arylC_1-6alkyl, heterocyclic group, (heterocyclic group)C_1-6alkyl or a group (D-E-);

wherein R¹, including group (D-E-), may be optionally substituted on carbon by one or more V; and

wherein, if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from J;

V is halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkylS(O)_a wherein a is 0 to 2, C_1-6alkoxycarbonyl, N-(C_1-6alkyl)sulphamoyl, N,N-(C_1-6alkyl)₂sulphamoyl or a group (D′

-E′

-);

wherein V, including group (D′

-E′

-), may be optionally substituted on carbon by one or more W;

W and Z are independently selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkylS(O)_a wherein a is 0 to 2, C_1-6alkoxycarbonyl, N-(C_1-6alkyl)sulphamoyl or N,N-(C₁ I₆alkyl)₂sulphamoyl;

G, J and K are independently selected from C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-8alkanoyl, C_1-8alkylsulphonyl, C_1-8alkoxycarbonyl, carbamoyl, N-(C_1-8alkyl)carbamoyl, N,N-(C_1-8alkyl)carbamoyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl, aryl, arylC_1-6alkyl or (heterocyclic group)C_1-6alkyl;

wherein G, J and K may be optionally substituted on carbon by one or more Q; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from hydrogen or C_1-6alkyl;

Q is halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkylS(O), wherein a is 0 to 2, C_1-6alkoxycarbonyl, C_1-6alkoxycarbonylamino, N-(C_1-6alkyl)sulphamoyl, N,N-(C_1-6alkyl)₂sulphamoyl, aryl, aryloxy, arylC_1-6alkyl, arylC_1-6alkoxy, heterocyclic group, (heterocyclic group)C_1-6alkyl, (heterocyclic group)C_1-6alkoxy, or a group (D″

-E″

-);

wherein Q, including group (D″

-E″

-), may be optionally substituted on carbon by one or more Z;

D, D′ and

D″

are independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, C_3-8cycloalkylC_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic group, (heterocyclic group)C_1-6alkyl;

wherein D, D′ and

D″

may be optionally substituted on carbon by one or more F′

; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from K;

E, E′ and

E″

are independently selected from —

N(R^a)—

, —

O—

, —

C(O)O—

, —

OC(O)—

, —

C(O)—

, —

N(R^a)C(O)—

, —

N(R^a)C(O)N(R^b)—

, —

N(R^a)C(O)O—

, —

OC(O)N(R^a)—

, —

C(O)N(R^a)—

, S(O)_r—

, —

SO₂N(R^a)—

, —

N(R^a)SO₂—

;

wherein R^a and R^b are independently selected from hydrogen or C_1-6alkyl optionally substituted by one or more F and r is 0-2; and

F and F′

are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkylS(O)_a wherein a is 0 to 2, C_1-6alkoxycarbonyl, N-(C_1-6alkyl)sulphamoyl and N,N-(C_1-6alkyl)₂sulphamoyl;

or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof.

6. A compound of the formula (I) according to claim 1 wherein:

R¹ is a substituent on carbon and is selected from cyano, hydroxy, C_1-6alkyl or a group (D-E-);

wherein R¹, including group (D-E-), may be optionally substituted on carbon by one or more V;

V is cyano, hydroxy or a group (D′

-E′

-);

wherein V, including group (D′

-E′

-), may be optionally substituted on carbon by one or more W;

W and Z are independently selected from cyano, C_1-6alkyl or C_1-6alkoxy;

G and K are independently selected from C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, arylC_1-6alkyl or (heterocyclic group)C_1-6alkyl;

wherein G and K may be optionally substituted on carbon by one or more Q;

Q is cyano, hydroxy, oxo, C_1-6alkyl, C_2-6alkenyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkoxycarbonyl, C_1-6alkoxycarbonylamino, aryl, aryloxy or a group (D″

-E″

-);

wherein Q, including group (D″

-E″

-), may be optionally substituted on carbon by one or more Z;

D, D′ and

D″

are independently selected from aryl, arylC_1-6alkyl or heterocyclic group;

wherein D, D′ and

D″

may be optionally substituted on carbon by one or more F′

; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from K;

E, E′ and

E″

are independently selected from —

O—

, —

C(O)O—

, —

OC(O)—

, —

C(O)—

, —

N(R^a)C(O)—

, —

C(O)N(R^a)—

, —

S(O)_r—

;

wherein R^a is selected from hydrogen or C_1-6alkyl optionally substituted by one or more F and r is 0-2; and

F and F′

are independently selected from nitro, hydroxy, C_1-6alkyl, C_1-6alkoxy, C_1-6alkanoyl, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino or C_1-6alkoxycarbonyl;

or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof.

7. A compound of the formula (I) according to claim 1 wherein m is 1;

or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof.

8. A compound of the formula (I) according to claim 1 wherein R² is fluoro and n is 0 or 1;

or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof.

9. A compound of the formula (I) according to claim 1 wherein R³ is amino;

or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof.

10. A compound of the formula (I) according to claim 1 wherein p is 0;

or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof.

11. A compound of the formula (I) according to claim 1 wherein:

Ring A is a pyridyl, quinolyl, indolyl, pyrimidinyl, morpholinyl, piperidinyl, piperazinyl, pyridazinyl, pyrazinyl, thiazolyl, thienyl, thienopyrimidinyl, thienopyridinyl, purinyl, 1′

,2′

,3′

,6′

-tetrahydropyridinyl, triazinyl, oxazolyl, pyrazolyl, or furanyl;

wherein if Ring A contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from G;

Ring B is thienyl, thiadiazolyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl;

R¹ is a substituent on carbon and is selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkylS(O)_a wherein a is 0 to 2, C_1-6alkoxycarbonyl, N-(C_1-6alkyl)sulphamoyl, N,N-(C_1-6alkyl)₂sulphamoyl, aryl, aryloxy, arylC_1-6alkyl, heterocyclic group, (heterocyclic group)C_1-6alkyl or a group (D-E-);

wherein R¹, including group (D-E-), may be optionally substituted on carbon by one or more V; and

wherein, if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from J;

V is halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkylS(O)_a wherein a is 0 to 2, C_1-6alkoxycarbonyl, N-(C_1-6alkyl)sulphamoyl, N,N-(C_1-6alkyl)₂sulphamoyl or a group (D′

-E′

-);

wherein V, including group (D′

-E′

-), may be optionally substituted on carbon by one or more W;

W and Z are independently selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkylS(O)_a wherein a is 0 to 2, C_1-6alkoxycarbonyl, N-(C_1-6alkyl)sulphamoyl or N,N-(C_1-6alkyl)₂sulphamoyl;

G, J and K are independently selected from C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-8alkanoyl, C_1-8alkylsulphonyl, C_1-8alkoxycarbonyl, carbamoyl, N-(C_1-8alkyl)carbamoyl, N,N-(C_1-8alkyl)carbamoyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl, aryl, arylC_1-6alkyl or (heterocyclic group)C_1-6alkyl;

wherein G, J and K may be optionally substituted on carbon by one or more Q; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from hydrogen or C_1-6alkyl;

Q is halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkylS(O)_a wherein a is 0 to 2, C_1-6alkoxycarbonyl, C_1-6alkoxycarbonylamino, N-(C_1-6alkyl)sulphamoyl, N,N-(C_1-6alkyl)₂sulphamoyl, aryl, aryloxy, arylC_1-6alkyl, arylC_1-6alkoxy, heterocyclic group, (heterocyclic group)C_1-6alkyl, (heterocyclic group)C_1-6alkoxy, or a group (D″

-E″

-);

wherein Q, including group (D″

-E″

-), may be optionally substituted on carbon by one or more Z;

D, D′ and

D″

are independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, C_3-8cycloalkylC_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic group, (heterocyclic group)C_1-6alkyl;

wherein D, D′ and

D″

may be optionally substituted on carbon by one or more F′

; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from K;

E, E′ and

E″

are independently selected from —

N(R^a)—

, —

O—

, —

C(O)O—

, —

OC(O)—

, —

C(O)—

, —

N(R^a)C(O)—

, —

N(R^a)C(O)N(R^b)—

, —

N(R^a)C(O)O—

, —

OC(O)N(R^a)—

, —

C(O)N(R^a)—

, S(O)_r—

, —

SO₂N(R^a)—

, —

N(R^a)SO₂—

;

wherein R^a and R^b are independently selected from hydrogen or C_1-6alkyl optionally substituted by one or more F and r is 0-2;

F and F′

are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkylS(O)_a wherein a is 0 to 2, C_1-6alkoxycarbonyl, N-(C_1-6alkyl)sulphamoyl and N,N-(C_1-6alkyl)₂sulphamoyl;

m is 0, 1, 2, 3 or 4;

wherein the values of R¹ may be the same or different;

R² is fluoro or chloro;

n is 0, 1 or 2, wherein the values of R² may be the same or different;

R³ is amino or hydroxy;

R⁴ is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy or carbamoyl; and

p is 0, 1 or 2, wherein the values of R⁴ may be the same or different;

or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof.

12. A compound of the formula (I) according to claim 1 wherein:

Ring A is pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, morpholin-4-yl, piperidin-4-yl, piperidin-3-yl, piperdin-2-yl, piperazin-4-yl, thiazol-2-yl, thien-2-yl, furan-3-yl, pyrrolidin-1-yl, piperidin-1-yl, triazol-1-yl or 1′

,2′

,3′

,6′

-tetrahydropyridin-4-yl wherein if Ring A contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from G;

Ring B is thienyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl;

R¹ is a substituent on carbon and is selected from cyano, hydroxy, C_1-6alkyl or a group (D-E-);

wherein R¹, including group (D-E-), may be optionally substituted on carbon by one or more V;

V is cyano, hydroxy or a group (D′

-E′

-);

wherein V, including group (D′

-E′

-), may be optionally substituted on carbon by one or more W;

W and Z are independently selected from cyano, C_1-6alkyl or C_1-6alkoxy;

G and K are independently selected from C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, arylC_1-6alkyl or (heterocyclic group)C_1-6alkyl;

wherein G and K may be optionally substituted on carbon by one or more Q;

Q is cyano, hydroxy, oxo, C_1-6alkyl, C_2-6alkenyl, C_1-6alkoxy, C_1-6alkanoyl, C_1-6alkanoyloxy, N-(C_1-6alkyl)carbamoyl, N,N-(C_1-6alkyl)₂carbamoyl, C_1-6alkoxycarbonyl, C_1-6alkoxycarbonylamino, aryl, aryloxy or a group (D″

-E″

-);

wherein Q, including group (D″

-E″

-), may be optionally substituted on carbon by one or more Z;

D, D′ and

D″

are independently selected from aryl, arylC_1-6alkyl or heterocyclic group;

wherein D, D′ and

D″

may be optionally substituted on carbon by one or more F′

; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from K;

E, E′ and

E″

are independently selected from —

O—

, —

C(O)O—

, —

OC(O)—

, —

C(O)—

, —

N(R^a)C(O)—

, —

C(O)N(R^a)—

, —

S(O)_r—

;

wherein R^a is selected from hydrogen or C_1-6alkyl optionally substituted by one or more F and r is 0-2;

F and F′

are independently selected from nitro, hydroxy, C_1-6alkyl, C_1-6alkoxy, C_1-6alkanoyl, N-(C_1-6alkyl)amino, N,N-(C_1-6alkyl)₂amino, C_1-6alkanoylamino or C_1-6alkoxycarbonyl;

m is 0, 1, or 2;

wherein the values of R¹ may be the same or different;

R² is fluoro;

n is 0 or 1;

R³ is amino;

R⁴ is halo; and

p is 0, 1 or 2, wherein the values of R⁴ may be the same or different;

or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof.

13. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, according to claim 1, which process comprises of:

(a) The reaction of a compound of the formula (II)

wherein X is a reactive group, with a compound of the formula (III)

wherein L¹ and L² are ligands;

(b) The reaction of a compound of the formula (IV)

wherein L¹ and L² are ligands, with a compound of the formula (V)

wherein X is a reactive group;

or

(c) The reaction, in the presence of 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride, of a compound of the formula (VI)

with a compound of the formula (VII)

and thereafter if necessary;

i) converting a compound of the formula (I) into another compound of the formula (I); and

/or

ii) removing any protecting groups.

14. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof, according to claims 1 to 12 in association with a pharmaceutically-acceptable diluent or carrier.

17. A method for producing a HDAC inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof, according to claims 1 to 12.

19. A method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof, according to claims 1 to 12.

15-16. -16. (canceled)

18. (canceled)

20. (canceled)