Indian Patents
Title of Invention

A BISAMIDE COMPOUND OF FORMULA I USEFUL AS INHIBITORS OF THE PRODUCTION OF CYTOKINES
Abstract N/A
Full Text FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS RULES, 2003 COMPLETE SPECIFICATION
[See Section 10; rule 13]
"AMIDE DERIVATIVES USEFUL AS INHIBITORS OF THE PRODUCTION OF CYTOKINES"
ASTRAZENECA AB, a Swedish company, of S-15185 Sodertalje, Sweden,
The following specification particularly describes the invention and the manner in which it is to be performed:

WO 00/07991

PCT/GB99/02489

AMIDE DERIVATIVES USEFUL AS INHIBITORS OF THE PRODUCTION OF CYTOKINES
This invention concerns certain amide derivatives which are useful as inhibitors of cytokine mediated disease. The invention also concerns processes for the manufacture of the
5 amide derivatives of the invention, pharmaceutical compositions containing them and their use in therapeutic methods, for example by virtue of inhibition of cytokine mediated disease.
The amide derivatives disclosed in the present invention are inhibitors of the
production of cytokines such as Tumour Necrosis Factor (hereinafter TNF), for example
TNFa, and various members of the mterleukin (hereinafter IL) family, for example IL-1, IL-6
10 and IL-8. Accordingly the compounds of the invention will be useful in the treatment of
diseases or medical conditions in which excessive production of cytokines occurs, for
example excessive production of TNFa or IL-l. It is known that cytokines are produced by a
wide variety of cells such as monocytes and macrophages and that they give rise to a variety
of physiological effects which are believed to be important in disease or medical conditions
15 such as inflammation and immunoregulation. For example, TNFa and IL-1 have been
implicated in the cell signalling cascade which is believed to contribute to the pathology of
disease states such as inflammatory and allergic diseases and cytokine-induced toxicity. It is
also known that, in certain cellular systems, TNFa production precedes and mediates the
production of other cytokines such as IL-l.
20 Abnormal levels of cytokines have also been implicated in, for example, the
production of physiologically-active eicosanoids such as the prostaglandins and leukotrienes, the stimulation of the release of proteolytic enzymes such as collagenase, the activation of the immune system, for example by stimulation of T-helper cells, the activation of osteoclast activity leading to the resorption of calcium, the stimulation of the release of proteoglycans
25 from, for example, cartilage, the stimulation of cell proliferation and to angiogenesis.
Cytokines are also believed to be implicated in the production and development of disease states such as inflammatory and allergic diseases, for example inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis, Crohn's
30 disease and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and ^respiratory disease (especially asthma, bronchitis, allergic rhinitis and adult respiratory

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distress syndrome), and in the production and development of various cardiovascular and cerebrovascular disorders such as congestive heart failure, myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, reperfusion injury, vascular injury including restenosis and peripheral vascular diseaseand,
5 for example, various disorders of bone metabolism such as osteoporosis (including senile and postmenopausal osteoporosis), Paget's disease, bone metastases, hypercalcaemia, hyperparathyroidism, osteosclerosis, osteoperosis and periodontitis, and the abnormal changes in bone metabolism which may accompany rheumatoid arthritis and osteoarthritis. Excessive cytokine production has also been implicated in mediating certain complications of bacterial,
10 fungal and/or viral infections such as endotoxic shock, septic shock and toxic shock syndrome and in mediating certain complications of CNS surgery or injury such as neurotrauma and ischaemic stroke. Excessive cytokine production has also been implicated in mediating or exacerbating the development of diseases involving cartilage or muscle resorption, pulmonary fibrosis, cirrhosis, renal fibrosis, the cachexia found in certain chronic diseases such as
15 malignant disease and acquired immune deficiency syndrome (AIDS), tumour invasiveness and tumour metastasis and multiple sclerosis.
Evidence of the central role played by TNFa in the cell signalling cascade which gives
rise to rheumatoid arthritis is provided by the efficacy in clinical studies of antibodies of
TNFa (The Lancet, 1994,344, 1125 and British Journal of Rheumatology, 1995, 34> 334).
20. Thus cytokines such as TNFa and IL-1 are believed to be important mediators of a
considerable range of diseases and medical conditions. Accordingly it is expected that inhibition of the production of and/or effects of these cytokines will be of benefit in the prophylaxis, control or treatment of such diseases and medical conditions.
Without wishing to imply that the compounds disclosed in the present invention
25 possess pharmacological activity only by virtue of an effect on a single biological process, it is believed that the compounds inhibit the effects of cytokines by virtue of inhibition of the enzyme p38 kinase. p38 kinase, otherwise known as cytokine suppressive binding protein (hereinafter CSBP) and reactivating kinase (hereinafter RK), is a member of the mitogen-activated protein (hereinafter MAP) kinase family of enzymes which is known to be activated
30 by physiological stress such as that induced by ionising radiation, cytotoxic agents, and
toxins, for example endotoxins such as bacterial lipopolysaccharide, and by a variety of agents

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such as the cytokines, for example TOFα andIL-1. It is known that p38 kinase
phosphorylates certain intracellular proteins which are involved in the cascade of enzymatic
steps which leads to the biosynthesis and excretion of cytokines such as TNFα and IL-1.
Known inhibitors of p38 kinase have been reviewed by G J Hanson in Expert Opinions on
5 Therapeutic Patents, 1997, 7, 729-733. p38 kinase is known to exist in isoforms identified as
P38txandp38β.
It is known from J. Med. Chem.s 1996, 39, 3343-3356, that certain benzaraide
derivatives can upregulate the expression of the low density lipoprotein (LDL) receptor in
human hepatocyte cells. The disclosed compounds included two pyridinecarboxamide 10 derivatives, namely N-[5-(3-cyclohexyIpropionamido)-2-methylphenyl]pyridine-
3-carboxamideandN-[5-(3-cyclohexylpropionarnido)-2-methyIphenyl]pyridine-
4-carboxamide.
The compounds disclosed in the present invention are inhibitors of the production of
cytokines such as TNF, in particular of TNFa, and various interleukins, in particular IL-1.
15 According to one aspect of the present invention there is provided an amide derivative
of the Formula I

wherein R3 is (l-6C)alkyl or halogeno;
Q1 is heteroaryl which is optionally substituted with 1, 2, 3 or 4 substituents selected from
20 hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-3C)alkylenedioxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(I-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (l-6C)aIkanoylamino:
25 N-(l-6C)alkylsuIphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (l-6C)alkanesulphonyIamino, N-( 1 -6C)alkyl-(l -6C)alkanesulphonylamino, halogeno-( 1 -6C)alkyl, hydroxy-( I -6C)alky 1, "(l"-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-

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(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, carboxy-(l-6C)alkyl, (l-6C)alkoxycarbonyl-(l-6C)alkyl,carbamoyl-(l-6C)alkyl,N-(l-6C)alkylcarbamoyKl-6C)alkyl, N,N-di-[(l-6C)alkyl]carbamoyI-(l-6C)alkyl,halogeno-(2-6C)alkoxy,hydroxy-(2-6C)alkoxy,
(1 -6C)alkoxy-(2-6C)alkoxy, cyano-(l-6C)alkoxy, carboxy-(l -6C)alkoxy,
5 (l-6C)alkoxywrbonyl-(l-6C)aIkoxy,carbamoyl-(l-6C)aIkoxy,N-(l-6C)alkylcarbamoyl-(l-6C)aIkoxy,N,N-di-[(l-6C)alkyl]carbarnoyl-(l-6C)alkoxy, amino-(2-6C)alkoxy) (]-6C)alkylamino-(2-6C)alkoxy, di-[(l-6C)alkyl]amino-(2-6C)alkoxy, halogeno-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (l-6C)a!koxy-(2-6C)alkylamino, cyano-(l-6C)alkylamino, carboxy-(l-6C)alkylamino, (l-6C)alkoxycarbonyl-
10 (l-6C)alkylamino, carbamoyl-(l-6C)alkylamino, N-(l-6C)alkylcarbamoyl-(l-6C)alkylamino, N,N-di-[(l-6C)alkyl]carbamoyl-(I-6C)alkylamino)amino-(2-6C)alkylamino, (1 -6C)a]kylamino-(2-6C)alkylamino, di-[(l -6C)alkyl]amino-(2-6C)alkylamino, N-(I-6C)alkyl-halogeno(l-6C)alkylamino,N-(l-6C)alkyl-hydroxy-(2-6C)alkylamino, N-(l-6C)alkyl-(l-6C)alkoxy-(2-6C)alkyl
15 N-(l-6C)alkyl-carboxy-(l-6C)alkylamino;N-(l-6G)alkyl-(l-6C)alkoxycarbonyl-(l-6C)alkylaroino,N-(l-6C)alkyl-carba™^ N-(l-6C)alkylcarbamoyl-(l-6C)a^ (]-6C)alkylamino,N-(l-6C)alkyl-amino-(2-(2-6C)alkylajnino,N^l-6C)alkyl-di-[(l-6C)alkyl]amino-(2-6C)alkylamino,halogeno
20 (2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino, (l-6C)alkoxy-(2-6C)alkanoylarmno} cyano-(2-6C)alkanoylamino, carboxy-(2-6C)alkanoylamino, (I -6C)alkoxycarbonyI-(2-6C)alkanoyIamino, carbamoy l-(2-6C)alkanoylamino, N-( 1 -6C)alkylcarbamoyl-(2-6C)alkanoylamino, N>N-di-[(l-6C)alkyl]carbamoyI-(2-6C)alkanoylamino) amino-(2-6C)alkanoylamino, (l-6C)alkylamino-(2-6C)aIkanoylamino, di-[(l-6C)alkyl]amino-
25 (2-6C)alkanoylamino, aryl, aryl-(l-6C)alkyl, aryl-(l-6C)alkoxy, aryloxy, arylamino, N-(l-6C)alkyl-arylamino,aryl-(l-6C)dkylammo,N-(l-6C)alkyl-aryl-(N aroylamino, arylsulphonylamino, N-arylsulphamoyl, aryI-(2-6C)a]kanoylamino, heteroaryl, heteroaryI-(l-6C)alkyl, heteroaryloxy, heteroaryl-(l-6C)alkoxy, heteroarylamino, N-(l-6C)alkyl-heteroarylamino, heteroaryl-(l-6C)alkylamino,N-(l-6C)alkyl-heteroaryl-
30 (l-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino,
N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino, heterocyclyl, heterocyclyl-

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(l-6C)alkyl, heterocyclyloxy, heterocyclyl-(l-6C)alkoxy, heterocyclylamino, N-(l-6C)alkyl-heterocyclylamino, heterocyclyl-( 1 -6C)alky lamino, N-( 1 -6C)alkyl-heterocycly I-(1 -6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino, N-heterocyclylsulphamoyl and heterocyclyl-(2-6C)alkanoylamino,
5 and wherein any of the substituents on Q1 defined hereinbefore which comprise a CH2 group which is attached to 2 carbon atoms or a CH3 group which is attached to a carbon atom may optionally bear on each said CH2 or CH3 group a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and heterocyclyl; and wherein any aryl, heteroary] or heterocyclyl group in a substituent on Q1 may optionally
10 bear 1 or 2 substituents selected from hydroxy, halogeno, (l-6C)alkyl, (l-6C)alkoxy, carboxy, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, NsN-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, aryl and aryl-(l-6C)alkyl;
15 R2 is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy: (l-6C)alkoxycarbonyl, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, . (l-6C)alkylamino or di-[(l-6C)alkyl]amino; p is 0, 1 or 2; q is O, I, 2, 3 or 4; and
20 Q2 is aryl, aryl-(l-6C)alkoxy, aryloxy, arylamino, N-(]-6C)alkyl-arylamino, aryl-
(l-6C)alkylamino, N-(l-6C)alkyl-aryl-(l-6C)alkylamino, aroylamino, arylsulphonylamino, N-arylsulphamoyl, aryI-(2-6C)alkanoylamino, cycloalkyl, heteroaryl, heteroaryloxy, heteroaryl-(l-6C)alkoxy, heteroarylamino, N-(l-6C)alkyl-heteroarylamino, heteroaryl-(1 -6C)alkylamino, N-(l -6C)alkyl-heteroaryl-(l -6C)alkylamino, heteroarylcarbonylamino,
25 heteroarylsulphonylamino, N-heteroarylsulphamoyl, heteroaryI-(2-6C)aIkanoylamino,
heterocyclyl, heterocyclyloxy, heterocyclyl-(l-6C)aIkoxy, heterocyclylamino, N-(l-6C)alkyl-heterocyclylamino, heterocyctyl-( 1 -6C)alkylamino, N-( 1 -6C)alkyl-heterocycly 1-\( 1 -6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino, tf-heterocyclylsulphamoyl or heterocyclyl-(2-6C)alkanoylamino and Q2 is optionally instituted with 1, 2, 3 or 4 substituents selected from hydroxy, halogeno, trifluoromethyl, ano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (l-6C)alkyl, (2-6C)alkenyl,

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(2-6C)alkynyl, (l-6C)alkoxy,(l-3C)alkylenedioxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (]-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl,N)N-di-[(l-6C)alkyl]carbamoyl,(2-6C)alkanoyl) (2-6C)alkanoyloxy, (l-6C)aIkanoylamino, N-(l-6C)alkylsulphamoyl,
5 N,N-di-[(1-6C)alkyl]sulphamoyl,(1-6C)alkanesulphonylamino,N-(1-6C)alkyl-C)alkaneSulphonylamino, halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, 06C)alkoxy-(l-6C)alkyl, cyano-(]-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-Kl-eQalkyllamino-Cl-eQalkyUcarboxy-Cl-eQalkyl^l-eqalkoxycarbonyl-Cl-eqalky], carbamoyl-(1-6C)alkyl,N-, (1-6C)alkylcarbamoyl-(1-6C)alkyl,
10 N,N-di-[(l-6C)alkyl]carbamoyl-(l-6C)alkyl, halogeno-(2-6C)alkoxy, hydroxy-(2-6C)alkoxy, (]-6C)alkoxy-(2-6C)alkoxy, cyano(l-6C)alkoxy, carboxy-(l-6C)alkoxy, (l-6C)alkoxycarbonyl-(l-6C)alkoxy, carbamoyl-(l-6C)alkoxy,N-(l-6C)alky]carbamoyl-(1 -6C)alkoxy, N,N-di-[(l -6C)alkyl]carbamoyl-(I -6C)alkoxy, amino-(2-6C)alkoxy, (l-6C)alkylamino-(2-6C)alkoxy,di-[(l-6C)alkyl]amino-(2-6C)aIkoxy)haIogeno-
15 (2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (l-6C)alkoxy-(2-6C)alkylamino, cyano-(l-6C)alkylamino, carboxy-(l-6C)alkylamino} (l-6C)alkoxycarbonyl-(l-6C)alkylamino, carbamoyl-(1-6C)alkylamino-(2-6C)alkylamino,di[(1-6C)alkyl]amino-(2-6C)alkylamino,, N,N-di-[(l-6C)alkyl]carbamoyl-(l-6C)alkylamino, amino-(2-6C)alkylamino, (1 -6C)alkylamino-(2-6C)alkylamino, di-[(l-6C)alkyl]amino-(2-:6C)alkylamino,
20 N~(l-6C)alkyl-halogeno-(l-6C)alkylamino,N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,
N-( 1 -6C)alkyl-( 1 -6C)alkoxy-(2-6C)alkylamino, N-( 1 -6C)alkyl-cyano-(l-6C)alkylamino, N-(l-6C)alkyl-carboxy-(l-6C)alkylamino (l-6C)alkylamino,N-(l-6C)alkyl
N-(l-6C)alkylcarbamoyl-(l-6C)alkyl]carbamoyl
25 (l-6C)alkylamino, N-(l-6C)alkyl-amino-(2-6C)alkylamino, N-(l-6C)alkyl-(l-6C)alkylamino-(2-6C)alkylamino,N-(l-6C)alkyl-di-[(1-6C)alkyyoxy-(2-6C)alkylamino,halogeno-
(2-6C)alkanoylamino) hydroxy-(2-6C)aIkanoylamino, (1 -6C)alkoxy-(2-6C)alkanoy]amino, cyano-(2-6C)alkanoylamino, carboxy-(2-6C)alkanoylamino) (1 -6C)alkoxycarbonyl-(2-6C)alkanoylamino, carbamoyl-(2-6C)alkanoylamino, N-(l-6C)alkylcarbamoyI-
30 (2-6C)alkanoylamino, N,N-di-[(1-6C)alkyl]carbamoyl-(2-6C)alkanoylamino,, amino-(2-6C)aIkanoylamino> (1 -6C)alkylamino-(2-6C)alkanoyIamino, di-[( 1 -6C)alkyl]amino-

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(2-6C)alkanoylamino, aryl, aryl-(l-6C)alkyl, aryl-(l-6C)alkoxy, aryloxy, arylamino, N-(l-6C)alkyl-arylamino, aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino, aroylamino, arylsulphonylamino, N-arylsulphamoyl, aryl-(2-6C)alkanoylamino, heteroaryl, heteroaryl-(l-6C)alkyl, heteroaryloxy, heteroaryl-(l-6C)alkoxy, heteroarylamino,
5 N-(l-6C)alkyl-heteroarylamino, heteroaryl-(l-6C)alky]amino, N-(l-6C)alkyl-heteroaryl-(1 -6C)alkylamino> heteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroarylsulphamoyl, heteroaryI-(2-6C)alkanoylamino, heterocycly], heterocyclyl-(1 -6C)alkyl, heterocyclyloxy, heterocyclyl-(l-6C)alkoxy, heterocyclylamino, N-(l-6C)alkyl-heterocycly lamino, heterocyclyl-( 1 -6C)alky lamino, N-( 1 -6C)alkyl-heterocycly 1-
10 (l-6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino, N-heterocyclylsulphamoyI and heterocyclyl-(2-6C)alkanoylamino,
and wherein any of the substituents on Q2 defined hereinbefore which comprise a CH2 group which is attached to 2 carbon atoms or a CH3 group which is attached to a carbon atom may optionally bear on each said CH2or CH3 group a substituent selected from hydroxy, amino,
15 (I-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alky3]amino and heterocyclyl;
and wherein any aryl, heteroaryl or heterocyclyl group in a substituent on Q2 may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (l-6C)alkyl: (l-6C)alkoxy3 carboxy, (l-6C)aIkoxycarbonylsNKl-6C)alkylcarbamoyl,N:N-di-[(l-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, amino, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, halogeno-(l-6C)alkyl,
20 hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl,
(l-6C)alkylamino-(l-6C)alkyl, di-[(I-6C)alkyl]amino-(l-6C)alkyl, aryl and aryI-(l-6C)alkyl;
or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof;
except that N-[5-(3-cyclohexylpropionamido)-2-methyIphenyl]pyridine-3-carboxamide and
N-[5-(3-cyclohexylprppionamido)-2-methylphenyl]pyridine-4-carboxamide are excluded.
25 According to a further aspect of the invention there is provided a compound of the
Formula I
wherein R3 is (l-6C)alkyl or halogeno;
Q1 is heteroaryl which is optionally substituted with I, 2, 3 or 4 substituents selected from
hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl,
30 formyl, (I-6C)alkyl, (2-6C)alkenyI, (2-6C)alkynyl, (l-6C)alkoxy, (l-3C)alkylenedioxy,
'l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsuiphonyl) (I-6C)alkylamino,

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di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl,N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (l-6C)alkanoylamino, N-(l -6C)alkylsulphamoyl, N,N-di-[(l -6C)alkyl]sulphamoyl, (1 -6C)alkanesulphonylamino, N-(l-6C)alkyl-(l-6C)alkanesulphonylamino,halogeno-(l-6C)alkylshydroxy-(l-6C)alkyl,
5 (1-6C)alkoxy-(l-6C)alky], cyano-(l-6C)alkyl, amino-(l-6C)alky], (J-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, carboxy-(l-6C)alkyl, (l-6C)alkoxycarbonyl-(l-6C)alkyl,carbamoyl-(l-6C)alkyl,N-(l-6C)alkylcarbamoy]-(l-6C)alkyl, 3iN-di-[(l-6C)alkyl]carbamo(1-6C)alkyoxy,
(l-6C)alkoxy-(2-6C)alkoxy,cyano-(l-6C)alkoxy, carboxy-n-6C)alkoxy,
10 (l-6C)alkoxycarbonyl-(l-6C)alkoxy, carbamoyl-(l-6C)alkoxy, N-(l-6C)alkylcarbamoyl-(l-6C)alkoxy)N)N-di-[(l-6C)alkyl]carbamoyl-(l-6C)alkoxy)amino-(2T6C)alkoxy, (l-6C)alkylamino-(2-6C)alkoxy, di-[(l-6C)alkyl]amino-(2-6C)alkoxy, halogeno-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1 -6C)alkoxy-(2-6C)alkylamino, cyano-(l ~6C)alkylamino, carboxy-( 1 -6C)alkylamino, (1 -6C)alkoxycarbonyl-
15 (I-6C)alkylamino, carbamoyl-(l-6C)alkylamino,N-(l-6C)alkylcarbamoyl-(l-6C)aIkylamino, N3N-di-[(l-6C)alkyl]carbamoyl-(l-6C)alkylamino, amino-(2-6C)alkylamino, (l-6C)alkylamino-(2-6C)alkylamino, di-[(l-6C)alkylamino-(2-6C)alkylamino, N-(l-6C)alkyl-halogeno-(K6C)alkylamino)N-(I-6C)alkyl-hydroxy-(2-6C)alkylamino, N-(l-6C)alkyl-(l-6C)alkoxy-(2-6C)alkylamino,N-(l-6C)alkyl-cyano-(l-6C)d
20 N-(l-6C)alkyl-carboxy-(l-6C)alkylamino, N-(l-6C)alkyl-(l-6C)alkoxycarbonyl-(l-6C)alkylamino,N-(l-6C)alkyl-carbamoy]-(i-6C)alkylamino,N-(l- N-(l-6C)alkylcarbamoyHl-6C)alkylamino (l-6C)alkylamino,N-(l-6C)amino
(2-6C)alkylamino,N-(l-6C)alkyl-di-[(l-6C)alkyl]amino-(2-6C)alkylamino,halogeno-
25 (2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino, (l-6C)alkoxy-(2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino, carboxy-(2-6C)alkanoylamino, (l-6C)alkoxycarbonyl- (2-6C)aIkanoylamino, carbamoyl-(2-6C)alkanoylamino,N-(l-6C)alkylcarbamoyl-(2-6C)alkanoylamino,NJN-di-[(l-6C)alkyl]carbamoyl-(2-6C)alkanoylamino) amino-(2-6C)alkanoylamino, (l-6C)alkylamino-(2-6C)alkanoylamino, di-[(l-6C)alkyl]amino-
30 (2-6C)alkanoylamino, aryl, aryl-(l-6C)alkyl, aryl-(l-6C)alkoxy, aryloxy, arylamino, 'N-(l-6C)alkyl-arylamino,aryl-(1-6C)alkylamino,N-(1-6C)alkyl-aryl-(1-6C)alkylamino,,

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aroylamino, arylsulphonylamino, N-arylsulphamoyl, aryl-(2-6C)alkanoylamino, heteroaryl, heteroaryl-(l-6C)alkyl, heteroaryloxy, heteroaryl-(J-6C)alkoxy, heteroarylamino, N-( 1 -6C)alkyl-heteroarylamino, heteroary l-( 1 -6C)alkylarnino, N-(l -6C)alkyl-heteroaryl-(l-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino,
5 N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino, heterocyclyl, heterocyclyl-(1 -6C)alkyl, heterocyclyloxy, heterocyclyl-(i -6C)alkoxy, heterocyclylamino, N-(l -6C)alkyl-heterocyclylamino, heterocyclyl-(l-6C)alkylamino, N-(l-6C)alkyl-heterocyclyl-(] -6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino, N-heterocyclylsulphamoyl and heterocyclyl-(2-6C)alkanoylamino, and wherein any aryl,
10 heteroaryl or heterocyclyl group in a substituent on Q' may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (l-6C)alkyl, (l-6C)alkoxy, carboxy, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (l-6C)alkylamino and di-[(l-6C)alkyl]amino;
R2 is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy,
15 (l-6C)alkoxycarbonyl, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)a!koxy, (1 -6C)alkylamino or di-[(l -6C)alkyl]amino; p is 0, 1 or 2; q is 0, 1, 2, 3 or 4; and
Q2 is aryl, aryl-(l-6C)alkoxy, aryloxy, arylamino, N-(l-6C)alkyl-arylamino, aryl-
20 (l-6C)alkylamino, N-(l-6C)alkyl-aryl-(l-6C)alky]amino, aroylamino, arylsulphonylamino, N-arylsulphamoyl, aryl-(2-6C)alkanoylamino, cycloalkyl, heteroaryl, heteroaryloxy, heteroaryl-(l-6C)alkoxy, heteroarylamino, N-(l-6C)alkyl-heteroarylamino, heteroaryl-(1 -6C)alkylamino, N-( 1 -6C)alkyl-heteroaryl-( 1 -6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroaryIsulphamoyl,heteroaryl-(2--6C)alkanoylamino,
25 heterocyclyl, heterocyclyloxy, heterocyclyl-(l-6C)alkoxy, heterocyclylamino, N-(l-6C)alkyl-heterocyclylamino,heterocycIyl-(1-6C)alkylamino, N-(l-6C)alkyl-heterocyclyl-(1 -6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino, N-heterocyclylsulphamoyl or heterocyclyl-(2-6C)alkanoyIamino and Q2 is optionally substituted with 1, 2, 3 or 4 substituents selected from hydroxy, halogeno, trifluoromethyl,
30 cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-3C)alkylenedioxy, (l-6C)alkylthio, (1-6C)aIkylsulphinyl,

WO 00/07991 PCT/GB99/02489
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(l-6C)alkylsulphonyl, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)alkoxycarbonyl, N(l-6C)alkylcarbamoyl,N,N-di-[(l-6C)alkyl]carbamoyl,(2-6C)alkanoyl, (2-6C)alkanoyloxy, (l-6C)alkanoylamino, N-(l-6C)alkylsulphamoyl, N)N-di-[(I-6C)alkyl]sulphamoy])(l-6C)alkanesu]phonylarnino)N-(l-6C)alkyl-
5 (l-6C)alkanesuIphonylamino, halogeno-(l-6C)alkyl, hydroxy-(l-6C)alky], (l-6C)alkoxy-(l-6C)alkyl, cyano-(]-6C)alky], amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alky]]amino-(l-6C)alkyl,(1-6C) carbamoyl-(l-6C)alkyl,N-(l-6C)alkylcarbamoyI-(l-6C)alkyl,
N)N-di-[(l-6C)alkyl]caxbamoyl-(l-6C)alky], halogeno-(2-6C)alkoxy, hydroxy-(2-6C)alkoxy, 10 (l-6C)alkoxy-(2-6C)alkoxy, cyano-(l-6C)alkoxy, carboxy-(l-6C)alkoxy,
(1 -6C)alkoxycarbonyl-( 1 -6C)alkoxy, carbamoyI-(l-6C)aIkoxy, N-( 1 -6C)alkylcarbamoyl-(l-6C)alkoxy,N)N-di-[(l-6C)alkyl]carbamoyl-(l-6C)alkoxy,amino-(2-6C)alkoxy, (] -6C)alkylamino-(2-6C)alkoxy, di-[(l -6C)alkyl]amino-(2-6C)alkoxy, halogeno-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1 -6C)alkoxy-(2-6C)alkylamino,
15 cyano-(l-6C)alkylamino, carboxy-(l-6C)alkylamino, (l-6C)alkoxycarbonyl-
(1 -6C)alkylamino, carbamoy]-( 1 -6C)alkylamino, N-( 1 -6C)alkylcarbamoyl-(l -6C)alkylamino, W.N-di-[(l-6C)alkyl]carbamoyI-(]-6C)alky]amino: amino-(2-6C)alkylamino, (]-6C)alky]amino-(2-6C)alky]amino,di-[(l-6C)alkyl]amino-(2-6C);aIkylamino, N-(l-6C)alkyl-halogeno-(l-6C)alkylamino,N-(l-6C)alkyl-hydroxy-(2-6C)alkylamino)
20 N-( 1 -6C)alkyl-( 1 -6C)alkoxy-(2-6C)alky lamino, N-( 1 -6C)aIkyl-cyano-( 1 -6C)alkylamino, N-(l -6C)alkyl-carboxy-(l -6C)alkylamino, N-(l -6C)alkyl-(l -6C)alkoxycarbonyI-(l-6C)alkylamino,N-(l-6C)alkyl-carbamoyl-(l-6C)alkylamino,N-(l-6C)alkyl-JHl-6C)alkylcarbamoyHl-6C)alkylamino(l-6C)alkylamino,N-(l-6C)alky]-amino-(2-6)
25 (2-6C)alkylamino, N-(l-6C)alky]-di-[(l-6C)alkyl]amino-(2-6C)alkylamino, halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino, (1 -6C)alkoxy-(2-6C)alkanoyIamino, cyano-(2-6C)alkanoy]amino,carboxy-(2-6C)aIkanoylamino, (l-6C)aIkoxycarbonyl-(2-6C)alkanoy]amino> carbamoyl-(2-6C)aIkanoylamino, N-(l- 6 C) a Iky] carbamoyl-{2-6C)alkanoy lamino, N,N-di-[( 1 -6C)alkyl]carbamoyI-(2-6C)alkanoylamino, amino-
30 (2-6C)alkanoylamino, (l-6C)alkylamino-(2-6C)alkanoylamino, di-[(l-6C)alkyl]amino-:"(2-6C)aJkanoylamin6, aryl, aryl-(I-6C)alkyl, aryl-(]-6C)alkoxy, aryloxy, arylamino,

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N-(l -6C)alkyl-arylamino, aryl-( 1 -6C)alky lamino, N-( 1 -6C)alkyl-aryl-(1 -6C)alkylamino, aroylamino, arylsulphonylamino, N-arylsuIphamoyl, aryl-(2-6C)alkanoylamino, heteroaryl, heteroary l-( 1 -6C)alkyl, heteroaryloxy, heteroaryl-( 1 -6C)alkoxy, heteroarylamino, N-(l-6C)alkyl-heteroarylamino, heteroaryl-(l-6C)alkylamino,N-(l-6C)alkyl-heteroaryl-
5 (l-6C)alkylamino, beteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroarylsulpharnoyl, heteroaryl-(2-6C)alkanoylamino, heterocyclyl, heterocyclyl-(l-6C)alkyl, heterocyclyloxy, heterocyclyl-(l-6C)alkoxy, heterocyclylamino(1-6C)alkyl-heterocyclylamino, heterocyclyl-(l-6C)alkylamino, N-(l-6C)alkyl-heterocyclyl-(1 -6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino,
10 N-heterocyclylsulphamoyl and heterocyclyI-(2-6C)alkanoylamino, and wherein any aryl, heteroaryl or heterocyclyl group in a substituent on Q2 may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (l-6C)alkyl, (l-6C)alkoxy, carboxy, (l-6C)alkoxycarbony], N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (l-6C)alkylamino and di-[(l-6C)aIkyI]amino;
15 or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof.
In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as !'propyl" are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain version only. An
20 analogous convention applies to other generic terms.
It is to be understood that, insofar as certain of the compounds of Formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting cytokines, in particular TNF. The synthesis
25 of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, inhibitory properties against TNF may be evaluated using the standard laboratory techniques referred to hereinafter.
Suitable values for the generic radicals referred to above include those set out below.

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A suitable value for Q2 or for a substituent on Q1 or Q2 when it is aryl or for the aryl group within a Q2 group or within a substituent on Q1 or Q2 is, for example, phenyl or naphthyl, preferably phenyl.
A suitable value for Q1 or Q2 or for a substituent on Q1 or Q2 when it is heteroaryl or
5 for the heteroary] group within a Q2 group or within a substituent on Q1 or Q2 is, for example, an aromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
10 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl,
benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl, preferably furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl,
15 benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl or naphthyridinyl, more preferably thienyl, isoxazolyl, pyridyl, benzothiazolyl, quinolyl, quinazolinyl, quinoxalinyl or naphthyridinyl.
A suitable value for Q2 or for a substituent on Q1 or Q2 when it is heterocyclyl or for the heterocyclyl group within a Q2 group or within a substituent on Q1 or Q2 is, for example, a
20 non-aromatic saturated or partially saturated 3 to 10 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur, for example oxiranyl, oxetanyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperaziny], dihydropyridiny], tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl, preferably pyrrolidin-1-yl, pyrroIidin-2-yl,
25 morpholino, piperidino, piperazin-l-yl orhomopiperazin-l-yl.
Suitable values for various R3 or R2 groups, or for various substituents on Q1 or Q2 or
on an aryl, heteroaryl, heterocyclyl or other group in a substituent on Q1 or Q2 include:-
for halogeno: fluoro, chloro, bromo and iodo;
for (l-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl;
30 for(2-6C)alkenyl: vinyl and ally 1;
for (2-6C)aIkynyl: ethynyl and 2-propynyl;

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for (l-6C)alkoxy: for(l-6C)alkoxycarbonyl:
for N-( 1 -6C)alkylcarbamoyl:
-13-
methoxy, ethoxy, propoxy, isopropoxy and butoxy;
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and
tert-butoxycarbony 1;
N-methylcarbamoyl, N-ethylcarbamoyl and
N-propylcarbamoyl;
forN,N-di-[(l-6C)a(kyl]carbamoyl: N3N-dimethy]carbamoyI, N-ethyl-N-methylcarbamoyl
for(2-6C)alkanoyl: for (l-6C)alkylamino: 10 for di-[(l-6C)alkyl]amino:
forhalogeno-(l-6C)alkyl:
and N,N-diethyicarbarnoyl;
acetyl and propionyl;
methylamino, ethyiamino and propylamino;
dimethylamino, diethylamino.and
N-ethyl-N-methylamino;
fluoromethyl, chloromethyl, bromomethyl,
15 for hydroxy-( 1 -6C)aIkyI: for(l-4C)aIkoxy-(l-6C)alkyl: for cyano-(l-6C)alkyl:
difluoromethyl, dichloromethyl, dibromomethyl,
2-fluoroelhyl, 2-chIoroethyl and 2-bromoethyl;
hydroxymetbyl, 2-hydroxyethy], 1-hydroxyethyl and
3-hydroxypropyl;
methoxymethyl, ethoxymethyl, l-methoxyethyl,
2-meLhoxyethyl, 2-ethoxyethyl and 3-methoxypropyl;
cyanomethyl, 2-cyanoethyI, l-cyanoethyl and
20
3-cyanopropyl;
for amino-(l-6C)alkyl:
aminomethyl, 2-aminoethy], 1-aminoethyl and
3-aminopropyl; for (l-6C)alkylarnino-(l-6C)alkyl: methylaminomethyl, ethylaminomethyl,
l-methylaminoethyl-methylaminoethyl,
25 2-ethylaminoethyl and 3-methylaminopropyl;
for di-[(l-6C)alkyl]amino-(l-6C)alkyl: dimethylaminomethyl, diethylaminomethyl,
1-dimethylaminoethyl, 2-dimethyIaminoethyl and
3-dimethylaminopropyl. A suitable value for Q2 when it is cycloalkyl is, for example, a non-aromatic mono- or
30 bicyclic 4- to 10-membered carbon ring such as cyclobutyl, cyclopentyl, cyclohexyl,

WO 00/07991 PCT/GB99/02489
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cycloheptyl, bicyclo[2.2.1]heptyl and bicyclo[4.4.0]decyl, preferably cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, more preferably cyclohexyl.
Suitable values for Q2 and suitable values for a substituent on Q1 or Q2 include:-
for aryl-(l-6C)alkyl: benzyl, 2-phenylethyl, 2-phenylpropyl and
5 3-phenyIpropyl;
for aryl-(l -6C)alkoxy: benzyloxy and 2-phenylethoxy;
for aryloxy: phenoxy and 2-naphthyloxy;
for arylamino: anilino;
for N-(l-6C)alkyl-arylamino: N-methylanilirio and N-ethylanilino;
10 for aryl-(l-6C)alkylamino: benzylamino, 2-phenethylamino, 2-phenylpropylamino
and 3-phenylpropylamino;
for N-( 1 -6C)aIky 1-ary l-( 1 -6C)alkylamino: N-benzyl-N-methylamino;
for aroylamino: benzamido and 2-naphthoylamino;
arylsulphonylamino: benzenesulphonylamido;
15 for N-arylsulphamoyl: N-phenylsulphamoyl;
for aryI-(2-6C)alkanoylamino: phenylacetamido and 3-phenylpropionamido;
for heteroaryl-(l-6C)alkyl: heteroarylmethyl, 2-heteroaryletbyl. 2-heieroaryipropy!
and 3-heteroarylprcpyl;
for heteroaryl-(l-6C)alkoxy: heteroarylmethoxy and 2-heteroarylethoxy;
20 for N-(l-6C)alkyl-heteroarylamino: N-methylheteroarylamino;
for heteroaryl-(l -6C)alkylamino: heteroaryl methyl amino, 2-heteroaryIethylamino and
3-heteroaryIpropyIamino;
for N-(l-6C)alkyl-heteroaryl-(l-6C)alkylamino: N-methylheteroarylmethylamino
and
25 N-methyl-2-heteroarylethylamino;
for heteroaryl-(2-6C)alkanoylamino: heteroarylacetamido and 3-heteroarylpropionamido;
for heterocyclyl-(l-6C)alkyl: heterocyclylmethyl and 2-heterocycIylethyl;
for heterocyclyl-(l -6C)alkoxy: heterocyclylmethoxy and 2-heterocyclyleLhoxy;
for N-(l-6C)alkyl-heterocyclylamino: N-methylheterocyclylamino;
30 for heterocyclyl-(l-6C)alkylamino: heterocyclylmethylamino, 2-heterocyclylethylamino and
3-heterocycly]propylamino;

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for N-(l-6C)alkyl-heterocyclyI-(]-6C)alkylamino: N-methylheterocyclylmethylamino
and N-methy 1-2-heterocyclyIethylamino;
for heterocyclyl-(2-6C)alkanoylamino: heterocyclylacetamido and
3-heterocyclylpropionamido;
5 for (l-3C)alkylenedioxy: methylenedioxy, ethylenedioxy and propylenedioxy;
for (l-6C)alkylthio: methylthio, ethylthio and propylthio;
for (l-6C)alkylsulphinyl: methylsulphiny], ethylsulphinyl and propylsulphinyl;
for (]-6C)alky]sulphonyl: methylsulpbonyl, ethylsulphonyl and propylsulphonyl;
for (2-6C)aIkanoyloxy: acetoxy and propionyloxy:
10 for (l-6C)alkanoylamino: formamido, acetamido and propionamido;
for N-(l-6C)alkylsulphamoyl: N-methylsulphamoyl and N-ethylsuIphamoyl;
for N,N-di-[(l-6C)alkyl]sulphamoyl: N,N-dimethylsulphamoyl;
for (1 -6C)alkanesulphonylamino: methanesulphonylamino and ethanesulphonylamino;
for N-( 1 -6C)alkyl-( 1 -6C)alkanesulphonylamino: N-methyImethanesulphonylamino and
15 N-methylethanesulphonylarnino;
for carboxy-(l-6C)alkyl: carboxymethy], 1-carboxyethyl, 2-carboxyethyl,
3-carboxypropyl and 4-carboxybutyI;
for (l-6C)alkoxycarbony]-(l-6C)alkyl: methoxycarbony] methyl, ethoxycarbonylmethyl,
tert-butoxycarbonylmcthyl, 1 -methoxycarbonylethyl,
20 1 -ethoxycarbonylethyl 2-methoxycarbonylethyl,
2-ethoxycarbony]ethyl} 3-methoxycarbonylpropyl and
3-ethoxycarbonylpropy 1;
for carbamoy]-(l-6C)alkyl: carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyI
and 3-carbamoylpropyI; 25 for N-(l-6C)alkylcarbamoyl-(I-6C)alkyl: N-methylcarbamoylmethyl,
N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl,
1 -(N-methylcarbamoyl)ethyl,
I -(N-ethylcarbamoyl)ethyl,
2-(N-methyIcarbamoyI)ethyl, 2-(N-ethyIcarbamoyl)ethyl
30 and 3-(N-methylcarbamoyl)propyl;

WO 00/07991 PCT/GB99/02489
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for N-(l-6C)alkyl-heterocyclyl-(l-6C)alkylamino: N-methylheterocyclylmethylamino
and N-methy]-2-heterocyclylethylamino;
for heterocyclyl-(2-6C)alkanoylamino: heterocyclylacetamido and
3-heterocyc!yIpropionamido;
5 for (l-3C)alkylenedioxy: methylenedioxy, ethylenedioxy and propylenedioxy;
for (l-6C)alkylthio: methylthio, ethylthio and propylthio;
for (l-6C)alkylsulphinyl: rnethylsulphinyl, ethylsulphinyl and propylsulphinyl;
for (1 -6C)alkylsulphonyl: methylsulphonyl, ethylsulphony] and propylsulphonyl;
for (2-6C)alkanoyloxy: acetoxy and propionyloxy:
10 for (l-6C)alkanoylamino: formamido, acetamido and propionamido;
for N-(l-6C)alkylsulphamoyl: N-methylsulphamoyl and N-ethylsulphamoyl;
forN,N-di-[(l-6C)alkyl]sulphamoyl: N.N-dimethylsuIphamoyl;
for (l-6C)alkanesulphonylamino: methanesulphonylamino and ethanesulphonylamino;
for N-(l-6C)alkyl-(l-6C)alkanesuIphonylarnino: N-m ethyl m ethanesulphonylamino and
15 N-methylethanesulphonylamino;
for carboxy-(l-6C)alkyl: carboxymethyl, 1-carboxyethyl, 2-carboxyethyl,
3-carboxypropyl and 4-carboxybutyl;
for (l-6C)alkoxycarbonyl-(l-6C)alkyl: methoxycarbonylmethyl, ethoxycarbonylmethyl,
tert-butoxycarbonylmethyl, l-methoxycarbonylethyl,
20 1 -ethoxycarbonylethyl, 2-methoxycarbonylethyl,
2-ethoxycarbonylethyl, 3-methoxycarbonylpropyI and
3-ethoxycarbony lpropy 1;
for carbamoyl-(l-6C)alkyl: carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl
and 3-carbamoyIpropyl; 25 for N-( 1 -6C)alkylcarbamoyl-( 1 -6C)alkyl: N-methy Icarbamoylmethyl,
N-ethylcarbamoylmethyl,N-propylcarbamoylmethyI, l-(N-methylcarbarnoyl)ethyl, l-(N-ethylcarbamoyl)ethyl,
2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamoyl)ethyl
30 and 3-(N-methy lcarbamoyl)propyl;

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forN,N-di-[(l-6C)a]kyl]carbamoy]-(I-6C)alkyl: N,N-dimethylcarbamoylmethyl,
10 for halogeno-(2-6C)alkoxy: for hydroxy-(2-6C)alkoxy:
N-ethyl-N-methylcarbamoylmethyl, N^-diethylcarbamoylmethyl, 1 -(N,N-dimethy lcarbamoyl)ethyI, ] -(N,N-diethylcarbamoyOethyl, 2-(N,N-dimethylcarbamoyl)ethyl, 2-(N)N-diethylcarbamoyl)ethyl, 3-(N,N-dimethylcarbamoyl)propyl and 4-(N,N-dimethylcarbamoyl)butyl; 2-chloroethoxy, 2-bromoethoxy and 3-chloropropoxy; 2-hydroxyethoxy, 2-hydroxy-l -methylethoxy, 3-hydroxypropoxy, 2-hydroxypropoxy and 4-hydroxybutoxy;
for (l-6C)alkoxy-(2-6C)aIkoxy:
for cyano-(l-6C)alkoxy: for carboxy-(l-6C)alkoxy:
15
2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 2-methoxy-l-methylethoxy and 4-ethoxybutoxy; cyanomethoxy, 2-cyanoethoxy and 3-cyanopropoxy; carboxymethoxy, 1-carboxyethoxy, 2-carboxyethoxy and 3-carboxypropoxy;
20 for (l-6C)alkoxycarbonyl-(l-6C)alkoxy: methoxycarbonylmethoxy,
ethoxvcarbonylmethoxy. tert-butoxycarbonylmethoxy,
2-methoxycarbonylethoxy and
3-ethoxycarbonylpropoxy;
for carbamoyl-(l-6C)alkoxy: carbarnoylmethoxy and 2-carbamoyIethoxy;
25 for N-(l-6C)alkylcarbamoyl-(l-6C)alkoxy: N-methylcarbamoylmethoxy,
2-(N-ethyIcarbamoyl)ethoxy and 3-(N-methylcarbamoyl)propoxy; forN,N-di-[(l-6C)alkyl]carbamoyl-(l-6C)alkoxy: N,N-dimethylcarbamoylmethoxy,
2-(NJN-dimethylcarbamoyl)ethoxy and
30 3-(N,N-diethylcarbamoyl)propoxy;

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for amino-(2-6C)alkoxy: 2-aminoethoxy, 2-amino- ] -methylethoxy,
3-aminopropoxy, 2-amino-2-methylpropoxy and
4-aminobutoxy;
for (l-6C)alkylamino-(2-6C)a!koxy: 2-methyIaminoethoxy, 2-methylaminO"
5 1 -melhylethoxy and 3-ethylaminopropoxy;
for di-[( 1 -6C)alkyl]amino-(2-6C)alkoxy: 2-dimethylaminoethoxy, 2-diethylaminoethoxy,
2-dimetbylaminopropoxy, 2-dimethylarnino-2-methylpropoxy, 3-dimethylaminopropoxy and 4-dimethylaminobutoxy;
10 for halogeno-(2-6C)alkylamino: 2-fluoroethylamino, 2-chloroethylamino,
2-bromoethyIamino, 3-fluoropropylamino and
3-chloropropylamino;
for hydroxy-(2-6C)alkylamino: 2-hydroxyethylamino, 3-hydroxypropyIamino,
2-hydroxy-2-methy]propylamino and
15 4-hydroxybutylamino;
for (l-6C)alkoxy-(2-6C)alkylamino: 2'methoxyethylamino, 2-ethoxyethylamino,
3-methoxypropylamino and 3-ethoxypropyIamino;
for cyano-(3-6C)alkylamino: cyanomethylamino, 2-cyanoethylamino and
3-cyanopropyiamino;
20 for carboxy-(l -6C)alkylamino: carboxymethylamino, 1-carboxyethylamino,
2-carboxyethyiamino and 3-carboxypropyIamino;
for(l-6C)alkoxycarbonyl-(l-6C)alkylamino: methoxycarbonylmethylamino,
2-(ethoxycarbonyl)ethylamino and 3-(tert-butoxycarbonyI)propylainino;
25 for carbamoyl-(l-6C)alkylamino: carbamoylmethylamino and 2-carbamoyIethylamino; forN-(l-6C)alkylcarbamoyl-(l-6C)aIkyIamino: N-methylcarbamoylmethylamino,
N-ethylcarbamoylmethylamino and
2-(N-methylcarbamoyl)ethylamino;
forN}N-di-[(l-6C)alkyl]carbamoyl-(l-6C)alkylamino: N,N-dimethylcarbamoyl
30 methylamino, N,N-diethylcarbamoylmethylamino and
2-(N,N-dimethylcarbamoyI)ethylamino;

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-18-
for amino-(2-6C)alkylamino: 2-aminoethylamino, 3-aminopropylamino, 2-amino-
2-methyipropylamino and 4-aminobutylamino;
for (1 -6C)alkylamino-(2-6C)alkylamino: 2-methylaminoethylamino,
2-ethylaminoethylamino, 2-propyIarninoethylamino,
5 3-methyIaminopropylarnino, 3-ethylaminopropylamino,
2-methylamino-2-methy]propylamino and 4-methyl aminobutyl amino;
for di-[(]-6C)alkyl]amino-(2-6C)alkylamino: 2-dimethyiaminoethyJamino,
2-(N-ethyl-N-methylamino)ethylamino5
10 2-diethylaminoethylamino, 2-dipropylaminoethylamino,
3-dimethylaminopropylamino, 3-diethylaminopropylamino, 2-dimethylamino-2-methylpropylamino and 4-dimethylaminobuty!amino;
for N-( 1 -6C)alkyl-halogeno-(2-6C)alkylamino: N-(2-chloroethyl)-N-methylamino,
15 N-(2-bromoethyI)-N-methylamino and
N-(2-bromoethy])-N-ethylamino;
forN-(l-6C)alkyl-hydroxy-(2-6C)alkylamino: N-(2-hydroxyethy])-N-rnethylamino:
N-(3-hydroxypropyl)-N-methylamino and N-ethyl-N-(2-bydroxyethyl)amino;
20 for N-(l-6C)alkyl-(]-6C)alkoxy-(2-6C)alkylamino:
N-methyI-N-(2-methoxyethyl)amino,N-methyl-N-(3-methoxypropyl)amino and N-ethyl-N-(2-methoxyethyl)amino;
forN-(l-6C)alkyl-cyano-(l-6C)alkylamino: N-(cyanomethyl)-N-methylamino;
25 forN-(I-6C)alkyl-carboxy-(l-6C)alky]amino: N-carboxymethyl-N-methylamino and
N-(2-carboxyethyl)-N-methylamino;
for N-( 1 -6C)alkyl-( ] -6C)alkoxycarbony]-( 1 -6C)alkylamino:
N-methoxycarbonylmethyl-N-methylamino,
N-(2-ethoxycarbonylethyl)-N-ethylamino and
50 N-(2-tert-butoxycarbonyIethyl)-N-methylamino;

WO 00/07991 PCT/GB99/02489
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for N-(l-6C)alkyl-carbamoyl-(l-6C)alkylamino: N-carbamoylmethyl-N-methylamino and
N-(2-carbamoylethyl)-N-methylamino; for N-( 1 -6C)alkyl-N-(l -6C)alkylcarbamoyl-( ] -6C)alkylamino:
N-(N-methylcarbamoylrnethy])-N-methyIamino3
5 N-(N-ethylcarbamoyImethy])-N-methy]amino and
N-[2-(N-methylcarbamoyl)ethyl]-N-methylamino; forN-(l-6C)alkyl-N,N-di-[(]-6C)alkyl]carbamoyl-(l-6C)alkylamino:
N-(N-dimethylcarbamoy]methyl)-N-methylamino and
N-[2-Q^N-diiriethylcarbarnoyl)ethyl]-N-rnethyIamino;
10 forN-(l-6C)alkyl-amino-(2-6C)alkylamino: N-(2-aminoethyl)-N-melhylamino,
N-(3-aminopropyl)-N-methy]amino and N-(4-aminobutyl)-N-methyIamino; forN~(l-6C)alkyl-(l-6C)alkylamino-(2-6C)alkylamino: N-(2-methylaminoethyl)-
N-methyIamino)N-(2-ethylaminoethy])-N-rnethyIamino,
15 N-(3-methylaminopropyl)-N-methylamino,
N-(3-ethylammopropyl)-N-ethyIamino and N-(4-methylaminobutyl)-N-methylamino; forN-(l-6C)alkyl-di-[(l-6C)alkyl]amino-(2-6C)alkylamino:
N-(2-dimethy]aminoethyl)-N-methyIamino,
20 N-(2-diethyIaminoethyI)-N-methylamino,
N-(3-dimethylaminopropyl)-N-methylamino and
N-(4-dimethylaminobutyl)-N-methylamino;
for halogeno-(2-6C)alkanoyIamino: 2-chloroacetamido and 3-chloropropionamido;
for hydroxy-(2-6C)alkanoylamino: 2-hydroxyacetamido and
25 3-bydroxypropionamido;
for (l-6C)alkoxy-(2-6C)alkanoyIarnino: 2-methoxyacetamido and
3-methoxypropionamido; for cyano-(2-6C)altkanoylamino: 2-cyanoacetamido and 3-cyanopropionamido; for carboxy-(2-6C)alkanoylamino: 2-carboxyacetamido and 3-carboxypropionamido;

WO 00/07991 PCT/GB99/02489
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for (1 -6C)alkoxycarbonyl-(2-6C)alkanoylamino: 2-methoxycarbonylacetamido,
2-(tert-butoxycarbonyl)acetamido and 3-methoxycarbonylpropionamido;
for carbamoyl-(2-6C)alkanoylamino: 2-carbamoylacetamido,
5 3-carbamoyipropionamido and 4-carbamoylbutyramido;
for N-( 1 -6C)alkylcarbamoy l-(2-6C)alkanoylamino: 2-(N-methylcarbamoyl)acetamido
and3-(N-ethylcarbamoyl)propionamido;
for N,N-di-[(] -6C)alkyl]carbamoyl-(2-6C)alkanoylamino:
2-(N,N-dimethylcarbamoyl)acetamido, ■
10 2-(N,N-diethyIcarbamoyl)acetamido and
3-(N)N-dimethylcarbarnoyI)propionamido; for amino-(2-6C)alkanoylamino: 2-aminoacetamido, 2-aminopropionamido and
3-aminopropionamido;
for (1 -6C)alkylamino-(2-6C)alkanoyIamino: 2-methylaminoacetamido,
15 2-ethylaminoacetamido, 2-methylaminopropionamido
and 3-methylaminopropionamido; for di-[(l-6C)alkyl]amino-(2-6C)alkanoylarnino: 2-dimethyIaminoacetamido.
2-dielhylaminoacetarnido,
2-dimethylaminopropionamido and
20 3-dimemylaminopropionamido.
When, as defined hereinbefore, any of the substituents on Q1 or Q2 which comprise a CH2 group which is attached to 2 carbon atoms or a CH3 group which is attached to a carbon atom may optionally bear on each said CH2 or CH3 group a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and heterocyclyl, suitable
25 substituents so formed include, for example, substituted heterocyclyl-(l -6C)aIkoxy groups such as 2-hydroxy-3-piperidinopropoxy and 2-hydroxy-3-morphoIinopropoxy, substituted amino-(2-6C)alkoxy groups such as 3-amino-2-hydroxypropoxy, substituted (I-6C)alkylarnino-(2-6C)alkoxy groups such as 2-hydroxy-3-methy]aminopropoxyJ substituted di-[(l-6C)alkyl]amino-(2-6C)alkoxy groups such as 3-dimethylamino-
30 2-hydroxypropoxy, 3-[N-(3-dimethylaminopropyl)-N-methyIamino]propoxy and
3r[N-(3-dirnethylaminopropyl)-N-methylamino]-2-hydroxypropoxy, substituted heterocyclyl-

WO 00/07991 PCT/GB99/02489
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(l-6C)alkylamino groups such as 2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morphoIinopropylamino, substituted amino-(2-6C)alkylamino groups such as 3-amino-2-hydroxypropylamino, substituted (l-6C)alkylamino-(2-6C)alky]amino groups such as 2-hydroxy-3-methylarninopropylamino, substituted di-[(l -6C)alkyl]amino-(2-6C)alky]amino
5 groups such as 3-dimethylamino-2-hydroxypropylarnmo, 3-[N-(3-dimethylaminopropyl)-N-methylamino]propylamino and 3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-hydroxypropylamino and substituted (l-6C)alkylamino-(l-6C)alkyl groups such as 2-morpholinoethylaminomethyl, 2-piperazin-l-ylethylaminomethyl and 3-morpholinopropylaminomethyI.
10 A suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for
example, an acid-addition salt of a compound of the Formula I which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth
15 metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see:
20 a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in
Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et a!. (Academic Press, 1985);
b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); 25 c) H. Bundgaard, Advanced Drue Delivery Reviews. 8, 1-38 (1992);
d) H. Bundgaard, et g/.. Journal of Pharmaceutical Sciences, 77, 285 (1988); and
e) N. Kakeya, et ai. Chem. Pharm. Bull., 32, 692 09841.
Examples of such pro-drugs may be used to form in-vivo-cleavable esters of a compound of the Formula I. An in-vivo-cleavable ester of a compound of the Formula I
30 containing a carboxy group is, for example, a pharmaceutically-acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically-

WO 00/07991

PCT/GB99/02489

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acceptable esters for carboxy include (l-6C)alkoxymethyl esters, for example
methoxymethyl;
(l-6C)alkanoyloxymethyl esters, for example pivaloyloxymethyl; phthalidyl esters;
(3-8C)cycloalkoxycarbonyloxy(l-6C)alkyl esters, for example l-cyclohexylcarbonyloxyethyl; 5 1,3-dioxolan-2-ytmethyl esters, for example 5-methyI-l ,3-dioxolan-2-ylmethyl; and
(l-6C)alkoxycarbonyloxyethyl esters, for example 1-methoxycarbonyloxyethyl; and may be
formed at any carboxy group in the compounds of this invention.
Particular novel compounds of the invention include, for example, amide derivatives
of the Formula I, or pharmaceutically-acceptable salts thereof, wherein:-
10 (a) R3 is (l-6C)alkyl such as methyl, ethyl, propyl and isopropyl, preferably methyl and
ethyl, more preferably methyl; and Q1, R2, Q!, p and q have any of the meanings defined
hereinbefore or in this section relating to particular novel compounds of the invention;
(b) ' R3 is halogeno such as fluoro, bromo and chloro, preferably chloro and bromo, more
preferably chloro; and Q1, R2, Q2, p and q have any of the meanings defined hereinbefore or in
15 this section relating to particular novel compounds of the invention;
(c) Q1 is a heteroaromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered
bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur
which optionally bears 1, 2 or 3 substituents selected from hydroxy, halogeno,
trifluoromethyl, cyano, nitro, amino, carboxy, (l-6C)alkyl, (l-6C)alkoxy, (1-
20 3C)alkylenedioxy,
(l-6C)alkylamino, di-[(l-6C)a]kyl]amino, (I-6C)alkoxycarbonyl, (2-6C)alkanoyl, halogeno-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, amino-(I-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l -6C)alkyl]amino~(l-6C)alkyl, halogeno-(2-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1 -6C)alkoxy-(2-6C)alkoxy, cyano-(l-6C)alkoxy, carboxy-(l-6C)alkoxy,
25 (l-6C)alkoxycarbonyl-(l-6C)alkoxy, amino-(2-6C)alkoxy, (l-6C)alkylamino-(2-6C)alkoxy, di-[(l-6C)alkyl]amino-(2-6C)alkoxy, pyridyl-(l-6C)alkyl, imidazolyl-(l-6C)alkyl, pyridyl-(l-6C)alkoxy, imidazolyl-(l-6C)alkoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-( 1 -6C)alkylpiperazinyl, 4-(2-6C)alkanoylpiperazinyl, pyrrolidinyl-(l -6C)alkyl, piperidinyl-(l-6C)alkyl, morpholinyI-(l-6C)alkyl, piperazinyl-(l-6C)alkyl, 4-(l-6C)alkylpiperazinyl-
30 (l-6C)alkyl, 4-(2-6C)alkanoyIpiperazinyl-(l-6C)alkyl, pyrrolidinyloxy, piperidinyloxy, <:.l- pyrrolidinyl- piperidinyl->
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morpholinyl-(2-6C)alkoxy, piperazinyH2-6C)alkoxy, 4-(l-6C)alkylpiperazinyl-(2-6C)alkoxy and 4-(2-6C)alkanoylpiperazinyl-(2-6C)aIkoxy; and R2, R3, Q2, p and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;
5 (d) Q1 is fury], thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl or naphthyridinyl which optionally bears 1 or 2 substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, nitro, amino, carboxy,
10 (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and
(l-6C)alkoxycarbonyI; and R2, R3, Q2, p and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;
(e) Q1 is 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-oxazoIyl, 3-, 4- or 5-isoxazoIyI,
2-, 4- or 5-imidazolyl, 3- or 4-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazoly],
15 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 2-, 3-, 5- or 6-benzofuranyl, 2-, 3-, 5- or 6-indoIyl, 2-, 3-, 5- or 6-benzothienyl, 2-, 5- or 6-benzoxazolyl, 2-, 5- or 6-benzimidazoIyl, 2-, 5- or 6-benzothiazolyl, 3-, 5- or 6-indazolyI, 5-benzofurazanyl, 2-, 3-, 6- or 7-quinolyl, 3-, 6- or 7-isoquinolyl, 2-, 6- or 7-quinazolinyl, 2-, 6- or 7-quinoxalinyl, or l,8~naphthyridin-2-yl or 3,8-napbthyridin-3-yl which optionally bears 1 or
20 2 substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, nitro, amino, carboxy, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and (I-6C)alkoxycarbonyl; and R2, R3, Q2, p and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;
(f) p is 0; and Q', R3, Q2 and q have any of the meanings defined hereinbefore or in this
25 section relating to particular novel compounds of the invention;
(g) q is 0, and Q2 is phenyl which optionally bears 1, 2 or 3 substituents selected from
hydroxy, halogeno, trifluoromethyl, cyano, amino, (1 -6C)alkyl, (l-6C)a!koxy,
(l-3C)alkylenedioxy, (l-6C)alkylamino, di-[(l-6C)alkyl]arnmo, (2-6C)alkanoyl, halogeno-
(]-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-
30 6C)alkyl]amino-
(l-6C)alkyl, halogeno-(2-6C)alkoxy, hydroxy-(2-6C)alkoxy, (l-6C)alkoxy-(2-6C)alkoxy,

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cyano-(2-6C)alkoxy, carboxy-(2-6C)aIkoxy, (l-6C)alkoxycarbonyl-(]-6C)alkoxy, amino-(2-6C)alkoxy, (l-6C)alkylamino-(2-6C)alkoxy, di-[(l-6)alkyl]amino-(2-6C)alkoxy, halogeno-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (l-6C)alkoxy-(2-6C)alkylamino, amino-(2-6C)alkylamino)(l-6C)alkylamino-(2-6C)alkylamino,di-[(l-6C)alkyl]amino-
5 (2-6C)alkylamino, N-(l-6C)alkyl-halogeno-(2-6C)alkylamino, N-(l-6C)alkyl-hydroxy-(2-6C)alkylammo,N-(I-6C)alkyl-(I-6C)alkoxy-(2-6C)alkytamino,N-(l-6C)alkyl-amino-(2-6C)alkylamino,N-(l-6C)alkyl-(l-6C)a]kylamino-(2-6C)a]kylamino)N-(l-6C)alky]-di-[(l-6C)alkyl]amino-(2-6C)alkylamino, phenyl, benzyl, benzyloxy, pyridyl, imidazolyl, pyridyl-(l-6C)alkyl, imidazoIyl-(l-6C)alkyl, pyridyl-(l-6C)alkoxy, imidazoIyl-(1-6C)alkoxy,
10 pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-(l-6C)alkylpiperazinyl,
4-(2-6C)alkanoylpiperazinyl, pyrrolidinyI-(l-6C)alkyl, piperidinyI-(l-6C)alkyl, morpholinyl-(l-6C)alkyl,piperazinyl-(1-6C)alkyl,4-(1-6C)alkyl,piperidinyl-(1-6C)alkyl,, 4-(2-6C)alkanoylpiperazinyl-(l -6C)alkyl, pyrrolidinyloxy, piperidinyloxy, ]-(]-6C)alkylpiperidinyIoxy, pyrrolidinyl-(2-6C)alkoxy, piperidinyI-(2-6C)alkoxy,
15 rnorpholinyl-(2-6C)aIkoxy, piperazinyl-(2-6C)alkoxy, 4-(l-6C)alkylpiperazinyH2-6C)alkoxy and 4-(2-6C)aIkanoyIpiperazinyl-(2-6C)alkoxy; and Q1, R2, R3 and p have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;
(h) q is 0, and Q2 is furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl,
20 isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinoly], isoquinolyl, quinazolinyl, quinoxalinyl or naphthyridinyl which optionally bears 1 or 2 substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, nitro, amino, carboxy, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and
25 (l-6C)alkoxycarbonyl; and Q1, R2, R3 and p have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (i) q is 0, and Q2 is 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-imidazoIyl, 3- or 4-pyrazolyl, 2-, 4- or 5-thiazoIyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl,
30 2-, 3-, 5- or 6-benzofuranyl, 2~y 3-, 5- or 6-indolyI, 2-, 3-, 5- or 6-benzothienyl, 2-, 5- or 6-ben20xazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 5- or 6-benzothiazolyI, 3-, 5- or 6-indazolyI,

WO 00/07991 PCT7GB99/02489
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5-benzofurazanyl, 2-, 3-, 6- or 7-quinolyl, 3-, 6- or 7-isoquinolyl, 2-, 6- or 7-quinazolinyl, 2-, 6- or7-quinoxalinyl, l,8-naphthyridin-2-yl or l,8-naphthyridin-3-yl which optionally bears 1 or 2 substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, nitro, amino, carboxy, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and
5 (3-6C)aIkoxycarbonyl; and Q1, R2, R3 and p have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (j) q is 0, and Q2 is 4- or 5-oxazolyl, 4- or 5-isoxazolyl, 4- or 5-thiazolyI,
4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 5- or 6-benzofuranyl, 5- or 6-benzothienyl,
5- or 6-benzothiazoiyl, 2-, 3-, 6- or 7-quinolyl, 2-, 6- or 7-quinazolinyl,
10 2-, 6- or 7-quinoxalinyl, l,8-naphthyridin-2-yl or I,8-naphthyridin-3-yl which optionally bears 1, 2 or 3 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, methyl, ethyl, methoxy and ethoxy; and Q1, R2, R3 and p have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; and (k) q is 1, 2, 3 or 4, and Q2 is cycloalkyl; and Q1, R2, R3 and p have any of the meanings
15 defined hereinbefore or in this section relating to particular novel compounds of the invention. A preferred compound of the invention is an amide derivative of the Formula I wherein R3 is methyl, ethyl, chloro or bromo;
Q' is furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl. pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, ben2ofuranyl, indolyl, benzothienyl,
20 benzoxazolyl. benzimidazolyl, benzothiazolyl, indazolyl, benzoflirazany], quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl or naphthyridinyl which optionally bears 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, methyl, ethyl, methoxy and ethoxy; p is O;
25 q is 0; and
Q2 is phenyl which bears 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylammo, dimethylamino, diethylamino, acetyl, propionyl, chloromethyl, methoxymethyl,
30 2-methoxyethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,
diethylaminomethyl, 2-chloroethoxy, 3-chioropropoxy, 2-hydroxyethoxy, 3-hydroxypropoxy,

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2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, cyanomethoxy, carboxymethoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, tert-butoxycarbonylmethoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy,
5 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-chloroethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 2-aminoethylamino, 2-methylaminoethylamino, 2-ethyl amino ethyl amino, 2-dimethylaminoethylaminO, 2-diethylaminoethylamino, N-(2-chloroethyl)-N-methylamino, N-(2-hydroxyethyl)-N-methylamiDO,N-(2-methoxyethyl)-N-methyIamino,N-(2-'
10 ethoxyethyl)-N-methylarnino, N-(2-aminoethyl)-N-methylamino, N-(2-methyiaminoethyl)-N-m ethyl amino,
N-(2-dimethylaminoethy])-N-methylamino, N-(3-aminopropyl)-N-methylamino, N-(3-"methylaminopropyl)-N-methylamino, N-(3-ethylaminopropyI)-N-methylamino, N-(3-dimethylaminopropyl)-N-memylamino, N-(3-imidazol-
15 phenyl, benzyl, benzyloxy, 2-pyridylmethoxy, 2-(imidazol-l-yl)ethoxy, 3-(imidazol-
1 -yl)propoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-l-yl, 4-methylpiperazin-l-yl,
4-acetylpiperazin-I-yl, pyrrolidin-1-ylmethyl. piperidinomcihyl. morpholinomethyl.
piperazin-
1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-l-ylmethyl, piperidin-4-yIoxy,
20 l-methylpiperidin-4-yloxy, 2-(pyrrolidin-l-yl)ethoxy, 3-(pyrrolidin-l-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-l -ylethoxy, 3-piperazin-l-ylpropoxy, 2-(4-methylpiperazin-l -yI)ethoxy, 3-(4-methylpiperazin-1 -yl)propoxy, 2-(4-acetylpiperazin-1 -yl)ethoxy and 3-(4-acetylpiperazin-1 -y l)propoxy,
25 or Q2 is oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, benzofuranyl, benzothienyl, benzothiazolyl, quinolyl, quinazolinyl, quinoxalinyl or 1,8-naphthyridinyl which optionally bears 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, methyl, ethyl, methoxy and ethoxy; or a pharmaceutically-acceptable salt thereof.
30 A further preferred compound of the invention is an amide derivative of the Formula I
Wherein R3 is methyl or chloro;

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Q' is 3-isoxazolyl, 4-thiazolyl, 3- or 4-pyridyl, 5- or 6-benzothiazolyl, 6- or 7-quinolyl,
6- or 7-quina2oliny], 2-, 6-or 7-quinoxalinyl or l,8-naphthyridin-3-yl which optionally bears
1 or 2 substituents selected from hydroxy, fluoro, chloro, methyl and ethyl;
p is 0;
5 q is 0; and
Q2 is phenyl which optionally bears 1 or 2 substituents selected from fluoro, chloro,
trifluoromethyl, cyano, methoxy and dimethylammo;
or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the invention is an amide derivative of the Formula I
10 wherein R is methyl or chloro;
Q1 is 3-isoxazolyl, 4-thiazolyl, 3- or 4-pyridyl, 5- or 6-benzothiazolyl, 6- or 7-quinolyl,
6- or 7-quinazolinyl, 2-, 6- or 7-quinoxalinyl or l,8-naphthyridin-3-yl which optionally bears
1 or 2"substituents selected from hydroxy, fluoro, chloro, methyl and ethyl;
p is 0;
15 q is 0; and
Q2 is 4- or 5-isoxazolyl, 4-thiazolyl, 3- or 4-pyridyl, 5- or 6-benzothiazolyl, 6- or 7-quinolyl,
6- or 7-quinazolinyl, 2-. 6- or 7-quinoxalinyl or L8-naphthyridin-3-yl which optionally bears
a substituent selected from hydroxy, fluoro, chloro: methyl and ethyl;
or a pharmaceutically-acceptable salt thereof.
20 A further preferred compound of the invention is an amide derivative of the Formula I
wherein R3 is methyl or chloro;
Q1 is 3-isoxazolyl, 4-thiazolyl, 3- or 4-pyridyl, 5- or 6-benzothiazolyl, 6- or 7-quinolyl,
6- or 7-quinazolinyl, 2-, 6- or 7-quinoxalinyl or l,8-naphthyridin-3-yl which optionally bears
1 or 2 substituents selected from hydroxy, fluoro, chloro, methyl and ethyl;
25 p is 0;
q is 1 or 2; and
Q2 is cyclobutyl, cyclopentyl or cyclohexyl;
or a pharmaceutically-acceptable salt thereof.
A more preferred compound of the invention is an amide derivative of the Formula I
30 wherein R3 is methyl or chloro;

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Q1 is 3-isoxazolyl, 3-pyridyl, 6-benzothiazolyl, 6-quinolyl, 6-quinazolinyI, 6-quinoxaliny] or ] ,8-naphthyridin-3-y! which optionally bears a substituent selected from hydroxy, chloro and methyl; p is O;
5 q is 0; and Q2 is phenyl which optionally bears 1 or 2 substituents selected from fluoro, chloro, trifluoromethyl, cyano, methoxy and dimethylamino; or a pharmaceutically-acceptabie salt thereof.
A further more preferred compound of the invention is an amide derivative of the
10 Formula I wherein R3 is methyl or chloro;
Q1 is 3-isoxazolyl, 3-pyridyl, 6-benzothiazolyl, 6-quinolyl, 6-quinazolinyl, 6-quinoxaiinyl or l,8-naphthyridin-3-yl which optionally bears a substituent selected from hydroxy, chloro and methyl; p is O;
15 q is 0; arid
Q2 is 5-isoxazolyl or 3-pyridyl which optionally bears a substituent selected from chloro and
methyl;
or a pharmaceutically-acceptabie salt thereof.
A further more preferred compound of the invention is an amide derivative of the
20 Formula I wherein R3 is methyl or chloro;
Q1 is 3-isoxazolyl, 3-pyridyl, 6-benzothiazolyl, 6-quinolyl, 6-quinazolinyl, 6-quinoxalinyl or l,8-naphthyridin-3-yl which optionally bears a substituent selected from hydroxy, chloro and methyl; p is O;
25 q is 2; and
Q2 is cyclohexyl;
or a pharmaceutically-acceptabie salt thereof.
A particular preferred compound of the invention is, for example :-6-chloro-N-[5-(3-dimethy]aminobenzamido)-2-methylphenyl]pyridine-3-carboxamide)
30 N-[2-methyl-5-(3-trifluoromethylbenzamido)phenyl]quinoline-6-carboxamideT Nr[:5-(3-dimethylaminobenzarnido)-2-methylphenyI]benzothiazole-6-carboxamide>

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N-[5-(4-cyanobenzamido)-2-methylphenyl]quinoline-6-carboxamide, N-(5-benzamido-2-methylphenyl)quinoline-6-carboxamide,
N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-hydroxyquinazoline-6-carboxamide, N-[5-(3-dimethylaminobenzamido)-2-methyIphenyl]-2-methyl-]f8-naphthyridine-
5 3-carboxamide, N-[2-chloro-5-(4-cyanobenzamido)phenyl]quinoline-6-carboxamide or N-[5-(5-isoxa2o]ylcarbonylamino)-2-methylphenyI]quinoIine-6-carboxamide; or a pharmaceutically-acceptable salt thereof.
In a further aspect of the present invention there is provided a group of novel
10 compounds of the Formula I wherein Q1 is substituted by a basic substituent selected from the substituents for Q1 defined hereinbefore. This group of compounds possesses improved TNFa inhibitory potency in one or both of the PBMC and Human Whole Blood (HWB) tests described hereinafter
In a further aspect of the present invention there is provided a group of novel
15 compounds of the Formula I wherein Q1 is substituted by a basic substituent selected from the substituents for Q1 defined hereinbefore and Q2 is a phenyl or heteroaryl group as defined hereinbefore which also bears a basic substituent selected from the substituents for Q2 defined hereinbefore. This group of compounds possesses improved TNFa inhibitory potency in one or both of the PBMC and Human Whole Blood tests described hereinafter.
20 Suitable basic substituents include, for example, amine derivatives such as amino,
(l-6C)alkylamino,di-[(l-6C)alkyl]amino-(1-6C)alkyl,di-[(1-6C)alkyl]amino-(2-6C)alkoxy,
di-[(l-6C)alkyl]amino-(2-6C)alkylamino, a heteroaryl group such as a nitrogen-containing heteroaryl group, for example imidazolyl and pyridyl and a heterocyclyl group such as a nitrogen-containing heterocyclyl group, for example morpholino.
25 Particular novel compounds of these further aspects of the invention include, for
example, amide derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein:-
(a) R3 is (l-6C)alkyl such as methyl, ethyl, propyl and isopropyl, preferably methyl and ethyl, more preferably methyl; and Q1, R2, Q2, p and q have any of the meanings defined in
30 this section relating to particular novel compounds of the invention;

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(b) R3 is halogeno such as fluoro, bromo and chloro, preferably chloro and bromo, more
preferably chloro; and Q1, R2, Q2, p and q have any of the meanings defined in this section
relating to particular novel compounds of the invention;
(c) Q1 is a heteroaromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered
5 bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur
which bears 1 or 2 basic substituents selected from amino, (l-6C)alkylamino, di-[(l-6C)alkyl]amino,amino-(K6Q
di-[(l-6C)alkyl]amino-(l-6C)alkyl,amino:(2-6C)alkoxy](l-6C)alky]amino-(2-6C)alkoxy) di-[(l-6C)alkyl]amino-(2-6C)alkoxyIamino-(2-6C)alkylamino, (l-6C)alkylamino-
10 (2-6C)aikylamino, di-[(l-6C)alkyl]amino-(2-6C)alkylamino, N-(l-6C)alkyl-amino-(2-6C)alkylamino)N-(l-6C)alkyl-(l-6C)alky]amino-(2-6C)alkylamino>N-(l-6C)alky di-[(l-6C)alkyl]amino-(2-6C)alkylamino, amino-(2-6C)alkanoylamino, (l-6C)alkylamino-(2-6C)alkanoylamino, di-[(l-6C)alkyl]ammo-(2-6C)alkanoylarnino, arylamino, N-(l-6C)alkyl-arylamino, aryl-(l-6C)alkylamino,N-(l-6C)alkyl-aryl-(l-6C)alkylamino,
15 heteroaryl, heteroaryl-(l-6C)alkyl, heteroaryloxy, heteroaryl-(l-6C)alkoxy, heteroarylammo, N-(l-6C)alkyl-heteroarylamino, heteroaryl-(l-6C)alkylamino;N-(l-6C)alkyl-heteroaryI-(]-6C)alkylamino. heterocyclyl. heterocyclyl-(l-.5C)alkyl} heterccyclyloxy, hcterocycl;,\-(1 -6C)alkoxy, heterocyclylamino, N-(l -6C)alky!-heterocyclylamino, heterocyclyl-(l-6C)alkylamino and N-(l-6C)alkyl-heterocycly]-(]-6C)alkylamino, and wherein any of the
20 basic substituents on Q1 as defined hereinbefore which comprise a CH2 group which is
attached to 2 carbon atoms or a CH3 group which is attached to a carbon atom may optionally bear-on each said CH2 or CH3 group a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and heterocyclyl, and wherein any aryl, heteroaryl or heterocyclyl group in a basic substituent on Q1 may optionally bear 1 or 2
25 substituents selected from hydroxy, halogeno, (l-6C)alkyl, (l-6C)alkoxy,
(2-6C)alkanoyl, amino, (I-6C)alkylamino, di-[(l-6C)alkyl]amino, hydroxy-(l-6C)alkyl, (1-6C)alkoxy-(1-6C)alkylamino-(1-6C)alkyl-(1-6C)alkylamino-(1-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, aryl and aryl-(l-6C)alkyl, and wherein Q' may optionally bear 1 further substituent selected from hydroxy, halogeno, trifluoromethyl, cyano,
30 (l-6C)alkyl and (l-6C)alkoxy; and R3, R2, Q2, p and q have any of the meanings defined in "his section relating to particular novel compounds of the invention;

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(d) Q1 is a heteroaromatic 5- or6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur which bears 1 basic substituent selected from amino, (l-6C)alkylamino, di-[(l-6C)alkyl]amino,amino-(l-6C)alkyl,(l-6C)alkylamino-(l-6C)alkyl,
5 di-[(l-6C)alkyl]amino-(l-6C)alkyl,amino-(2-6C)alkoxy,(l-6C)alkylamino-(2-6C)alkoxy, di-[(l-6C)alky]]amino-(2-6C)alkoxy,amino-(2-6C)alkylamino) (l-6C)alkylamino-(2-6C)alkylamino,di-[(]-6C)alkyl]amino-(2'6C)alkylamino,N-(l-6C)alkyl-amino-(2-6C)alkylamino,N-(]-6G)alkyl-(l-6C)alkylamino-(2-6C)alkylamino,N-(l-6C)alkyl-di-[( I -6C)alkyl]amino-(2-6C)alkylamino, amino-(2-6C)alkanoylamino, (1 -6C)alkylamino-
10 (2-6C)alkanoylamino, di-[(l-6C)alkyl]amino-(2-6C)alkanoylamino, pyridyl, pyridyl-
(l-6C)alkyl, pyridyloxy, pyridyl-(l-6C)aIkoxy, pyridylamino, N-(l-6C)alkyl-pyridyiamino) pyridyI-(l-6C)alkylamino, N-(l-6C)alkyl-pyridyl-(l-6C)alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4~(l-6C)alkylpiperazinyl, homopiperazinyl, 4-(l-6C)alkylhomopiperazinyl, pyn-oIidinyl-(l-6C)alkyl, piperidinyl-(l-6C)alkyl,
15 morpholinyl-(l-6C)alky], piperazinyl-(l-6C)alkyl, 4-(l-6C)alkylpiperazinyl-(l-6C)alkyl, homopiperazinyl-(l-6C)alkyl)4-(l-6C)alkylhomopiperazinyl-(l-6C)alkyl>pyrrolidinyIoxy, piperidinyloxy, l-(]-6C)alkylpiperidinyloxy, pyrrolidmy]-(2-6C)alkoxy, piperidinyl-(2-6C)a!koxy, morpholinyl-(2-6C)alkoxy,piperazinyI-(2-6C)alkoxy? 4-( 1 -6C)alkylpiperazinyl-(2-6C)alkoxy, pyrrolidinylamino, piperidinylamino,
20 N-(l-6C)alkyl-pyiroIidinylamino, N-(l-6C)alkyl-piperidinylamino, pyrrolidinyl-(1 -6C)alky lamino, piperidinyl-( I -6C)alkylamino, morpholiny l-( 1 -6C)aIky lamino, piperazinyKl-dQalkylamino, 4-(l -6C)alkylpiperazinyl-(l -6C) alky lamino, N-(l -6C)alkyl-pyrrolidinyl-(l-6C)alkylamino,N-(l-6C)alkyl-piperidinyl-(]-6C)alkylamino)N-(l-6C)alkyl-morpholinyl-(l-6C)alkylamino, N-(l-6C)alkyl-piperazinyl-(l-6C)alkylamino and
25 N-(l-6C)alkyl-4-(l-6C)alkylpiperazinyl-(l-6C)alkylamino) and wherein any of the basic substituents on Q1 as defined hereinbefore which comprise a CH2 group which is attached to 2 carbon atoms or a CH3 group which is attached to a carbon atom may optionally bear on each said CH2or CH3 group a substituent selected from hydroxy, amino, (l-6C)alkylamino and di-[(l-6C)alkyl]amino, and wherein any pyridyl or heterocyclyl group in a basic substituent
30 on Q1 may optionally bear 1 or 2 substituents selected from hydroxy, (I-6C)alkyl, (1-
-6C)alkoxy, (2-6C)alkanoyl, hydroxy-(l-6C)alkyl and benzyl, and wherein Q1 may optionally

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bear 1 further substituent selected from hydroxy, halogeno, trifluoromethyl, cyano, (1-6C)alkyl and (3-6C)alkoxy; and R3, R2, Q2, p and q have any of the meanings defined in this section relating to particular novel compounds of the invention;
(e) Q1 is furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,
5 pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl,
benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl or naphthyridinyl which bears 1 or 2 basic substituents selected from those defined in paragraph (c) or (d) immediately hereinbefore and optionally bears 1 further substituent selected from those defined in paragraph (c) or (d) immediately
10 hereinbefore; and R3, R2, Q2, p and q have any of the meanings defined in this section relating to particular novel compounds of the invention;
(f) Q1 is 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-oxazolyI, 3-, 4- or 5-isoxazolyl,
2-y 4- or 5-imidazolyl, 3- or 4-pyrazolyl, 2-, 4- or 5-thiazoIyl, 3-, 4- or 5-isothiazolyl,
2~, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl,
15 2-, 3-, 5- or 6-benzofiiranyl, 2-, 3-, 5- or 6-indolyl, 2-. 3-, 5- or 6-benzothienyl, 2-, 5- or 6-benzoxazolyI, 2-, 5- or 6-benzimidazoIyl, 2-, 5- or 6-benzothiazolyI, 3-. 5- or 6-indazolyL 5-benzofurazanyl, 2-. 3-. 6- or 7-ouinolyl. 3-, 6- or 7-iscqi:inoly!, 2-, 6- or 7-quinazolinyl, 2-, 6- or 7-quinoxalinyl, l,S-naphthyridin-2-yl or 1,8-naphthyridin-3-yl which bears 1 or 2 basic substituents selected from those defined in
20 paragraph (c) or (d) immediately hereinbefore and optionally bears 1 further substituent
selected from those defined in paragraph (c) or (d) immediately hereinbefore; and R\ R2, Q2, p and q have any of the meanings defined in this section relating to particular novel compounds of the invention;
(g) Q1 is 2-, 3- or 4-pyridyl which bears 1 basic substituent selected from those defined in
25 paragraph (c) or (d) immediately hereinbefore and optionally bears 1 further substituent
selected from those defined in paragraph (c) or (d) immediately hereinbefore; and R3, R2, Q2, p and q have any of the meanings defined in this section relating to particular novel compounds of the invention;
(h) p is 0; and Q1, R3, Q2 and q have any of the meanings defined in this section relating to 30 particular novel compounds of the invention;

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(i) q is 0, and Q1, R\ R2, Q2 and m have any of the meanings defined in this section relating to particular novel compounds of the invention;
(i) Q2 is aryl or a heteroaromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen
5 and sulphur which optionally bears J or 2 basic substituents selected from amino, (]-6C)alkylamino, di-[(l-6C)alkyl]amino, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(I-6C)alkyl]amino-(l-6C)alkyl,amino-(2-6C)alkoxy,(1-6C)alkylamino-(2-6C)alkyoxy,
di-[(l-6C)alkyl]amino-(2-6C)alkoxy, amino-(2-6C)alkylamino5 (l-6C)alkylamino-(2-6C)alkylamino di-[(l -6C)alkyl]ammo-(2-6C)alkylamino, N-( 1 -6C)alkyl-amino-
10 (2-6C)alkylamino, N-(l-6C)alkyl-(l-6C)alkylamino-(2-6C)alkylamino, N-(l-6C)alkyl-di-[(l-6C)alkyl]amino-(2-6C)alkylamino, amino-(2-6C)alkanoylamino, (l-6C)alkylamino-(2-6C)alkanoylamino, di-[(l -6C)alkyl]amino-(2-6C)alkanoylamino, arylamino, N-(l-6C)alkyl-arylamino,aryl-(l-6C)alkylamino
heteroaryl, heteroaryl-(l-6C)alkyl, heteroaryloxy, heteroaryl-(l-6C)alkoxy] heteroarylamino,
15 N-(l-6C)alkyl-heteroarylamino, heteroaryl-(l-6C)a]kylamino) N-(]-6C)alkyl-heteroaryI-(l-6C)alkylamino, heterocyclyl, heterocyclyl-(l-6C)alkyl, heterocyclyloxy, heterocyclyl-(l-6C)alkoxy, heterocyclylamino, N-(l-6C)alky]-heterocyclylamino, heterocyclyl-(l-6C)a]kylamino and N-(l-6C)alkyl-heterocyclyl-(l-6C)alkylamino, and wherein any of the basic substituents on Q2 as defined hereinbefore which comprise a CH2 group which is
20 attached to 2 carbon atoms or a CH3 group which is attached to a carbon atom may optionally bear on each said CH2 or CH3 group a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and heterocyclyl, and wherein any aryl, heteroaryl or heterocyclyl group in a basic substituent on Q2 may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (I-6C)alkyl, (l-6C)alkoxy, (2-6C)alkanoyl,
25 amino, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, aryl and aryl-(l-6C)alkyl, and wherein Q2 may optionally bear 1 further substituent selected from hydroxy, halogeno, trifluoromethyl, cyano, (l-6C)alkyl and (l-6C)aIkoxy; and Q', R3, R2, p and q have any of the meanings defined in this section relating
30 to particular novel compounds of the invention;

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(j) Q3 is aryl or a heteroaromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur which optionally bears 1 basic substituent selected from amino, (l-6C)alky lamino, di-[(l-6C)alkyl]amino, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl,
5 di-[(l-6C)alkyl]amino-(l-6C)alkyl, amino-(2-6C)alkoxy, (l-6C)alkylamino-(2-6C)alkoxy, di-[(l-6C)alkyl]amino-(2-6C)alkoxy, amino-(2-6C)alkylamino, (l-6C)alkylamino-(2-6C)alkylamino)di4(l-6C)alkyl]arnino-(2-6C)alkylamino,N-(]-6C)alkyI-amino(2-6C)alkylamino, N-(l-6C)alkyl-(l-6C)alkylamino-(2-6C)alkylamino, N-(l-6C)alkyl-di-[(l-6C)alkyl]amino-(2-6C)alkylamino, amino-(2-6C)alkanoylamino, (l-6C)alkylamino-
10 (2-6C)alkanoylamino, di-[(l-6C)alkyl]amino-(2-6C)alkanoylamino, pyridyl, pyridyl-
(1 -6C)alky 1, pyridyloxy, pyridyl-(l -6C)alkoxy, pyridylamino, N-( 1 -6C)alkyl-pyridylamino, pyridyl-(l-6C)alkylamino, N-(l-6C)alkyl-pyridyl-(l-6C)alkylarnino, pyrroldinyl, piperidinyl, morpholinyl, piperazinyl, 4-(l-6C)alkylpiperazinyl, homopiperazinyl, 4-(l-6C)alkylhomopipera2inyl,pyrrolidinyl-(l-6C)alkyl, piperidinyl-(l-6C)alkyl)
15 morpholmyl-(l-6C)alkyl) piperazinyl-(l-6C)alkyl, 4-(l-6C)alkylpiperaminyl-(l-6C)alky], homopiperazinyl-(l-6C)alkyl, 4-(l-6C)alkylhomopiperazinyl-(l-6C)alkyl, pyrrolidinyloxy, piperidinyloxy, l-(l-6C)alkylpiperidinyloxy: pyrrolidinyl-(2-6C)alkoxy! piperidmyl-(2-6C)alkoxy, morpholinyl-(2-6C)aIkoxy, piperaziny]-(2-6C)alkoxy,
4-(]-6C)alkylpiperazinyl-(2-6C)alkoxy, pyrrolidinylamino, piperidinylamino, N-(l-6C)alkyl-20 pyrrolidinylamino, N-(l-6C)alkyl-piperidinylamino, pyrrolidinyl-(l-6C)alkylamino,
piperidiny l-( 1 -6C)alkylamino, morpholinyI-( 1 -6C)alkylamino, piperazinyl-( 1 -6C)alkylamino, 4-( 1 -6C)alkylpiperazinyl-( 1 -6C)alkylamino, N-( 1 -6C)alky 1-pyrrolidinyl-( 1 -6C)alkylamino, N-(l-6C)alkyl-piperidinyI-(l-6C)alkylamino, N-(1-6C)alkyl-morphoIiny(1-6C)alkylamino, N-(l-6C)alkyl-piperazinyl-(l-6C)alkylaminoandN-(l-6C)a!kyl-4-(l-6C)alkylpiperazinyl-
25 (l-6C)alkylamino, and wherein any of the basic substituents on Q2 as defined hereinbefore which comprise a CH2 group which is attached to 2 carbon atoms or a CH3 group which is attached to a carbon atom may optionally bear on each said CH2or CH3 group a substituent selected from hydroxy, amino, (l-6C)alkylamino and di-[(l-6C)alkyl]amino) and wherein any pyridyl or heterocyclyl group in a basic substituent on Q2 may optionally bear 1 or 2
30 substituents selected from hydroxy, (l-6C)alkyl, (l-6C)aIkoxy, (2-6C)alkanoyl, hydroxy-(1-6C)alkyl and benzyl, and wherein Q2 may optionally bear 1 further substituent selected

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from hydroxy, halogeno, trifluoromethyl, cyano, (l-6C)alkyl and (N6C)alkoxy; and Q1, R3, R2, p and q have any of the meanings defined in this section relating to particular novel compounds of the invention;
(1) Q2 is aryl or a heteroaromatic 5- or 6-membered monocyclic ring with up to five ring
5 heteroatoms selected from oxygen, nitrogen and sulphur which bears 1 basic substituent selected from amino, (l-6C)alkylamino, di-[(l-6C)alkyl]arnino, amino-(l -6C)alkyl, (l-6C)alkylaminO'(l-6C)alkyl]di-[(l-6C)alkyl]amino(l-6C)alkyl,amino-(2-6C)alkox7, (l-6C)alkylamino-(2-6C)alkoxy1di-[(l-6C)alkyl]amino-(2-6C)alkoxy, amino-(2-6C)alkylamino,(l-6C)alkylamino-(2-6C)alkylamino) di-[(l-6C)alkyl]amino-
10 (2-6C)alkylamino, N-(l-6C)alkyl-amino-(2-6C)alkylamino, N-(l-6C)a]kyl-(l-6C)alkylamino-(2-6C)alkylamino)N-(l-6C)alkyl-di-[(l-6C)alkyl]amino-(2-6C)alkylamino, amino-(2-6C)alkanoylamino)(l-6C)alkylamino-(2-6C)aIkanoylamino) di-[(l-6C)alkyl]amino-(2-6C)alkanoylamino, pyridyl, pyridyl-(l-6C)alkyl, pyridyloxy, pyridyl-(l-6C)alkoxy, pyridylamino, N-( 1 –6C)alkyl-pyridylamino, pyridyl-( 1 -6C)alkylamino, N-(] -6C)alkyl-
15 pyridyl-(l-6C)alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,
4-(l-6C)alkylpiperazinyl, homopiperazinyl, 4-(l-6C)alkylhomopiperazinyI) pyrrolidinyl-(l-6C)alkyLpiperidiny]-(]-6C)alkyl; morpho]iny!-(l-6C)alkyl, piperaziny]-(l-6C)alkyl; 4-(l-6C)alkylpiperazinyl-(l-6C)alkyl; homopiperazinyl-(]-6C)alkyl, 4-(l-6C)alkylhomopiperazinyl-(l-6C)alkyl, pyrrolidinyloxy, piperidinyloxy,
20 1 -(1 -6C)alkylpiperidinyloxy, pyrrolidinyl-(2-6C)alkoxy, piperidinyl-(2-6C)alkoxy,
morpholinyl-(2-6C)alkoxy, piperazinyl-(2-6C)alkoxy, 4-(l-6C)aIkyIpiperazinyl-(2-6C)aIkoxy, pyrrolidinylamino, piperidinylamino, N-(l-6C)alkyl-pyrrolidinyIamino, N-(l-6C)alkyl-piperidinylamino, pyrrolidinyl-( 1 -6C)alkylamino, piperidinyl-( 1 -6C)alkylamino, morpholinyl-
25 (l-6C)alkylamino, piperaziny]-(l-6C)alkylamino, 4-(l-6C)alkylpiperazinyI-(l-6C)alkylamino,
N-(I-6C)alkyl-pyrrolidinyl-(l-6C)alkylamino,N-(l-6C)alkyl-piperidinyl-(l-6C)alkylamino, N-( I -6C)alkyl-morphoIiny l-( I -6C)alkylamino, N-( 1 -6C)alkyl-piperazinyl-( 1 -6C)alkylamino and N-(l-6C)alkyl-4-(l-6C)alkylpiperazinyl-(l-6C)alkylamino, and wherein any of the basic
30 substituents on Q3 as defined hereinbefore which comprise a CH2 group which is attached to :2 .carbon atoms or a CH3 group which is attached to a carbon atom may optionally bear on

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each said CH2or CH3 group a substituent selected from hydroxy, amino, (l-6C)alkylamino and di-[(l-6C)alkyl]amino, and wherein any pyridyl or heterocyclyl group in a basic substituent on Q2 may optionally bear 1 or 2 substituents selected from hydroxy, (1 -6C)alkyl, (l-6C)alkoxy, (2-6C)alkanoyl, hydroxy-(l-6C)alkyland benzyl, and wherein Q2 may
5 optionally bear 1 further substituent selected from hydroxy, halogeno, trifluoromethyl, cyano, (l-6C)alkyl and (l-6C)alkoxy; and Q1, R3, R2, p and q have any of the meanings defined in this section relating to particular novel compounds of the invention;
(m) Q2 is fury!, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl,
10 benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl,
isoquinolyl, quinazolinyl, quinoxalinyl ornaphthyridinyl which bears 1 or 2 basic substituents selected from those defined in paragraph (j), (k) or (1) immediately hereinbefore and optionally bears 1 further substituent selected from those defined in paragraph (j), (k) or (1) immediately hereinbefore; and Q1, R3, R2, p and q have any of the meanings defined in this
15 section relating to particular novel compounds of the invention;
(n) Q2 is 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazoiyl, 2-, 4- or 5-imidazolyl, 3- or 4-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-. 4- or 5-isothiazolyl. 2-, 3- or 4-pyridyI, 3- or4-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 2-, 3-, 5- or 6-benzofuranyl, 2-, 3-, 5- or 6-indolyl, 2-, 3-, 5- or 6-benzothienyl,
20 2-, 5- or 6-benzoxazolyi, 2-, 5- or 6-benzimidazolyl, 2-, 5- or 6-benzothiazolyl,
3-, 5- or 6-indazolyl, 5-benzofurazanyI, 2-, 3-, 6- or 7-quinoIyl, 3-, 6- or 7-isoquinolyl, 2-, 6- or 7-quinazoIinyl, 2-, 6- or 7-quinoxalinyl, l,8-naphthyridin-2-yl or l,8-naphthyridin-3-yl which bears 1 or 2 basic substituents selected from those defined in paragraph (j), (k) or (1) immediately hereinbefore and optionally bears 1 further substituent
25 selected from those defined in paragraph (j), 00 or (1) immediately hereinbefore; and Q1, R3, R\ p and q have any of the meanings defined in this section relating to particular novel compounds of the invention; and
(o) Q2 is phenyl or 2-, 3- or 4-pyridyl which bears I basic substituent selected from those defined in paragraph (j), (k) or (1) immediately hereinbefore and optionally bears 1 further
30 substituent selected from those defined in paragraph (j), (k) or (J) immediately hereinbefore;

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and Q', R3, R", p and q have any of the meanings defined in this section relating to particular novel compounds of the invention;
A preferred compound of this aspect of the invention is an amide derivative of the Formula I
5 wherein R3 is methyl, ethyl, chloro orbromo; Q1 is 2-, 3- or4-pyridyl which bears 1 basic substituent selected from amino, methylamino, ethylamino, dimethylamino, diethylamino, methyiaminomethyl, ethylaminomethyl, dirnethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methyIaminoethoxy, 2-ethyIaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy,
10 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropyIamino, 2-amino-2-methylpropylamino, 4-aminobuty]amino, 3-methylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethyiamino} 3-dimethylaminopropylamino, 4-dimemylaminobutylamino,N-(2-dimethy]aminoethyl)-N-methylamino,
15 N-(3-dimethylaminopropyl)-N-methylamino, 4-pyridyI, 2-pyridylmethyl, 2-pyridylmethoxy, pyrrolidin-l-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yI, 4-acetylpiperazin-l-yl, homopiperazin-1-yl. 4-methylhomopiperazin-1-yl, pyrrolidin-I-ylmethyl, piperidinomethyl, morpholinometbyl, piperazin-l-ylmethyl, 4-methylpiperazin-1 -ylmethyl, 4-acetylpiperazin-1 -ylmethyl, 4-(2-hydroxyethyl)piperazin-
20 l-yl,piperidin-4-yioxy, I-methylpiperidin-4-yloxy, 2-pyrrolidin-l-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morphoIinopropoxy, 2-piperazin-l-yIethoxy, 3-piperazin-l-ylpropoxy, 2-(4-methylpiperazin-l-yI)ethoxy>3-(4-methyIpiperazin-l-yl)propoxy3 2-(4-acety]piperazin-l-yI)ethoxy, 3-(4-acetyIpiperazin-l-yl)propoxy, l-benzylpiperidin-4-ylamino, 2-pyrrolidin-
25 I-ylethyiamino, 3-pyrrolidin-l-ylpropylamino, 2-morpholinoethylamino,
3-morpholinopropylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 2-piperazin-1 -ylethylamino, 3-piperazin-1 -ylpropylamino, 2-(4-methylpiperazin-1 -yl)ethylamino, 3-(4-methylpiperazin-l-yl)propylamino, 2-(l-methylpyrrolidin-2-yl)ethylamino, 3-(l-methylpyrrolidin-2-yl)propyiaraino, 3-amino-2-hydroxypropoxy,
30 2-hydroxy-3-methyIaminopropoxy, 3-dimethyIamino-2-hydroxypropoxy, -r3.-amino-2-hydroxypropylamino, 2-hydroxy-3-melhylaminopropyIarninoJ 3-dimethyIamino-

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2-hydroxypropylamino, 3-|N-(3-dimethylarninopropy])-N-rnethylamino]-2-hydroxypropoxy) 2-hydroxy-3-pyrrolidin-1 -ylpropoxy, 2-hydroxy-3-piperidinopropoxy, 2-hydroxy-3-morpholinopropoxy, 2-hydroxy-3-pyrrolidin-l -ylpropylamino, 2-hydroxy-3-piperidinopropylamino, 2-hydroxy-3-morpholinopropylamino,
5 3-[N-(3-dimethyIaminopropyl)-N-rnethylarnino]-2-hydroxypropyIarnino, 2-aminoethylaminomethyl, 3-aminopropylaminomethyl, 2-methylaminoethylarninomethyl, 3-methylaminopropylarninornethyI, 2-dimethylaminoethylaminomethyl, 3-dimethylaminopropylaminomethy], 2-pyrrolidin-l-ylethyIaminomethyl, 3-pyrrolidin-l-ylpropylammomethyJ^-piperidinoethylaminomethyl, 3-piperidinopropylaminomethy],
10 2-morpholinoethylaminorriethyl, 3-morpholinopropylaminomethyl, 2-piperazin-1 -y lethylaminometbyl, 3-piperazin-l -y] propyl aminomethyl, 2-(4-methylpiperazin-l-y])ethylaminomethyl and 3-(4-memy]piperazin-l-yl)propyIaminomethyl, and wherein Q! may optionally bear 1 further substituent selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, methyl, ethyl, methoxy and ethoxy;
15 p is O; q is 0; and
Q2 is phenyl, 5-isoxazolyl or 3- or 4-pyridyl which optionally bears 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylamino. dimethylamino, aminomethyl, methylaminomethyl,
20 dimethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 3-methylaminopropoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 2-aminoethylamino, 3-aminopropylarnino, 4-aminobutyIamino, 3-methylaminopropylamino, 2-dimethylaminoethylamino, 3-dimethylaminopropylamino, 4-dimethyIaminobutylamino, N-(2-dimethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-N-methyIamino,
25 4-pyridyl, 2-pyridylmethoxy, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 4-methylpiperazin-l-yI, 4-ethylpiperazin-l-yl, 4-acetylpiperazin-l-yI, homopiperazin-I-yl, 4-methylhomopiperazin-l-yl, pyrrolidin-l-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-l-yJmethy], 2-pyrrolidin-l-ylethoxy, 3-pyrroIidin-l-y]propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy,
30 3-morpholinopropoxy, 2-piperazin-]-y]ethoxy, 3-piperazin-1-ylpropoxy, 2-(4"methyIpiperazin-l-yl)ethoxy, 3-(4-methyIpiperazin-l-yl)propoxy, 2-pyrrolidin-

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1 -ylethylamino, 3-pyrrolidin-l-ylpropylamino, 2-morpholinoelhylamino,
3-morpholinopropylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 2-piperazin-
1-ylethylamino, 3-piperazin-l-ylpropylamino, 2-(4-methylpiperazin-l-yl)ethylarnino and
3-(4-memylpiperazin-l-yl)propylamino;
5 or a pharmaceutically-acceptable salt thereof.
A further preferred compound of this aspect of the invention is an amide derivative of
the Formula 1
wherein R3 is methyl or chloro;
Q1 is 3-pyridyl or 4-pyridyl which bears a substituent selected from 2-aminoethylamino,
10 3-aminopropylamino, 2-amino-2-methylpropylamino, 4-aminobutylamino,
3-methylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino,
3-dimethylaminopropylamino, 4-dimethylaminobutylamino, N-(2-dimethylaminoethyI)-
N-methylamino, N-(3-dimethy]aminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino,
piperidino, piperazin-l-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl,
15 4-(2-hydroxyethyl)piperazin-l-yl, 4-methylhomopiperazin-l-yl, l-benzylpiperidin-4-ylamino, 2-pyrrolidin-lylethylamino, 3-pyrrolidin-l ylpropylamino, 2-morpholino ethyl amino, 3-rnorpholinopropylamino, 2-piperidinoethylamir.o. 3-piperidinopropylamino, 2-piperazin-1-ylethylamino, 3-piperazin-l-ylpropylamino, 2-(4-methylpiperazin-l-yl)ethylamino, 3-(4-methyIpiperazin-1 -yl)propylamino, 2-( 1 -methylpyrrolidin-2-yl)ethylamino,
20 3-(l-methyIpyrrolidin-2-yl)propylamino or 3-amino-2-hydroxypropylamino; pisO; q is 0; and
Q2 is phenyl, 5-isoxazolyl, 3-pyridyl or 4-pyridyl which optionally bears 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoro methyl, cyano, amino, methyl, ethyl, methoxy,
25 ethoxy, methylamino. dimethylamino, pyrrolidin-l-yl, morpholino, piperidino, piperazin-l-yl or 4-methylpiperazin-l-yl; or a pharmaceutically-acceptable salt thereof.
A further preferred compound of this aspect of the invention is an amide derivative of the Formula I
30 wherein R3 is methyl or chloro;
'Ql is 3-pyridyl or 4-pyridyl which bears a substituent selected from 2-aminoethylamino,

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3-aminopropylamino, 2-amino-2-methylpropylamino, 4-aminobutylamino, 3-methylaminopropylamino, 2-dimethylarninoethylamino, 2-diethylaminoethylamino, 3-dimethyIaminopropylamino, 4-dimethylaminobutylamino, N-(2-dimethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropy])-N-methylamino, pyrrolidin-1-yl, morpholino,
5 piperidino, piperazin-1 -yl, 4-methyIpiperazin-1 -yl, 4-ethylpiperazin-1 -yl, 4-(2-hydroxyethyl)piperazin-1 -yl, 4-methylhomopiperazin-1 -yl, 1 -benzylpiperidin-4-ylamino, 2-pyrrolidin-lylethylarnino, 3-pyrrolidin-lylpropylamino, 2-morphoIinoethylamino, 3-morphoIinopropylamino, 2-piperidinoethyIamino, 3-piperidinopropylamino, 2-piperazin-l-ylethylamino, 3-piperazin-l-ylpropylamino, 2-(4-methylpiperazin-l-yl)ethylamino,
10 3-(4-methylpiperazin-l-yl)propylamino, 2-(l-methylpyrrolidin-2-yl)ethylamino, ' 3-(l-methylpyrrolidin-2-yI)propyIaminoor3-amino-2-hydroxypropylamino; p is 0; qis 0; and
Q2 is phenyl or 4-pyridyl which bears a substituent selected from pyrrolidin-1-yl, morpholino 15 and piperidino;
or a pharmaceutically-acceptable salt thereof.
A further preferred compound of this aspect of the invention is an amide derivative of the Formula I
wherein R3 is methyl or chloro;
20 Q1 is 3-pyridyI or 4-pyridyl which bears a substituent selected from 2-aminoethyiamino, 3-aminopropylamino, 2-ammo-2-methyIpropyiarnino, 4-aminobutylamino, 3-methylaminopropylamino, 2-dimethyIaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 4-dimethylaminobutylamino, N-(2-dimethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino,
25 piperidino, piperazin- 1-yl, 4-methyIpiperazin-l-yl, 4-ethylpiperazin-1-yl,
4-(2-hydroxyethyl)piperazin-l-yl, homopiperazin-1-yl, 4-methylhomopiperazin-l-yl, 1 -benzylpiperidin-4-ylamino, 2-pynolidin-lyIethylamino, 3-pyrrolidin-lylpropylamino, 2-morpholinoethylamino, 3-morpholinopropyIamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 2-piperazin-l-yIethylamino, 3-piperazin-l-ylpropylamino,
30 2-(4-methyIpiperazin-1 -yl)ethylamino, 3-(4-methylpiperazin-1 -yl)propylamino,
2-(l-methylpyrrolidin-2-yl)ethylarnino, 3-(l-methyIpyrrolidin-2-yl)propylamino or 3-amino-

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2-hydroxypropylamino;
p is 0;
q is 0; and
Q2 is phenyl or 4-pyridyl which bears a substituent selected from pyrrolidin-1-yl, morpholino 5 and piperidino and which optionally bears a further substituent selected from fluoro and
trifluoromethyl;
or a pharmaceutically-acceptable salt thereof.
A further more preferred compound of this aspect of the invention is an amide
derivative of the Formula I
10 wherein R3 is methyl;
Ql is 3-pyridyl or 4-pyridyl which bears a substituent selected from 2-aminoethylamino,
3-aminopropylamino, 2-amino-2-methylpropylamino, 4-aminobutylamino,
2-dimethylaminoethylamino, 2-diethylaminoethyIarnino, 3-dimethylaminopropylamino,
4-dimethylaminobutylamino)N-(2-dimethylaminoemyl)-N-methylamino) 15 N-(3-dimethylaminopropyl)-N-methyIamino) 4-methylpiperazin-l-yl,
4-(2-hydroxyethyl)piperazin-l-yl, 3-morpholinopropylamino or 2-(l-methylpyrrolidin-
2-yl)ethylamino;
pisO;
q is 0; and 20 Q2 is 2-morpholinopyrid-4-yl;
or a pharmaceutically-acceptable salt thereof.
A further more preferred compound of this aspect of the invention is an amide
derivative of the Formula I
wherein R3 is methyl or chloro;
25 Q' is 3-pyridyl or 4-pyridyl which bears a substituent selected from 2-aminoethylamino,
3-aminopropylamino, 2-arnino-2-methylpropylamino, 4-aminobutylamino,
2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino,
4-dimethyIaminobutylamino)N-(2-dimethyIaminoethyl)-N-methylammo,
N-(3-dimemylarninopropyl)-N-methylamino,homopiperazin-l-yl, 4-methylpiperazin-l-yl,
30 4-ethylpiperazin-l-yl, 4-(2-hydroxyethyl)piperazin-l-yI, 3-morpholinopropylamino or
2-( 1 -methy IpyrroIidin-2-y l)ethylamino;

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p is 0; q is 0; and
Q2 is 2-morpho!inopyrid-4-yl, 3-fluoro-5-morphoIinophenyl or 3-morpholino-5-trifluoromethylphenyl;
5 or a pharmaceutically-acceptable salt thereof.
A particular preferred compound of these farther aspects of the invention is, for example :-
6-|N-(2-dimethylaminoethyl)-N-methylarnino]-N-[2-methyI-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-3-carboxamide,
10 6-(2-amino-2-methyIpropylamino)-N-[2-methyl-5-(2-morphoHnopyrid-4-yIcarbonylamino)phenyI]pyridine-3-carboxamide, 6-(2-diethylaminoethylamino)-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)pheny]]pyridine-3-carboxamide3 6-(3-dimethyIaminopropylamino)-N-[2-methyl-5-(2-morpholinopyrid-
15 4-ylcarbonylamino)phenyl]pyridine-3-carboxamide,
6-[2-(I-methylpyrrolidin-2-yl)ethylamino]-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-3-carboxamide, 6-(3-morpholinopropyIamino)-N-[2-methyl-5-(2-mcrpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-3-carboxamide,
20 6-(4-dimethylaminobutylamino)-N-[2-methyl-5-(2-morpholmopyrid-4-ylcarbonyIamino)phenyl]pyridine-3-carboxamide,
2-(4-memylpipera2m-l-yI)-N-[2-methyl-5-(2-morphoIinopyrid-4-ylcarbonylamino)phenyl]-pyridine-4-carboxamide .or
2-[4-(2-hydroxyethyl)piperazin-l-yl]-N-[2-methyl-5-(2-morpholinopyrid-
25 4-ylcarbonylamino)phenyl]pyridine-4-carboxamide; or a pharmaceutically-acceptable salt thereof.
A further particular preferred compound of these further aspects of the invention is, for example :-
6-(3-moipholinopropylamino)-N-[2-memyl-5-(3-iluoro-5-moipholinobeiizarnJdo)phenyl]-
30 pyridine-3-carboxamide,
6-(4-methylpiperazin-l-yl)-N-[2-methyl-5-(3-iluoro-5-morpholinoberizamido)phenyl]-

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pyridine-3-carboxamide,
6-(4-ethylpiperazin-l-yl)-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-pyridine-3 -carboxamide,
N-[2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-2-(4-methylpiperazin-
5 1 -yl)pyridine-4-carboxamide or N-[2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-2-[4-(2-hydroxyethyl)piperazin-l-yl]pyridine-4-carboxamide; or a pharmaceutically-acceptable salt thereof.
An amide derivative of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-
10 cleavable ester thereof, may be prepared by any process known to be applicable to the
preparation of chemically-related compounds. Such processes, when used to prepare a novel amide derivative of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated, Q1, R2, R3, p, q and Q2 have any of the meanings defined hereinbefore. Necessary starting
15 materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.

with an acid of the Formula III, or a reactive derivative thereof,
20 (a) A compound of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, may be prepared by reacting an aniline of the Formula II

25 under standard amide bond forming conditions, wherein variable groups are as defined hereinbefore and wherein any functional group is protected if necessary, and: (i) removing any protecting groups; and

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(ii) optionally forming a pharmaceutically-acceptable salt or in-vivo-cleavable
ester. A suitable activated derivative of an acid of the Formula III is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid
5 chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol, an ester such as pentafluorophenyl trifluoroacetate or an alcohol such as N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the
10 acid and an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbodiimide such as dicyclohexylcarbodiimide.
" The reaction is preferably carried out in the presence of a suitable base such as, for
example, an alkali or alkaline earth metal carbonate, alkoxide, hydroxide or hydride, for
15 example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide,
sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an
organometallic base such as an alkyl-lithium, for example n-butyl-!ithium, or a
dialkylamino-lithium, for example lithium di-isopropylamide, or, for example, an organic
amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,
20 triethylamine, morpholine or diazabicyclo[5.4.0]undec-7-ene. The reaction is also preferably
carried out in a suitable inert solvent or diluent, for example tetrahydrofuran, methylene
chloride, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethyIacetamide,
N-methylpyrroIidin-2-one, dimethylsulphoxide or acetone, and at a temperature in the range,
for example, -78 to 150°C, conveniently at or near ambient temperature.
25 Typically a carbodiimide coupling reagent is used in the presence of an organic
solvent (preferably an anhydrous polar aprotic organic solvent) at a non-extreme temperature, for example in the region -10 to 40°C, typically at ambient temperature of about 20°C.
Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in
30 question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as

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appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
Specific examples of protecting groups are given below for the sake of convenience, in
5 which "lower", as in, for example, lower alkyl, signifies that the group to which it is applied
preferably has 1 -4 carbon atoms. It will be understood that these examples are not exhaustive.
Where specific examples of methods for the removal of protecting groups are given below
these are similarly not exhaustive. The use of protecting groups and methods of deprotection
not specifically mentioned is of course within the scope of the invention.
10 A carboxy protecting group may be the residue of an ester-forming aliphatic or
arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (for example isopropyl, tert-butyl); lower alkoxy lower alkyl groups (for example methoxymethyl, ethoxymethyl, isobutoxymethyl); lower aliphatic
15 acyloxy lower alkyl groups, (for example acetoxymethy], propionyloxymethyl,
butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (for example 1-methoxycarbonylbxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (for example benzyl, p-methoxybenzyl, o-nitrobenzyl, p.-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyl and
20 tert-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (for example
trimethylsilylethyl); and (2-6C)alkenyl groups (for example allyl and vinylethyl). Methods particularly appropriate for the removal of carboxy 1 protecting groups include for example acid-, base-, metal- or enzymically-catalysed hydrolysis.
Examples of hydroxy protecting groups include lower alkyl groups
25 (for example tert-butyl). lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for example benzoyloxycarbonyI, r>rnethoxybenzyloxycarbonyI, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri lower alkylsilyl (for example trimethylsilyl,
30 tert-butyldimethylsilyl) and aryl lower alkyl (for example benzyl) groups.

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Examples of amino protecting groups include formyl, aralkyl groups (for example benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-rj-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl
5 lower alkoxycarbonyl groups (for example benzyloxycarbonyl, p-methoxy benzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example methylidene); benzylidene and substituted benzylidene groups.
Methods appropriate for removal of hydroxy and amino protecting groups include, for
10 example, acid-, base-, rrietal- or enzymically-catalysed hydrolysis for groups such as p-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as o-nitrobenzyloxycarbonyl.
The reader is referred to Advanced Organic Chemistry, 4th Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and
15 reagents. The reader is referred to Protective Groups in Organic Synthesis, 2nd Edition, by Green et al, published by John Wiley & Sons for general guidance on protecting groups. The aniline of Formula II may be prepared by reduction of the corresponding nitro compound of Formula IV.

20 Typical reaction conditions include the use of ammonium formate in the presence of a
catalyst (for example palladium-on-carbon) in the presence of an organic solvent (preferably a polar protic solvent), preferably with heating, for example to about 60°C. Any functional groups are protected and deprotected as necessary.
The nitrobenzene of Formula IV may be prepared by the reaction of a benzoic acid of
25 Formula V, or an activated derivative thereof as defined hereinbefore,



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with an aniline of Formula VI
under suitable amide bond forming conditions as defined hereinbefore.
Typical conditions include activating the carboxy group of the compound of
5 Formula V, for example by treatment with a halo reagent (for example oxalyl chloride) to form an acyl halide in an organic solvent at ambient temperature and then reacting the activated compound with the aniline of Formula VI. Any functional groups are protected and deprotected as necessary.
with an aniline of the Formula VII
(b) - A compound of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-
10 cleavable ester thereof, may be prepared by reacting an acid of the Formula V, or an activated derivative thereof as defined hereinbefore,


15 under standard amide bond forming conditions as defined hereinbefore, wherein variable groups are as defined hereinbefore and wherein any functional group is protected, if necessary, and:
(i) removing any protecting groups;
(ii) optionally forming a pharmaceutically-acceptable salt or in-vivo-cleavable
20 ester.

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The aniline of Formula VII may be prepared by reduction of the corresponding nitro compound using convention procedures as defined hereinbefore or as illustrated in the Examples.
(c) A compound of the Formula I wherein a substituent on Q1 or Q2 is
5 (l-6C)alkoxy or substituted (I -6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylamino,
di-[(l-6C)alkyl]amino or substituted (l-6C)alkylamino, may be prepared by the alkylation,
conveniently in the presence of a suitable base as defined hereinbefore, of an amide derivative
of the Formula I wherein a substituent on Q1 or Q2 is hydroxy, mercapto or amino as
appropriate.
10 * The reaction is preferably carried out in the presence of a suitable inert solvent or
diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyIpyrrolidin-2-one or dimethylsulphoxide. The reaction is
15 conveniently carried out at a temperature in the range, for example, 10 to 150°C, preferably in the range 20 to 80°C.
A suitable alkylating agent is, for example, any agent known in the art for the alkylation of hydroxy to alkoxy or substituted alkoxy, or for the alkylation of mercapto to alkylthio, or for the alkylation of amino to alkylamino or substituted alkylamino, for example
20 an alkyl or substituted alky 1 halide, for example a (1 -6C)alkyl chloride, bromide or iodide or a substituted (l-6C)alkyl chloride, bromide or iodide, in the presence of a suitable base as defined hereinbefore, in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 140°C, conveniently at or near ambient temperature.
25 (d) A compound of the Formula I wherein a substituent on Q1 or Q2 is
(I-6C)alkanoylamino or substituted (2-6C)alkanoylamino may be prepared by the acylation of a compound of the Formula I wherein a substituent on Q( or Q2 is amino.
A suitable acylating agent is, for example, any agent known in the art for the acylation of amino to acylamino, for example an acyl halide, for example a (!-6C)aIkanoyl chloride or
30 bromide, conveniently in the presence of a suitable base, as defined hereinbefore, an alkanoic acid anhydride or mixed anhydride, for example a (1 -6C)alkanoic acid anhydride such as

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acetic anhydride or the mixed anhydride formed by the reaction of an alkanoic acid and a (l-6C)alkoxycarbonyl halide, for example a (1-6C)alkoxycarbonyl chloride, in the presence of a suitable base as defined hereinbefore. In general the acylation is carried out in a suitable inert solvent or diluent as defined hereinbefore and at a temperature, in the range, for example,
5 -30 to 120°C, conveniently at or near ambient temperature.
(e) A compound of the Formula I wherein a substituent on Q1 or Q2 is
(l-6C)alkanesulphonylamino may be prepared by the reaction of a compound of the Formula I
wherein a substituent on Q1 or Q2 is amino with a (1 -6C)alkanesulphonic acid, or an activated
derivative thereof.
10 A suitable activated derivative of a (l-6C)alkanesulphonic acid is, for example, an
alkanesulphonyl halide, for example an alkanesulphonyl chloride formed by the reaction of the sulphonic acid and an inorganic acid chloride, for example thionyl chloride. The reaction is preferably carried out in the presence of a suitable base as defined hereinbefore, particularly pyridine, and in a suitable inert solvent or diluent as defined hereinbefore, particularly
15 methylene chloride.
(f) A compound of the Formula I wherein a substituent on Q1 or Q2 is carboxy, carboxy-
(l-6C)alkyl, carboxy-(l-6C)alkoxy, carboxy-(l-6C)aIkyIamino, N-(l-6C)alkyl-carboxy-
(l-6C)alkylamino or carboxy-(2-6C)alkanoylarnino may be prepared by the cleavage of a
compound of the Formula I wherein a substituent on Q1 or Q2 is (l-6C)alkoxycarbonyI,
20 (1 -6C)alkoxycarbony!-(l-6C)alkyl, (I -6C)alkoxycarbonyl-(l -6C)alkoxy,
(l-6C)alkoxycarbonyl-(l-6C)alkylamino, N-(l-6C)alkyl-(l-6C)alkoxycarbonyl-(l-6C)alkylamino or (l-6C)alkoxycarbonyl-(2-6C)alkanoyIamino as appropriate.
The cleavage reaction may conveniently be carried out by any of the many procedures known in the art for such a transformation. The reaction may be carried out, for example, by
25 hydrolysis under acidic or basic conditions. A suitable base is, for example, an alkali metal, alkaline earth metal or ammonium carbonate or hydroxide, for example sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or ammonium hydroxide. The reaction is preferably carried out in the presence of water and a suitable solvent or diluent such as methanol or ethanol. The reaction is conveniently carried out at a temperature in the
30 range 10 to 150°C, preferably at or near ambient temperature.

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(f) A compound of the Formula I wherein a substituent on Q1 or Q2 is amino, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, substituted (l-6C)alkylamino, substituted N-(l-6C)alkyl-(l-6C)alkylamino or a N-linked heterocyclyl group may be prepared by the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of an amide
5 derivative of the Formula 1 wherein a substituent on Q' or Q2 is a suitable leaving group with an appropriate amine or a N-containing heterocycle.
A suitable. N-containing heterocycle is, for example, pyrrolidine, morpholine, piperidine, piperazine, homopiperazine or a 4-(l-6C)alkylpiperazine.
A suitable leaving group is, for example, a halogeno group such as fluoro, chloro or
10 bromo, a (l-6C)alkanesulphonyloxy group such as methanesulphonyloxy or an arylsulphonyloxy group such as 4-toIuenesulphonyloxy.
The reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range, for example, 20 to 200°C, conveniently in the range 75 to 150°C.
15
The following biological assays and Examples serve to illustrate the present invention. Biological Assays
The following assays can be used to measure the p38 kinase-inhibitory, the TNF-inhibitory and anti-arthritic effects of the compounds of the present invention:
20 In vitro enzyme assay
The ability of compounds of the invention to inhibit the enzyme p38 kinase was assessed. Activity of test compounds against each of the p38ct and p38p isoforms of the enzyme was determined.
Human recombinant MKJC6 (GenBank Accesion Number G1209672) was isolated
25 from Image clone 45578 (Genomics, 1996, 33, 151) and utilised to produce protein in the form of a GST fusion protein in a pGEX vector using analogous procedures to those disclosed by J. Han el ah, Journal of Biological Chemistry, 1996, 271,2886-2891. p38a (GenBank Accession Number G529039) and p38p (GenBank Accession Number G1469305) were isolated by PCR amplification of human lymphoblastoid cDNA (GenBank Accession Number
30 GM1416) and human foetal brain cDNA [synthesised from mRNA (Clontech, catalogue no. 6525-1) using a Gibco superscript cDNA synthesis kit] respectively using

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oligonucleotides designed for the 5' and 3' ends of the human p38a and p38p genes using
analogous procedures to those described by J. Han et al., Biochimica et Biophysica Acta,
1995, 1265, 224-227 and Y. Jiang et al. Journal of Biological Chemistry. 1996,27i, 17920-
17926.
5 Both p38 protein isoforms were expressed in e coli in PET vectors. Human
recombinant p38a and p38p isoforms were produced as 5' c-myc, 6His tagged proteins. Both
MKK6 and the p38 proteins were purified using standard protocols: the GST MKK6 was
purified using a glutathione sepharose column and the p38 proteins were purified using nickel
chelate columns.
10 The p38 enzymes were activated prior to use by incubation with MKK6 for 3 hours at
30°C. The unactivated coli-expressed MKK6 retained sufficient activity to fully activate both isoforms of p38. The activation incubate comprised p38a (10u.I of l0mg/ml) orp38p (l0μl of 5mg/ml) together with MKK6 (l0μl of lmg/ml), 'Kinase buffer' [100μl; pH 7.4 buffer comprising Tris (50mM), EGTA (O.lmM), sodium orthovanadate (O.lmM) and
15 β-mercaptoethanol (0.1%)] and MgATP (30μ1 of 50mM Mg(OCOCH3)2 and 0.5mM ATP). This produced enough activated p38 enzyme for 3 Microliter plates.
Test compounds were solubilised in DMSO and l0uiofa 1:10 diluted sample in 'Kinase Buffer' was added to a well in a Microtiter plate. For single dose testing, the compounds were tested at 10u-M. 'Kinase Assay Mix' [30ul; comprising Myelin Basic
20 Protein (Gibco BRL cat. no. 1322B-010; 1ml of a 3.33mg/ml solution in water), activated p38 enzyme (50μl) and 'Kinase Buffer' (2ml)] was then added followed by 'Labelled ATP' [10μl; comprising 50uM ATP, 0.1u.Ci 33P ATP (Amersham International cat. no. BF1000) and 50mM Mg(OCOCH3)J. The plates were incubated at room temperature with gentle agitation. Plates containing p38a were incubated for 90min and plates containing p38P were incubated
25 for 45min. Incubation was stopped by the addition of 50uJ of 20% trichloroacetic acid
(TCA). The precipitated protein was phosphorylated by p38 kinase and test compounds were assessed for their ability to inhibit this phosphorylation. The plates were filtered using a Canberra Packard Unifilter and washed with 2% TCA, dried overnight and counted on a Top Count scintillation counter.
30 Test compounds were tested initially at a single dose and active compounds were
retested to allow IC50 values to be determined.

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In vitro cell-based assays
(i) PBMC
The ability of compounds of this invention to inhibit TNFa production was assessed by using human peripheral blood mononuclear cells which synthesise and secrete TNFa when
5 stimulated with lipopolysaccharide.
Peripheral blood mononuclear cells (PBMC) were isolated from heparinised (l0units/ml heparin) human blood by density centrifugation (Lymphoprep™ ; Nycomed). Mononuclear cells were resuspended in culture medium [RPMI 1640 medium (Gibco) supplemented with 50 units/ml penicillin, 50ug/ml streptomycin, 2mM glutamine and 1%
10 heat-inactivated human AB serum (Sigma H-1513)]. Compounds were solubilised in DMSO at a concentration of 50mM, diluted 1:100 in culture medium and subsequently serial dilutions were made in culture medium containing 1% DMSO. PBMCs (2.4xl05 cells in 160ul culture medium) were incubated with 20u.l of varying concentrations of test compound (triplicate cultures) or 20pil culture medium containing 1% DMSO (control wells) for 30
15 minutes at 37°C in a humidified (5%C02/95% air) incubator (Falcon 3072 ; 96 well flat-bottom tissue culture plates). 20ul lipopolysaccharide [LPS E.Coli 0111 :B4 (Sigma L-4130), final concentration l0μg/ml] solubilised m culture medium was added to appropriate wells. 20μl culture medium was added to "medium alone" control wells. Six "LPS alone" and four "medium alone" controls were included on each 96 well plate. Varying concentrations of a
20 known TNFa inhibitor were included in each test, i.e. an inhibitor of the PDE Type IV enzyme (for example see Semmler, J. Wachtel. H. and Endres, S., Int. J. Immunopharmac. (1993), 15(3), 409-413) or an inhibitor of proTNFa convertase (for example, see McGeehan, G. M. et al. Nature (1994) 370, 558-561). Plates were incubated for 7 hours at 37°C (humidified incubator) after which l00μl of the supernatant was removed
25 from each well and stored at -70°C (96 well round-bottom plates; Coming 25850). TNFa levels were determined in each sample using a human TNFa ELISA (see W092/10190 and Current Protocols in Molecular Biology, vol 2 by Frederick M. Ausbel et al., John Wiley and Sons Inc.).
% inhibition = (LPS alone - medium alone) - (test concentration - medium alonel x JQQ
30 (LPS atone - medium alone)

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(ii) Human Whole Blood
The ability of the compounds of this invention to inhibit TNFα production was also assessed in a human whole blood assay. Human whole blood secretes TNFα when stimulated with LPS. This property of blood forms the basis of an assay which is used as a secondary
5 test for compounds which profile as active in the PBMC test.
Heparinised (10 units/ml) human blood was obtained from volunteers. 160jil whole blood were added to 96 well round-bottom plates (Corning 25850). Compounds were solubilised and serially diluted in RPMI 1640 medium (Gibco) supplemented with 50 units/ml penicillin, 50jig/ml streptomycin and 2mM glutamine, as detailed above. 20uJ of each test
10 concentration was added to appropriate wells (triplicate cultures). 20u.l of RPMI 1640
medium supplemented with antibiotics and glutamine was added to control wells. Plates were incubated for 30 minutes at 37°C (humidified incubator), prior to addition of 20|il LPS (final concentration I0|ig/ml). RPMI 1640 medium was added to control wells. Six "LPS alone" and four "medium alone" controls were included on each plate. A known TNFα
15 synthesis/secretion inhibitor was included in each test. Plates were incubated for 6 hours at 37°C (humidified incubator). Plates were centrifuged (2000rpm for 10 minutes) and l00μl plasma removed and stored at -70°C (Corning 25850 plates). TNFα levels were measured by ELISA (see W092/10190 and Current Protocols in Molecular Biology, vol 2 by Frederick M. Ausbel et al, John Wiley and Sons Inc.). The paired antibodies that were used in the
20 ELIZA were obtained from R&D Systems (catalogue nos. MAB610 anti-human TNFα coating antibody, B AF210 biotinylated anti-human TNFα detect antibody).
Ex vivo / In vivo assessment
The ability of the compounds of this invention as ex vivo TNFa inhibitors were
25 assessed in the rat or mouse. Briefly, groups of male Wistar Alderley Park (AP) rats
(180-210g) were dosed with compound (6 rats) or drug vehicle (10 rats) by the appropriate route, for example peroral (p.o.), intraperitoneal (i.p.) or subcutaneous (s.c). Ninety minutes later rats were sacrificed using a rising concentration of CO2 and bled out via the posterior
vena cavae into 5 Units of sodium heparin/ml blood. Blood samples were immediately placed
30 on ice and centrifuged at 2000 rpm for 10 min at 4°C and the harvested plasmas frozen at -20°C for subsequent assay of their effect on TNFα production by LPS-stimulated human

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blood. The rat plasma samples were thawed and 175ul of each sample was added to a set format pattern in a 96 well round bottom plate (Coming 25850). 50jil of heparinized human blood was then added to each well, mixed and the plate was incubated for 30 min at 37°C (humidified incubator). LPS (25 μl; final concentration l0μg/ml) was added to the wells and
5 incubation continued for a further 5.5 hours. Control wells were incubated with 25ul of medium alone. Plates were then centrifiiged for 10 min at 2000 rpm and 200jil of the supematants were, transferred to a 96 well plate and frozen at -20°C for subsequent analysis of TNF concentration by ELISA.
Data analysis by dedicated software calculates for each compound/dose:
10 % inhibition of TNFα = Mean TNFα (Controls) - Mean TNFa (Treated) x 100
Mean TNFa (Controls) Alternatively, mice could be used instead of rats in the above procedure.
Test as anti-arthritic agent
15 Activity of a compound as an anti-arthritic agent was tested as follows. Acid soluble
native type II collagen was shown by Trentham et al [1] to be arthritogenic in rats; it caused polyarthritis when administered in Freunds incomplete adjuvant. This is now known as collagen-induced arthritis (CIA) and similar conditions can be induced in mice and primates. Recent studies have shown that anti-TNF monoclonal antibodies [2] and TNF receptor-IgG
20 fusion proteins [3] ameliorate established CIA indicating that TNF plays a key role in the pathophysiology of CIA. Moreover, the remarkable efficacy reported for anti-TNF monoclonal antibodies in recent rheumatoid arthritis clinical trials indicates that TNF plays a major role in this chronic inflammatory disease. Thus CIA in DBA/1 mice as described in references 2 and 3 is a tertiary model which can be used to demonstrate the anti-arthritic
25 activity of a compound. Also see reference 4.
1. Trentham, D.E. et al„ (1977) J. Exp. Med., 146, 857.
2. Williams, R.O. et al, (1992) Proc. Natl. Acad. ScL 89, 9784.
3. Williams, R.O. et al, H995i Immunology. 84. 433.
4 Badger, M. B. et al, (1996) The Journal of Pharmacology and Experimental Therapeutics
30 279, 1453-1461.

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Although the pharmacological properties of the compounds of the Formula I vary with structural change as expected, in general a compound of the Formula I gives over 30% inhibition of p38a and/or p38p at concentrations up to 30uM and over 30% inhibition in the PBMC test at concentrations up to 50pM. No physiologically unacceptable toxicity was
5 observed at the effective dose for compounds tested of the present invention. By way of example, 6-chloro-N-[5-(3-dimethylaminobenzamido)-2-methylphenyI]pyridine-3-carboxamide [Example 1] has an IC50 of approximately lμM against p38ct and an IC50 of approximately 9JJ.M in the PBMC test; N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]benzothiazole-6-carboxamide 1 o [Example 8, Compound No. 2] has an ICS0 of approximately 0.1 uM against p3 8a and an ICf 0 of approximately 5uM in the PBMC test;
N-[2-chloro-5-(4-cyanoben2amido)phenyl]quinoline-6-carboxamide [Example 10] has an IC50 of approximately 0.05pM against p38ct and an IC50 of approximately 2uM in the PBMC test and N-[5-(5-isoxa2olylcarbonylamino)-2-methylphenyl]quinoline-6-carboxamide
15 [Example 14] has an iC50 of approximately 0.1 pM against p38a and an IC50 of approximately 3uM in the PBMC test.
As disclosed hereinbefore, a further aspect of the present invention concerns compounds of the Formula I wherein Q1 is substituted by a basic substituent selected from the substituents for Q1 denned hereinbefore and Q2 is a phenyl or heteroaryl group as defined
20 hereinbefore which also bears a basic substituent selected from the substituents for Q2 defined hereinbefore, which compounds possess improved TNFα inhibitory potency in one or both of the PBMC and HWB tests. By way of example,
6-[2-(l-memylpyrrolidin-2-yl)emyIamino]-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyI]pyridine-3-carboxamide [Example 22(18)] has an IC50 of
25 approximately 0.05uM against p38a, an IC50 of approximately 0.3|iM in the PBMC test and an IC50 of approximately 2uM in the HWB test; and 6-(3-dimemylarninopropylamino)-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyI]pyridine-3-carboxamide [Example 22(14)] has an IC50 of approximately 0.05pM against p38a and an IC50 of approximately 3uM in the HWB test.
30 According to a further aspect of the invention there is provided a pharmaceutical
composition which comprises an amide derivative of the Formula I, or a pharmaceutically-

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acceptable or in-vivo-cleavable ester thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible
5 powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing
10 or as a suppository for rectal dosing). 4
The compositions of the invention may be obtained by conventional procedures using
conventional pharmaceutical excipients, well known in the art. Thus, compositions intended
for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or
preservative agents.
15 The amount of active ingredient that is combined with one or more excipients to
produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent compounded with an appropriate and convenient amount of excipients which may vary
20 from about 5 to about 98 percent by weight of the total composition.
The size of the dose for therapeutic or prophylactic purposes of a compound of the
Formula I will naturally vary according to the nature and severity of the conditions, the age
and sex of the animal or patient and the route of administration, according to well known
principles of medicine.
25 In using a compound of the Formula I for therapeutic or prophylactic purposes it will
generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg body weight will
30 generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg body weight will be used. Oral administration is however

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preferred, particularly in tablet form. Typically, unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
According to a further aspect of the invention there is provided an amide derivative of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, as
5 defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
According to a further aspect of the invention there is provided the use of an amide
derivative of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester
thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment
10 of medical conditions mediated by cytokines. .
In a further aspect the present invention provides a method of treating diseases or
medical conditions mediated by cytokines which comprises administering to a warm-blooded
animal an effective amount of a compound of the Formula I, or a pharmaceutically-acceptable
salt or in-vivo-cleavable ester thereof, as defined hereinbefore.
15 In a further aspect the present invention provides the use of a compound of the
Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by TNF, IL-1, IL-6 or IL-8.
In a further aspect the present invention provides a method of treating diseases or
20 medical conditions mediated by TNF, IL-1, IL-6 or IL-8 which comprises administering to a warm-blooded animal an effective amount of a compound of the Formula I or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof.
In a further aspect the present invention provides the use of a compound of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof in the
25 manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by TNF.
In a further aspect the present invention provides a method of treating diseases or medical conditions mediated by TNF which comprises administering to a warm-blooded animal an effective amount of a compound of the Formula I, or a pharmaceutically-acceptable
30 salt or in-vivo-cleavable ester thereof.

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In a further aspect the present invention provides the use of a compound of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, in the manufacture of a medicament for use in inhibiting TNF, IL-1, IL-6 or IL-8.
In a further aspect the present invention provides a method of inhibiting TNF, IL-1,
5 IL-6 or IL-8 which comprises administering to a warm-blooded animal an effective amount of a compound of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof.
In a further aspect the present invention provides the use of a compound of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, in the
10 manufacture of a medicament for use in inhibiting TNF.
In a further aspect the present invention provides a method of inhibiting TNF which comprises administering to a warm-blooded animal an effective amount of a compound of the Formula I, or a pharmaceutically-acceptable salt or in vivo-cleavable ester thereof.
In a further aspect the present invention provides the use of a compound of the
15 Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by p38 kinase.
In a further aspect the present invention provides a method of treating diseases or medical conditions mediated by p38 kinase which comprises administering to a warm-
20 blooded animal an effective amount of a compound of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof.
In a further aspect the present invention provides the use of a compound of the
Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, in the
manufacture of a medicament for use in the production of a p38 kinase inhibitory effect.
25 In a further aspect the present invention provides a method of providing a p38 kinase
inhibitory effect which comprises administering to a warm-blooded animal an effective amount of a compound of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof.
In a further aspect the present invention provides the use of a compound of the
30 Formula I, or a pharmaceutically-acceptable salt or in-vivo- cleavable ester thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, asthma, irritable

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bowel disease, multiple sclerosis, AIDS, septic shock, congestive heart failure, ischaemic heart disease or psoriasis.
In a further aspect the present invention provides a method of treating rheumatoid arthritis, asthma, irritable bowel disease, multiple sclerosis, AIDS, septic shock, congestive
5 heart failure, ischaemic heart disease or psoriasis which comprises administering to a warm blooded animal an effective amount of a compound of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof.
The compounds of this invention may be used in combination with other drugs and
therapies used in the treatment of disease states which would benefit from the inhibition of
10 cytokines, in particular TNF and IL-1. For example, the compounds of the Formula I could
be used in combination with drugs and therapies used in the treatment of rheumatoid arthritis,
asthma, irritable bowel disease, multiple sclerosis, AIDS, septic shock, congestive heart
failure, ischaemic heart disease, psoriasis and the other disease states mentioned earlier in this
specification.
15 For example, by virtue of their ability to inhibit cytokines, the compounds of the
Formula I are of value in the treatment of certain inflammatory and non-inflammatory diseases which are currently treated with a cyclooxygenase-inhibitory non-steroidal anti-inflammatory drug (NSAID) such as indomethacin, ketorolac, acetylsalicyclic acid, ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of a compound of the
20 Formula I with a NSAID can result in a reduction of the quantity of the latter agent needed to produce a therapeutic effect. Thereby the likelihood of adverse side-effects from the NSAID such as gastrointestinal effects are reduced. Thus according to a further feature of the invention there is provided a pharmaceutical composition which comprises a compound of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, in
25 conjunction or admixture with a cyclooxygenase inhibitory non-steroidal anti-inflammatory agent, and a pharmaceutically-acceptable diluent or carrier.
.The compounds of the invention may also be used with anti-inflammatory agents such as an inhibitor of the enzyme 5-lipoxygenase.
The compounds of the Formula I may also be used in the treatment of conditions such 30 as rheumatoid arthritis in combination with antiarthritic agents such as gold, methotrexate,

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steroids and penicillinamine, and in conditions such as osteoarthritis in combination with steroids.
The compounds of the present invention may also be administered in degradative diseases, for example osteoarthritis, with chondroprotective, anti-degradative and/or
5 reparative agents such as Diacerhein, hyaluronic acid formulations such as Hyalan, Rumalon, Arteparon and glucosamine salts such as Antril.
The compounds of the Formula I may be be used in the treatment of asthma in combination with antiasthmatic agents such as bronchodilators and leukotriene antagonists. If formulated as a fixed dose such combination products employ the compounds of
10 this invention within the dosage range described herein and the other pharmaceutically-active agent within its approved dosage range. Sequential use is contemplated when a combination formulation is inappropriate.
- Although the compounds of the Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required
15 to inhibit the effects of cytokines. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:-
(i) operations were carried out at ambient temperature, re. in the range 17 to 25°C
20 and under an atmosphere of an inert gas such as argon unless otherwise stated;
(ii) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration;
(ii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck
25 Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, Germany or high pressure liquid chromatography (HPLC) was performed on CI 8 reverse phase silica, for example on a Dynamax C-l 8 60A preparative reversed-phase column;
(iv) yields, where present, are given for illustration only and are not necessarily the
maximum attainable;
30 (v) in general, the end-products of the Formula I have satisfactory microanalyses and
their structures were confirmed by nuclear magnetic resonance (NMR) and/or mass spectral

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techniques; fast-atom bombardment (FAB) mass spectral data were obtained using a Platform spectrometer and, where appropriate, either positive ion data or negative ion data were collected; NMR chemical shift values were measured on the delta scale [proton magnetic resonance spectra were determined using a Varian Gemini 2000 spectrometer operating at a
5 field strength of 300MHz or a Bruker AM300 spectrometer operating at a field strength of 300MHz]; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad;
(vi) intermediates were not generally fully characterised and purity was assessed by
thin layer chromatographic, HPLC, infra-red (IR) and/or NMR analysis;
10 (vii) melting points are uncorrected and*were determined using a Mettler SP62
automatic melting point apparatus or an oil-bath apparatus; melting points for the
end-products of the Formula I were determined after crystallisation from a conventional
organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture;
and
15 (viii) the following abbreviations have been used:-
DMF N,N-dimethylformamide DMSO dimethylsulphoxide

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Example 1 6-chIoro-N-[5-(3-dimethyIaminobenzamido)-2-methylphenyl]pyrid' 3-carboxamide
6-Chloropyrid-3-ylcarbonyl chloride (0.37 g) was added to a mixture of N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (0.54 g), potassium carbonate
5 (0.304 g), DMF (5 ml) and methylene chloride (20 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic extracts were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 3:2:1 mixture of isohexane,
10 ethyl acetate and methylene chloride as eluent. There was thus obtained the title
compound as a solid (0.122 g); NMR Spectrum: (DMSOd6) 2.19 (s, 6H), 3.28 (s, 3H), 6.88 (m, 1H), 7.25 (m, 4H), 7.57 (m,TH), 7.7 (d, 1H), 7.84 (d, 1H), 8.36 (m, 1H), 8.95 (d, 1H), 10.11 (s, 1H), 10.16(5, 1H); Mass Spectrum: M+H* 409 and 411.
The N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide used as starting 15 material was prepared as follows :
Oxalyl chloride (13.0 ml) was added dropwise to a stirred mixture of 3-dimethylaminobenzoic acid (20.3 g) and DMF (a few drops) which had been cooled to 0°C. The mixture was allowed to warm.to ambient temperature and was stirred for 4 hours. The resultant mixture was evaporated and the residue was dissolved in methylene
20 chloride (150 ml). 4-Methyl-3-nitroaniline (15.2 g) and triethylamine (27.9 ml) were added in turn and the resultant mixture was stirred at ambient temperature for 16 hours. The reaction mixture was washed in turn with water, with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was triturated under a mixture of ethyl
25 acetate and isohexane. The solid so obtained was filtered off and recrystallised from ethanol to give N-(3-nitro-4-methylphenyl)-3-dimethylamino-benzamide (6.1 g); NMR Spectrum: (DMSOd6) 2.46 (s, 3H), 2.95 (s, 6H), 6.92 (d, 1H), 7.22 (m, 2H), 7.32 (t, 1H), 7.45 (d, 1H), 7.97 (d, 1H), 8.53 (s, 1H), 10.43 (s, 1H).
After repetition of the previous reactions, a sample (8.25 g) was added to a stirred
30 suspension of ammonium formate (17.4 g), and 10% palladium-on-carbon (1 g) in
methanol (250 ml). The mixture was stirred and heated to reflux for 4 hours. The mixture

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was allowed to cool and then filtered. The filtrate was evaporated and water was added to the residue. The resultant solid was isolated and washed in turn with water, with ethyl acetate and with diethyl ether. The solid was dried in a vacuum oven at 40°C to give N-(3-amino-4-methylphenyl)-3-dimethyiaminoben2amide (6.89 g); NMR Spectrum:
5 (DMSOd6) 2.0 (s, 3H), 2.94 (s, 6H), 4.78 (s, 2H), 6.82 (m, 3H), 7.07 (s, IH), 7.17 (m, 2H), 7.25 (m, IH), 9.74 (s, IH).
The 6-chloropyrid-3-ylcarbonyl chloride used as starting material was prepared by the reaction of 6-chloropyridine-3-carboxylic acid and qxalyl chloride using an analogous procedure to that described hereinbefore in the first part of the portion of this Example
10 which is concerned with the1 preparation of starting materials.
Example 2 N-[2-chloro-5-(4-cyanobenzamido)phenyI]pyridine-3-carboxaroide
A mixture of pyrid-4-ylcarbony! chloride (prepared by the reaction of pyridine-
4-carboxyIic acid and oxalyl chloride; 0.213 g), N-(3-amino-4-chlorophenyl)-
15 4-cyanobenzamide (0.27 g) and pyridine (4 ml) was stirred and heated to 110°C for
16 hours. After cooling, the mixture was poured into water (25 ml). The resultant
precipitate was collected, washed with water and dried to give the title compound as a
solid (0.32 g); NMR Spectrum: (DMSOd6) 7.58 (d, IH), 7.75 (m, IH), 7.85 (d, 2H), 8.01
(d, 2H), 8.10 (m, 3H), 8.80(d, 2H); Mass Spectrum: M+H+377.
20 The N-(3-amino-4-chlorophenyl)-4-cyanobenzamide used as starting material was
prepared as follows :
4-Cyanobenzoyl chloride (11.92 g) was added slowly to a stirred solution of 4-chloro-3-nitroaniline (10.4 g) in pyridine (20 ml) and the mixture was stirred and heated to 115°C for 18 hours. The mixture was cooled to ambient temperature and poured into
25 water (150 ml) and stirred for 30 minutes. The resultant precipitate was isolated, washed with water and dried to give N-[4-chloro-3-nitrophenyl]-4-cyanobenzamide (18 g), m.p. 213°C: NMR Spectrum: (DMSOd6) 7.78 (d, IH), 8:05 (m, 3H), 8.1 (d, 2H), 8.58 (s, IH), 10.93 (s, IH).
A portion (3.6 g) of the material so obtained was added to a stirred suspension of
30 iron powder (l0g) in a mixture of ethanol (130 ml), water (30 ml) and glacial acetic acid
(4 ml). The mixture was heated to 75°C for 1 hour and thereafter, whilst hot, basified by

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the addition of sodium carbonate. The mixture was filtered and the filtrate was evaporated. The resultant solid was stirred in water for 3 hours. The solid was isolated and dried to give the required starting material (2.7 g), m.p. 237.7°C; NMR Spectrum: (DMSOd6) 5.44 (s, 2H), 6.98 (m, 1H), 7.21 (d, 1H), 7.42 (d, 1H), 8.07 (d, 2H), 8.14 (d,
5 2H), 10.36 (s,lH).
Example 3 N-[5-(3-dimethyIaminobenzamido)-2-methyIphenyI]quinoxaline-2-carboxamide
Triethylamine (0.28 ml) was added to a stirred mixture of N-(3-amino-
10 4-methylphenyl)-3-dimethylaminobenzamide (0.27 g), 2-quinoxalinylcarbbnyl chloride (0.29 g) and methylene chloride (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate and evaporated. The residue was triturated under ethyl acetate. There
15 was thus obtained the title compound as a solid (0.175 g); NMR Spectrum: (DMSOd6) 2.31 (s, 3H), 2.95 (s, 6H), 3.31 (s, 3H), 6.91 (d, 1H) 7.27 (m, 4H), 7.59 (d, 1H), 8.01 (m, 2H), 8.24 (m, 3H), 9.56 (s, 1H), 10.15 (s, 1H), 10.42 (s, 1H); Mass Spectrum: M+H+ 426.
Example 4 N-[5-(4-chlorobenzaraido)-2-methyIphenyl]quinoIine-
20 6-carboxamide
Triethylamine (0.28 ml) was added to a stirred mixture of 4-chlorobenzoyl chloride (0.29 g))N-(5-aminp-2-methylphenyl)quinoline-6-carboxarriide (0.28 g) and methylene chloride (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated, washed with water and with methylene chloride. There was
25 thus obtained the title compound as a solid (0.208 g); NMR Spectrum: (DMSOd6) 2.24 (s, 3H), 7.24 (d, 1H), 7.52-7.62 (m, 4H), 7.87 (s, 1H), 7.98 (d, 2H), 8.12 (d 1H) 8.46 (d, 1H), 8.52 (d, 1H), 8.65 (s, 1H) 9.00 (s, 1H), 10.15 (s, 1H) 10.31 (s, \H): Mass Spectrum: M+HT416.
The N-(5-amino-2-methylphenyl)quinoline-6-carboxamide used as starting
30 material was prepared as follows :

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Oxalyl chloride (12.73 ml) was added to a solution of 6-quinolinecarboxylic acid (20.3 g) in a mixture of methylene chloride (150 ml) and DMF (1 ml) which had been cooled to 0°C. The mixture was allowed to warm to ambient temperature and was stirred for 4 hours. The mixture was evaporated and the residue was dissolved in a mixture of
5 methylene chloride (150 ml) and DMF (5 ml). 2-Methyl-5-nitroaniline (14.3 g) and triethylamine (20.35 ml) were added in turn and the mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated, washed with water and with ethyl acetate and dried under vacuum at 55°C. There was thus obtained N-(2~methyl-5-iutrophenyl)quinoline-6-carboxamide as a solid (26.7 g); NMR Spectrum: (DMSOd6)
10 2.43 (s, 3H), 7.59 (d, IH), 7.84 (m, IH), 8.06 (m, IH), 8.3 (m, IH), 8.4 (m, 2H), 8.83 (m, 2H), 9.16 (m, IH), 10.53 (s, IH).
A mixture of the material so obtained, 10% palladium-on-carbon (1.29 g), ammonium formate (36.5 g) and methanol (500 ml) was stirred and heated to reflux for 2 hours. The mixture was cooled to ambient temperature and filtered through
15 diatomaceous earth. The solvent was evaporated and the residue was triturated under water. The resultant solid was isolated and dried under vacuum at 55°C to give N-(5-amino-2-methylphenyI)quinoline-6-carboxamide as a solid (14.7 g); NMR Spectrum: (DMSOd6) 2.08 (s, 3H), 6.41 (m, IH), 6.64 (d, IH), 6.89 (d, IH), 7.62 (m, IH), 8.1 (d, IH), 8.23 (d, IH), 8.5 (d, IH), 8.6 (s, IH), 8.99 (d, IH), 9.86 (s, IH).
20
Example 5 N-[5-(3-dimethylaminobenzamido)-2-methylphenyI]quinoIine-6-carboxamide
6-Quinolinecarboxylic acid (0.173 g) was added to a stirred suspension of N-(3-amino-4-methylphenyl)-3-dimethyIaminobenzamide (0.135 g), diisopropylethylamine
25 (0.325 ml), 2-(7-azaben20tria2ol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate(V) (0.39 g) in DMF (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated and the residue was dissolved in methylene chloride and washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The residue was triturated under a mixture of ethyl acetate and
30 isohexane. There was thus obtained the title compound as a solid (0.052 g); NMR Spectrum: (DMSOd6) 2.24 (s, 3H), 2.95 (s, 6H), 6.89 (d, IH), 7.25 (m, 4H), 7.6 (m, 2H), 7.85 (s, IH),

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8.12 (d, 1H), 8.4 (d.lH), 8.52 (d, 1H), 8.65 (m, 1H), 8.99 (d, 1H), 10.11 (s, 1H), 10.16 (s, 1H): Mass Spectrum: M+H+425.
Example 6 N-[5-(3,4-dichIorobenzamido)-2-methylphenyl]quinoline-
5 6-carboxamide
Using an analogous procedure to that described in Example 4, 3,4-dichlorobenzoyl chloride was reacted with N-(5-amino-2-methylphenyl)quinoline-6-carboxamide in the presence of triethylamine. The reaction mixture was stirred at ambient temperature for 16 hours and then evaporated. The residue was purified by column chromatography on
10 silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound in 57% yield; Mass Spectrum: M+HM50.
Example 7 N-[2-methyl-5-(3-trifluoromethyIbenzamido)phenyI]quinoIine-6-carboxamide
15 Phosphoryl chloride (0.045 ml) was added to a stirred mixture of
6-quinoIinecarboxylic acid (0.084 g), N-(3-amino-4-methylphenyl)-3-trifluoromethyIbenzamide (0.119 g) and pyridine (1 ml) which had been cooled to 0°C. The reaction mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The mixture was poured into 2N aqueous hydrochloric acid solution. The
20 resultant precipitate was isolated, washed in turn with a saturated aqueous sodium bicarbonate solution and isohexane and dried at 55°C under vacuum. There was thus obtained the title compound as a solid (0.128 g); NMR Spectrum: (DMSOd6) 2.25 (s, 3H), 7.25 (d, 1H), 7.61 (m, 2H), 7.77 (t, 1H), 7.87 (d, 1H), 7.94 (d, 1H), 8.14 (d, 1H), 8.28 (m, 3H), 8.56 (d, 1H), 8.65 (broad s, 1H), 9.01 (broad s, 1H), 10.17 (s, 1H), 10.46 (s, 1H);
25 Mass Spectrum: M-H'448.
The N-(3-arnino-4-methylphenyl)-3-trifluoromethylbenzamide used as a starting material was obtained as follows :-
A mixture of 3-trifluoromethylbenzoyl chloride (9.9 ml), 3-nitro-4-methylaniline (10 g) and pyridine (100 ml) was stirred and heated to 80°C for 2 hours. The reaction
30 mixture was evaporated and the residue was triturated under 2N aqueous hydrochloric acid solution. The resultant solid was isolated, washed in rum with a saturated aqueous sodium

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bicarbonate solution, water and isohexane and dried under vacuum at 55°C. There was
thus obtained N-(4-methyl-3-nitropheny))-3-trifIuoromethyIbenzamide as a solid (21.91
g); NMR Spectrum: (DMSOd6) 7.49 (d, 1H), 7.78 (m, 1H), 7.99 (m, 2H), 8.27 (m, 2H),
8.51 (s,1H), 10.77 (s, 1H).
5 A mixture of a portion (10 g) of the material so obtained, 10% palladium-on-
carbon (1.0 g), ammonium formate (19 g) and methanol (250 ml) was stirred and heated to reflux for 1 hour. The mixture was filtered through diatomaceous earth and the filtrate was evaporated. The residue was triturated under water. The resultant solid was isolated and dried under vacuum at 55°C to give N-(3-amino-4-methylphenyl)-
10 3-trifluoromethylbenzamide as a solid (7.98 g); NMR Spectrum: (DMSOd6) 2.01 (s, 3H), 4.83 (s, 2H), 6.85 (m, 2H), 7.08 (s, 1H), 7.74 (t, 1H), 7.92 (d, 1H), 8.2 (d, 1H), 10.11 (s, 1H).
Example 8
15 Using analogous procedures to those described in the previous Examples, the
appropriate acyl chloride was reacted with the appropriate aniline to give the compounds described in Table I. Where required, heteroarylcarbonyl chlorides were prepared from the corresponding heteroarylcarboxylic acids by reaction with oxalyl chloride using an analogous procedure to that described in the first part of the portion of Example 4 which is
20 concerned with the preparation of starting materials.
Table I


No. Heteroaryl R Method Note
1 5-methylisoxazol-3-yl 3-dimethyIamino Ex.3 (a)
2 6-benzothiazolyl 3-dimethylamino Ex.3 .(b)
3 6-quinolyl 4-cyano Ex.4 (c)
4 6-quinoIyl hydrogen Ex.4 (d)
5 6-quinolyl 4-methoxy Ex.6 (e)

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6 6-quinolyl 3-fluoro Ex.6 (f)
7 6-quinolyl 2,4-dimethoxy Ex.4 (g)
8 4-hydroxyquinazoIin-6-yl 3-dimethylamino Ex.4 (h)
9 6-quinoxalinyI 3-dimethylamino Ex.3 (i)
10 2-methyl-l ,8-naphthyridin-3-yl 3-dimethylamino Ex.3 (j)
Notes
(a) The reactants were 5-methyIisoxazol-3-ylcarbonyI chloride and N-(3-amino-
4-methyiphenyI)-3-dimethy!aminobenzamide. The product gave the following data:
5 NMR Spectrum: (DMSOd6)2.1-7 (s,3H), 2.94 (s, 6H), 6.63 (s, 1H), 6.9(d, IH), 7.19-7.29 (m, 4H), 7.57 (d 1H) 7.81 (s, 1H), 10.09 s, 1H), 10.12 (s, TO; Mass Spectrum: M+H* 379.
(b) The reactants were benzothiazol-6-ylcarbonyl chloride and N-(3-amino-
4-methylphenyl)-3-dimethylaminobenzamide. The product gave the following data:
NMR Spectrum: (DMSOd6) 2.22 (s, 3H), 2.95 (s, 6H), 6.9 (d, IH), 7.21-7.28 (m, 4H), 7.58
10 (d 1H) 7.84 (s, 1H), 8.12 (d 1H) 8.2 (d, IH), 8.79 (s, IH), 9.55 (s, 1H) 10.04 (s, 1H), 10.1 (s, 1H); Mass Spectrum: M+H+ 431.
(c) The reactants were N-(5-amino-2-methylphenyl)quinoline-6-carboxamide and
4-cyanobenzoyl chloride. The product gave the following data: NMR Spectrum:
(DMSOd6) 2.25 (s, 3H), 7.26 (d, IH), 7.58-7.64 (m, 2H), 7.89 (s, IH), 8.0 (d, 2H), 8.09-
15 8.14 (m, 3H), 8.28 (d, IH), 8.49 (d, IH), 8.65 (s, IH), 9.0 (s, IH), 10.16 (s, IH), 10.48 (s, IH); Mass Spectrum: M+rT 407.
(d) The reactants were 6-quinolylcarbonyl chloride and N-(3-amino-
4-methylphenyl)benzamide. The product gave the following data: NMR Spectrum:
(DMSOd6) 2.24 (s, 3H), 7.24 (d, IH), 7.5-7.7 (m, 5H), 7.89-7.97(m, 3H), 8.12 (d, IH),
20 8.25 (d, IH) 8.49 (d, IH), 8.65 (s, IH) 9.01 (s, IH), 10.16 (s, IH) 10.25 (s, IH); Mass Spectrum: M+H+ 382.
The N-(3-amino-4-methylphenyI)benzamide used as a starting material was prepared as follows :- Benzoyl chloride (1.9 ml) was added to a stirred mixture of 2,4-diaminotoluene (2 g), triethylamine (5.57 ml) and methylene chloride (80 ml) and the
25 mixture was stirred at ambient temperature for 16 hours. The mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic phase was dried over magnesium sulphate and evaporated. The residue was triturated with a mixture of ethyl

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acetate and diethyl ether. There was thus obtained the required starting material (1.32 g); NMR Spectrum: (DMSOd6) 2.01 (s, 3H), 4.8 (s, 2H), 6.82 (m 2H), 7.11 (s, IH), 7.5 (m, 3H),7.91 (m,2H),9.86(s, IH).
(e) The reactants were N-(5-amino-2-methy!pheny!)quinoline-6-carboxamide and
5 4-methoxybenzoyl chloride. The product gave the following data: Mass Spectrum:
M+H+412.
(f) The reactants were N-(5-amino-2-methylphenyl)quinoline-6-carboxamide and
3-fluorobenzoyl chloride. The product gave the following data: Mass Spectrum:
M+H+398.
10 (g) The reactants were N-(5-amino-2-methylphenyl)quinoline-6-carboxamide*and 2,4-dimethoxybenzoyl chloride. The product gave the following data: NMR Spectrum: (DMSOd6) 2.22 (s, 3H), 3.82 (s, 3H), 3.94 (s, 3H), 6.6-6.69 (m, 2H), 7.2 (d, IH), 7.51 (d, 1H), 7.6-7.65 (m, 1H), 7.73 (d, IH), 7.83 (s, 1H), 8.11 (d, IH), 8.26 (d, IH), 8.57 (d, IH), 8.66 (s, IH), 9.0 (s, IH), 9.89 (s, IH), 10.17 (s, 1H); Mass Spectrum: M+H* 442.
15 (h) The reactants were 4-oxo-3,4-dihydroquinazolin-6-ylcarbonyl chloride [prepared by the reaction of the corresponding acid (J. Amer. Chem. Soc. 1907, 29, 85) and oxalyl chloride] and N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide. The product gave the following data: NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 2.95 (s, 6H), 6.9 (d, 1H), 7.19-7.32 (m, 4H), 7.58-7.69 (m, 2H), 7.79 (s, IH), 8.18 (s 1H), 8.24 (d, 1H), 8.74 (s,
20 IH), 10.1 (s, IH), 10.11 (s, IH): Mass Spectrum: M+H+ 442.
(i) The reactants were 6-quinoxalinylcarbonyl chloride and N-(3-arnino-4^memylphenyI)-3-dirnethylarninobenzamide. The product gave the following data: NMR Spectrum: (DMSOd6) 2.24 (s, 3H), 3.05 (s, 6H), 6.9 (d, IH), 7.23-7.32 (m, 4H), 7.6 (d, IH), 7.86 (s, IH), 8.22 (d, IH), 8.36 (d, IH), 8.76 (s, IH), 9.05 (s, 2H), 10.12 (s, IH), 10.3
25 (s, IH); Mass Spectrum: M+H* 426.
The 6-quinoxalinylcarbonyl chloride used as a starting material was prepared as follows:- A 2N aqueous sodium hydroxide solution (7.95 ml) was added to a solution of methyl quinoxaline-6-carboxylate (1 g) in a mixture of methanol (30 ml) and water (5 ml) and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was
30 evaporated and the residue was dissolved in water. The solution was acidified to pH3.5 by the addition of dilute aqueous hydrochloric acid and extracted with ethyl acetate. The

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organic extracts were evaporated and the residue was triturated under a mixture of ethyl acetate and isohexane. There was thus obtained quinoxaIine-6-carboxylic acid a solid (0.5 g); NMR Spectrum: (DMSOd6) 8.16 (d, 1H), 8.28 (d, 1H), 8.59 (s, 1H), 9.02 (s, 2H). Oxalyl chloride (0.065 ml) was added dropwise to a stirred solution of a portion
5 (0.181 g) of the acid so obtained in a mixture of methylene chloride (20 ml) and DMF (a few drops) which had been cooled to 0°C. The mixture was allowed to warm to ambient temperature and was stirred for 4 hours. The solvent was evaporated to give 6-quinoxalinylcarbonyl chloride which was used without further purification, (j) The reactants were 2-methyl-l,8-naphthyridin-3-ylcarbonyl chloride and
10 N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide. The product gave the
following data: NMR Spectrum: (DMSOd6) 2.29 (s, 3H), 2.82 (s, 3H), 2.95 (s, 6H), 6.9 (d, 1H), 7.21-7.28 (m, 4H), 7.58-7.67 (m, 2H) 7.95 (s, 1H), 8.54 (d, 1H) 8.62 (s, 1H), 9.1 (s, 1H), 10.13 (s, 2H); Mass Spectrum: M+H+ 440.
15 Example 9 N-(5-benzamido-2-chlorophenyl)quinoIine-6-carboxamide
Using an analogous procedure to that described in Example 7, quinoline-6-carboxyIic acid was reacted with N-(3-amino-4-chlorophenyl)benzamide to give the title compound in 47% yield; NMR Spectrum: (DMSOd6) 7.57 (m, 6H), 7.75 (m, 1H), 7.95 (d, 2H), 8.15 (d, 1H), 8.17 (d, 1H), 8.55 (d, 1H), 8.78 (s, 1H), 9.01 (in, 1H), 10.33 (s, 1H),
20 10.44 (s, 1H); Mass Spectrum: M-H" 400.
The N-(3-amino-4-chlorophenyl)benzamide used as a starting material was obtained as follows :-
Benzoyl chloride (5.2 ml) was added to a stirred mixture of 2,4-diaminochlorobenzene (6.42 g), triethylamine (12.5 ml) and methylene chloride
25 (100 ml) which had been cooled to 0°C. The mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The mixture was evaporated and the residue was triturated under a saturated aqueous sodium bicarbonate solution. The resultant solid was isolated, washed in turn with water and isohexane and dried under vacuum at 55°C. There was thus obtained N-(3-amino-4-chlorophenyl)benzarnide as a solid (10.38 g); NMR
30 Spectrum: (DMSOd6) 5.32 (s, 2H), 6.9 (m, 1H), 7.1 (d, 1H), 7.37 (d, 1H), 7.52 (m, 3H), 7.9 (d,2H), 10.05 (s, 1H).

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Example 10 N-|2-chloro-5-(4-cyanobenzamido)phenyl]quinoIine-6-carboxamide
Using an analogous procedure to that described in Example 3, quinoline-6-carboxylic acid was reacted with N-(3-amino-4-chlorophenyl)-4-cyanobenzamide. The crude reaction product was purified by column chromatography on silica using a 97:3
5 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound in 18% yield: NMR Spectrum: (DMSOd6) 7.58 (d, IH), 7.62 (m, 1H), 7.77 (m, IH), 8.01 (d, 2H), 8.12 (t, 4H), 8.28 (d, 2H), 8.56 (d, IH), 8.67 (s, 1H), 9.01 (d, IH), 10.34 (s, IH), 10.67 (s, IH); Mass Spectrum: M-H"425.
10 Example 11 6-chloro-N-[5-(3-cyclohexylpropionamido)-2-methyIphenyI]pyridine-3-carboxaraide
Using an analogous procedure to that described in Example 3, 6-chloropyrid-3-ylcarbonyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-cyclohexylpropionamide (J. Med. Chem., 1996, 39, 3343-3356) to give the title
15 compound; Mass Spectrum: M+H+ 400.
Example 12 N-(5-(3-cyc!ohexyIpropionamido)-2-merhyIphenyI]quinoIine-6-carboxamide
Using an analogous procedure to that described in Example 5, quinoline-20 6-carboxylic acid was reacted with N-(3-amino-4-methyIphenyl)-
3-cyclohexylpropionamide to give the title compound; NMR Spectrum: (DMSOd6) 0.76-
1.28 (m, 6H), 1.42-1.78 (m, 7H), 2.2 (s, 3H), 2.28 (t, 2H), 7.17 (d, IH), 7.39 (d, IH), 7.6
(m, IH), 7.69 (s, IH), 8.12 (d, IH), 8.24 (d, IH), 8.49 (d, IH), 8.63 (s, IH), 9.0 (m, IH),
9.82 (s, IH), 10.09 (s, IH); Mass Spectrum: M+H* 437.
25
Example 13 N-[5-(3-cyclohexylpropionamido)-2-methyIphenyl]quinoxaIine-
6-carboxamide
Using an analogous procedure to that described in Example 5, quinoxaline-
6-carboxylic acid was reacted withN-(3-amino-4-methylphenyI)-
30 3-cyclohexylpropionamide to give the title compound; NMR Spectrum: (DMSOd6) 0.76-
0.97 (m, 2H), 1.04-1.24 (m, 3H), 1.40-1.78 (m, 8H), 2.2 (s, 3H), 2.28 (t, 2H), 7.17 (d, IH),

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7.39 (d, 1H), 7.69 (s, 1H), 8.22 (d, 1H), 8.44 (d, 1H), 8.74 (s, 1H), 9.05 (m, 2H), 9.84 (s, 1H), 10.25 (s, 1H); Mass Spectrum: M+H+ 417.
Example 14 N-[5-(5-isoxazolyIcarbonylamino)-2-methylphenyl]quinoline-
5 6-carboxamide
Using an analogous procedure to that described in Example 4, 5-methylisoxazol-3-ylcarbonyl chloride was reacted with N-(5-amino-2-methylphenyl)quinoline-6-carboxamide in the presence of triethylamine. The reaction mixture was stirred at ambient temperature for 16 hours and then evaporated. The residue was purified by
10 column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent There was thus obtained the title compound; Mass Spectrum: M-H_425.
Example 15 N-[5-(6-chloropyrid-3-yIcarbonylamino)-2-methyIphenyl]quinoline-
15 6-carboxamide
Using an analogous procedure to that described in Example 4, 6-chloropyrid-3-ylcarbonyl chloride was reacted with N-(5-amino-2-methyIphenyl)quinoline-6-carboxamide in the presence of triethylamine. The reaction mixture was stirred at ambient temperature for 16 hours and then evaporated. The residue
20 was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound; Mass Spectrum: M-H" 415.
Example 16 N-[2-methyl-5-(3-morpholmobenzamido)phenyl]thiophene-
25 2-carboxamide
Thiophene-2-carbonyl chloride (0.069 g) was added to a stirred suspension of N-(3-amino-4-methyIphenyl)-3-morpholinobenzamide (0.104 g), triethylamine (0.15 ml) and methylene chloride (20 ml) and the resultant mixture was stirred at ambient temperature for 4 hours. The organic phase was washed with water and with a saturated
30 aqueous sodium bicarbonate solution, dried (MgS04) and evaporated. The residue was dissolved in methylene chloride (2 mi) and diethyl ether (20 ml) was added to give a

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precipitate which was isolated by filtration, washed with diethyl ether and dried. There was thus obtained the title compound (0.047 g); NMR Spectrum: (DMSOd6) 2.18 (t, 3H)> 3.18 (t, 4H), 3.76 (t, 4H), 7.14 (d, 1H), 7.20 (m, 2H), 7.38 (m, 2H), 7.41 (s, 1H), 7.58 (m, 1H), 7.78 (s, 1H), 7.82 (d, 1H), 7.98 (d, 1H), 9.93 (s, 1H), 10.13 (s, 1H); Mass Spectrum:
5 M+H+ 422.
The N-(3-amino-4-methylphenyl)-3-morpholinobenzamide used as a starting material was prepared as follows :-
A mixture of ethyl 3-bromobenzoate (1.92 ml), morpholine (1.25 ml), 2,2'-bis(diphenyIphosphino)-l,r-binaphthyI (0.336 g), sodium tert-butoxide (1.615 g) and
10 tris(dibenzylideneacetone)dipalladiurn(0) (0.33 g) and toluene (25 ml) was stirred and heated to 90°C for 18 hours under argon. The reaction mixture was allowed to cool to ambient temperature and extracted with IN aqueous hydrochloric acid. The aqueous phase was basified with concentrated sodium hydroxide solution and extracted with ethyl acetate. The organic phase was dried (MgS04) and evaporated. The residual oil was
15 purified by column chromatography on silica gel using a 47:3 mixture of methylene chloride and methanol as eluent. There was thus obtained N-(3-morpholinobenzoyl)morphoIine (0.45 g).
A mixture of the material so obtained, 5M sodium hydroxide solution (2.5 ml) and butanol (2 ml) was stirred and heated to 115°C for 18 hours. The mixture was evaporated
20 and the residue was acidified by the addition of IN aqueous hydrochloric acid solution (12.5 ml). The resultant precipitate was isolated, washed with water and dried to give 3-morpholinobenzoic acid (0.15 g); NMR Spectrum: (DMSOd6) 3.1 (t, 4H), 3.73 (t, 4H), 7.19 (d, IH), 7.32 (d, 1H), 7.38 (t, 1H), 7.42 (s, 1H).
Oxalyl chloride (0.14 ml) was added to a solution of 3-morpholinobenzoic acid
25 (0.28 g) in methylene chloride (10 ml) which contained DMF (2 drops). The reaction mixture was stirred for 18 hours at ambient temperature. The mixture was evaporated and azeotroped with toluene to give 3-morpholinobenzoyl chloride (0.3 g); Mass Spectrum: M+H+ 222.
A solution of 3-morpholinobenzoyl chloride (0.24 g) in methylene chloride (5 ml)
30 was added to a stirred mixture of 4-methyl-3-nitroaniIine (0.15 g), pyridine (0.24 ml) and methylene chloride (10 ml). The reaction mixture was stirred at ambient temperature for

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16 hours. The organic phase was washed with water and with a saturated aqueous sodium bicarbonate solution. The organic layer was dried (MgSO4) and evaporated. The residual solid was triturated under diethyl ether and the resultant solid was isolated and dried to give N~(3-nitro-4-methylphenyl)-3-morpholinoberizamide (0.28 g); NMR Spectrum:
5 (DMSOd.) 3.2 (t, 4H), 3.3 (s, 3H), 3.78 (t, 4H), 7.19 (s, IH), 7.4 (m, 2H), 7.47 (d, 2H), 8.0 (d, 1H),8.83(S,1H), 10.23 (s,lH).
10% Palladium-on-carbon (0.035 g) was added to a stirred solution in methanol (40 ml) of the nitro compound so obtained, (0.28 g) and the mixture was stirred at ambient temperature under 1 atmosphere pressure of hydrogen. After uptake of hydrogen had
10 ceased, the catalyst was removed by filtration and the filtrate was evaporated to give
N-(3-amino-4-methylphenyI)-3-morpholinobenzamide; NMR Spectrum: (DMSOd6) 2.0 (s, 3H), 3.19 (t, 4H), 3.78 (t, 4H), 4.8 (s, 2H), 6.8 (q, 2H), 7.08 (s, IH), 7.1 (d, IH), 7.34 (m, 2H), 7.4 (s, IH), 9.8 (s, IH); Mass Spectrum: M+H+ 312.
15 Example 17 2-chloro-N-[2-methyl-5-(2-morphoIinopyrid-4-ylcarbonyIamino)phenyl]pyridine-4-carboxamide
2-Chloropyridine-4-carbonyl chloride (0.143 g) was added to a stirred mixture of N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide (0.211 g), triethylarnine (0.164 g) and methylene chloride (10 ml) and the mixture was stirred at
20 ambient temperature for 16 hours. The precipitate was isolated, washed with a saturated aqueous sodium bicarbonate solution and with methylene chloride and dried under vacuum at 40°C. There was thus obtained the title compound (0.276 g); NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 3.50-3.53 (m, 4H), 3.69-3.73 (m, 4H), 7.08 (d, IH), 7.24 (d, 2H), 7.34 (d, IH) 7.81 (s, IH), 7.88 (d, IH), 7.98 (s, IH), 8.26 (d, IH), 8.6 (d, IH); Mass
25 Spectrum M+H* 452 and 454.
The N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide used as a starting material was prepared as follows :-
Triethylarnine (31.8 ml) was added to a stirred mixture of 4-methyl-3-nitroaniline (15.8 g), 2-chloropyridine-4-carbonyl chloride (20 g) and methylene chloride (1 litre) and
30 the resultant mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated, washed with a saturated aqueous sodium bicarbonate solution and with methylene

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chloride and dried under vacuum at 40°C. There was thus.obtained 2-chIoro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide (10.2 g). The organic filtrate was washed with a saturated aqueous sodium bicarbonate solution, dried (MgSO4) and evaporated. The residue was triturated under methylene chloride and the resultant solid was isolated and
5 dried under vacuum at 40°C. There was thus obtained a second crop (8.13 g) of 2-chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide; NMR Spectrum: (DMSOd6) 2.48 (s, 3H), 7.51 (d, IH), 7.86 (m, IH), 7.96 (m, 2H), 8.49 (m, IH), 8.64 (m, IH), 10.85 (s, 1H); Mass Spectrum: M+H+ 292 and 294.
A mixture of the pyridine-4-carboxamide so produced and morpholine (250 ml)
10 was stirred and heated to 100°C for 18 hours. The mixture was poured into water (250 ml) and stirred for 10 minutes. Methylene chloride (30 ml) was added and the resultant mixture was stirred for 30 minutes. The resultant solid was isolated, washed with methylene chloride and dried in a vacuum oven at 40°C for 18 hours. There was thus obtained N-(4-methyl-3-nitrophenyl)-2-morpholinopyridine-4-carboxamide (17.34 g);
15 NMR Spectrum: (DMSOd6) 2.48 (s, 3H), 3.52 (m, 4H), 3.71 (m, 4H), 7.1 (d, IH), 7.25 (s, IH), 7.49 (d, IH) 7.97 (m, IH), 8.29 (m, IH), 8.49 (m, IH), 10.62 (s, IH); Mass Spectrum: M+H+343.
A mixture of a portion (8.5 g) of the material so obtained, 5% palladium-on-carbon catalyst (0.85 g) and methanol (600 ml) was stirred under an atmosphere pressure of
20 hydrogen gas for 18 hours. Methylene chloride (400 ml) was added and the reaction mixture was filtered through diatomaceous earth. The filtrate was evaporated to give N-(3-amino-4-methyIphenyl)-2-morpholinopyridine-4-carboxaniide (6.41 g); NMR Spectrum: (DMSOd6) 2.01 (s, 3H), 3.52 (m, 4H), 3.73 (m, 4H), 4.83 (s, 2H), 6.78 (d, IH), 6.84 (d, IH) 7.04-7.08 (m, 2H), 7.2 (s, IH), 8.24 (d, IH), 9.95 (s, IH): Mass Spectrum
25 M+H+313.
Example 18 6-chloro-N-[2-methyl-5-(2-morphoIinopyrid-4-yIcarbonylamino)phenyl]pyridine-3-carboxamide
Using an analogous procedure to that described in Example 17, 6-chloropyridine-
30 3-carbonyl chloride was reacted withN-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide to give the title compound in 56% yield; NMR Spectrum: (DMSOd6): 2.21 (s,

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3H), 3.50-3.53 (m, 4H), 3.69-3.73 (m, 4H), 7.08 (d, 1H), 7.25 (d, 2H), 7.56 (d, IH) 7.69 (d, 1H), 7.82 (s, IH), 8.26 (d, IH), 8.37 (d, IH), 8.96 (d, IH); Mass Spectrum M+£T 452 and
454.
5 Example 19
Using an analogous procedure to that described in Example 17, the appropriate heteroarylcarbonyl chloride was reacted with the appropriate aniline to give the compounds described in Table II. Where required, heteroarylcarbonyl chlorides were prepared from the corresponding heteroarylcarboxylic acids by reaction with oxalyl
10 chloride using an analogous procedure to that described in the first part of the portion of Example 4 which is concerned with the preparation of starting materials.
Table II

15

No. Heteroaryl R Note
1 6-chIoropyrid-3-yl 3-trifluoromethyl (a)
2 6-chloropyrid-3-yl 4-cyano (b)
3 2-chloropyrid-4-yI 3-trifluoromethyl (c)
4 2-chloropyrid-4-yl 4-cyano (d)
Notes
(a) The product gave the following data: NMR Spectrum: (DMSOd6) 2.22 (s, 3H),
7.26 (d, IH), 7.59 (d, IH), 7.69 (d, IH), 7.77 (t, IH), 7.85 (s, IH), 7.95 (d, IH) 8.26 (m,
20 2H), 8.34 (m, IH), 8.96 (s, IH); Mass Spectrum: M+H+ 434 and 436.
(b) The product gave the following data: NMR Spectrum: (DMSOd6) 2.21 (s, 3H),
7.24 (d, IH), 7.76 (d, IH), 7.69 (d, IH), 7.86 (s, IH), 8.0 (d, 2H), 8.1 (d, 2H), 8.36 (m,
IH), 8.96 (s, IH); Mass Spectrum: M+H+ 391 and 393.
The N-(3-ammo-4-methyIphenyl)-4-cyanobenzamide used as a starting material 25 was prepared as follows :-

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Triethylamine (23 ml) was added to a suspension of 3-nitro-4-methylaniline (10 g), 4-cyanobenzoyl chloride (13.1 g), 4-dimethylaminopyridine (0.8 g) in methylene chloride (200 ml) which had been cooled to 0°C. The reaction mixture was allowed to warm to . ambient temperature and was stirred for 5 hours. The mixture was partitioned between
5 methylene chloride and 0.5N hydrochloric acid solution. The organic phase was dried (MgS04) and evaporated and the residue was triturated under isohexane. The solid was isolated and dried under vacuum at 55°C. There was thus obtained N-(3-nitro-4-methylphenyl)-4-cyanobenzamide (18.3.g); NMR Spectrum: (DMSOd6) 2.5 (s, 3H), 7.49 (d, 1H), 7.96 (m, 1H), 8.05 (d, 2H), 8.12 (d, 2H), 8.51 (d, 1H), 10.77 (s, 1H).
10 A solution of tin(II) chloride dihydrate (15.4 g) in concentrated hydrochloric acid
(80 ml) was added to a suspension of N-(3-nitro-4-methy]phenyl)-4-cyanobenzamide (6.39 g) in acetic acid (120 ml). The mixture was stirred and heated to reflux for 2 hours. The mixture was allowed to cool to ambient temperature and was basified by the addition of 2N sodium hydroxide solution. The precipitated solid was isolated and dried under
15 vacuum at 55°C to give N-(3-amino-4-methylphenyl)-4-cyanobenzamide (5.62 g); NMR Spectrum: (DMSOd6) 2.01 (s, 3H), 4.85 (s, 2H), 6.8 (d, 1H), 6.86 (d, 1H), 7.11 (s, 1H), 7.96 (d, 2H), 8.06 (d, 2H), 10.11 (s, 1H).
(c) The product gave the following data: NMR Spectrum: (DMSOd6) 2.21 (s, 3H),
7.26 (d, 1H), 7.59 (d, 1H), 7.77 (t, 1H), 7.83-7.90 (m, 2H), 7.92-7.99 (m, 2H) 8.20-8.29
20 (m, 2H), 8.61 (d, 1H), 10,38 (s, 2H); Mass Spectrum: M+H+ 434 and 436.
(d) The product gave the following data: NMR Spectrum: (DMSOdJ 2.21 (s, 3H),
7.26 (d, 1H), 7.58 (s, 1H), 7.87 (m, 2H), 8.0 (d, 3H), 8.09 (d, 2H), 8.61 (d, 1H), 10.27 (s,
1H), 10.48 (s, 1HV, Mass Spectrum: M+IT 391 and 393.
25 Example 20 N-[2-ch!oro-5-(4-cyanobenzamido)phenyIJpyridine-3-carboxamide
Using an analogous procedure to that described in Example 2, pyridine-3-carbonyl chloride was reacted with N-(3-amino-4-chIorophenyl)-4-cyanobenzamide to give the title compound in 67% yield; NMR Spectrum: (DMSOd6) 7.57 (d, 1H), 7.59 (m, 1H), 7.73 (d, IH), 8.01 (d, 2H), 8.10 (m, 3H), 8.34 (d, 1H), 8.79 (d, 1H), 9.15 (d, 1H), 10.33 (s, 1H),
30 10.66 (s. IH); Mass Spectrum M+H* 377.

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Examplc21 6-(4-dimcthylarainobutylamino)-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylarnino)phenyI]pyridine-3-carboxamide
A mixture of 4-dimethylaminobutylamine (5 ml) and 6-chloro-N-[2-methyl-5-(2-morpholinopyrid-4-yIcarbonylaxnino)phenyl]pyridine-3-carboxamide (0.181 g) was
5 stirred and heated to 100°C for 16 hours. The mixture was poured into water (50 ml) and stirred for 20 minutes. The resultant solid was isolated, washed with diethyl ether and dried under vacuum at 40°C. There was thus obtained the title compound (0.17 g); NMR Spectrum: (DMSOd6) 1.4-1.6 (m, 4H), 2.1 (s, 6H), 2.19 (s, 3H), 2.21 (m, 2H), 3.52 (m, 6H), 3.72 (m, 4H), 6.49 (d, 1H), 7.14 (m, 2H), 7.21 (m, 2H), 7.54 (d, 1H), 7.78 (s, 1H),
10 7.85 (d, 1H), 8.27 (d, 1H), 8.64 (s, 1H), 9.51 (s, 1H), 10.26 (s, 1H); Mass Spectrum M+H+ 532.
Example 22
Using an analogous procedure to that described in Example 21, the appropriate 15 chloro-substituted heteroarylcarboxamide was reacted with the appropriate amine to give the compounds described in Table III.


No. Q1 Q2 Note
1 6-morpholinopyrid-3-yl 3-trifluoromethylphenyl (a)
2 6-(2-armnoethylamino)pyrid-3-yl 3-trifluoromethylphenyl (b)
3 6-(3-morpholinopropylamino)pyrid-3-yl 3-trifluoromethylphenyl (c)
4 6-morpholinopyrid-3 -yl 4-cyanophenyl (d)
5 6-(2-aminoethylamino)pyrid-3-yl 4-cyanophenyl (e)
6 6-(3-morpholinopropylamino)pyrid-3-yl 4-cyanophenyl (f)
7 6-(l-benzyIpiperidin-4-ylamino)pyrid-3-yl 4-cyanophenyl (g)
8 6-(2-aminoethylamino)pyrid-3-yl 2-morpholinopyrid-4 -y 1 (h)
9 6-(2-dimethylaminoethylamino)pyrid-3-yl 2-morpholinopyrid-4-yl (i)

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10 6-[N-(2-dimethylaminoethyl)-N-methylamino]pynd-3-yl 2-morpholinopyrid-4-yl G)
11 6-(2-amino-2-methylpropylamino)pyrid-3-yl 2-morpholinopyrid-4-yl 00
12 6-(2-diethylaminoethylamino)pyrid-3-yl 2-morpholinopyrid-4-yl (1)
13 6-(3-aminopropylamino)pyrid-3-y] 2-morpholinopyrid-4-yl (m)
14 6-(3-dimethylaminopropylamino)pyrid-3-yl 2-morpholinopyrid-4-yl (n)
15 6-(3-methylaminopropylamino)pyrid-3-yl 2-morpholinopyrid-4-yl (o)
16 6-(3-morpholinopropylamino)pyrid-3-yI 2-morpholinopyrid-4-yl (p)
17 6-[N-(3-dimethylaminopropyl)-N-methylamino]pyrid-3-yl 2-morpholinopyrid-4-yl (q)
18 6-[2-(N-methylpyrroIidin-2-yl)ethylamino]-pyrid-3-yl 2-morpholinopyrid-4-yl «
19 6-(4-aminobutylamino)pyrid-3-yI 2-morpholinopyrid-4-yl (s)
20 6-(4-methyIpiperazin-1 -yl)pyrid-3-yI 2-morpholinopyrid-4-yl (t)
21 6-(4-ethylpiperazin-l-yl)pyrid-3-yI 2-morpholinopyrid-4-yl (u)
22 6-(4-methylhornopiperazin-l-yl)pyrid-3-yl 2-morpholinopyrid-4-yl (v)
23 6-[4-(2-hydroxyethyl)pipera2in-l-yl]pyTid~3-yI 2-morpholinopyrid-4-yl (w)
24 6-(3-amino-2-hydroxypropylamino)pyrid-3-yl 2-morphoIinopyrid-4-yI (x)
25 2-morpholinopyrid-4-yl 3-trifluoromethylphenyl (y)
26 2-(2-aminoethyIamino)pyrid-4-yl 3-trifluoromethylphenyl (z)
27 2-morpholinopyrid-4-yl 4-cyanophenyI (aa)
28 . 2-(2-aminoethylamino)pyrid-4-yl 4-cyanophenyl (bb)
29 2-(4-methylpiperazin-1 -yl)pyrid-4-yl 2-morpholinopyrid-4-yl (cc)
30 2-[4-(2-hydroxyethyl)piperazin-l-yl]pyrid-4-yI 2-morphoIinopyrid-4-yl (dd)
Notes
(a) The reactants were 6-chloro-N-[2-methyl-5-(3-trifluoromethylbenzamido)phenyl]-pyridine-3-carboxamide [Example 19(1)] and morpholine. The product gave the following
5 data: NMR Spectrum: (DMSOd6) 2.05 (s, 3H), 3.57 (m, 4H), 3.69 (m, 4H), 6.9 (d, 1H), 7.23 (d, 1H), 7.58 (d, IH), 7.76-7.82 (m, 2H), 7.94 (ds 1H), 8.1 (d, 1H), 8.21-8.28 (m, 2H), 9.67 (s; IH), 10.42 (s, IH): Mass Spectrum: M+H+485.

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(b) The reactants were 6-chloro-N-[2-methy]-5-(3-trifluoromethylbenzamido)pheny]]-
pyridine-3-carboxamide and ethylenediamine. The product gave the following data:
NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.69 (m, 2H), 3.26 (m, 2H), 6.52 (d, IH), 7.08-
7.24 (m, 2H), 7.58 (d, IH), 7.72-7.82 (m, 2H), 7.92 (t, 2H), 8.27 (m, 2H), 8.62 (s, IH),
5 9.58 (s, IH), 10.41 (s, IH); Mass Spectrum: M+H+ 458.
(c) The reactants were 6-chloro-N-[2-methyl-5-(3-trifluoromethy]benzamido)phenyl]-
pyridine-3-carboxamide and 3-morpholinopropylamine. The product gave the following
data: NMR Spectrum: (DMSOd6) 1.62-1.76 (m, 2H), 2.19 (s, 3H), 3.28-3.33 (m, 8H), 3.56
(m, 4H), 6.5 (d, IH), 7.11 (t, IH), 7.21 (d, IH), 7.58 (d, IH), 7.78 (m, 2H), 7.84-7.98 (m,
10 2H), 8.25 (m, 2H), 8.64 (s, IH), 9.52 (s, IH), 10.41 (s, IH); Mass Spectrum: M+H+ 542.
(d) The reactants were 6-chloro-N-[2-methyI-5-(4-cyanoben2amido)phenyl]pyridine-
3-carboxamide [Example 19(2)] and morpholine. The product gave the following data:
NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 3.48 (m, 4H), 3.69 (m, 4H), 6.84 (d, IH), 7.12 (d,
IH), 7.68 (d, IH), 7.82 (s, IH), 7.99 (d, 2H), 8.09 (d, 3H), 8.75 (s, IH), 9.67 (s, IH), 10.43
15 (s. IH): Mass Spectrum: M+H* 442.
(e) The reactants were 6-chloro-N-[2-methyl-5-(4-cyanobenzamido)phenyl]pyridine-
3-carboxamide and ethylenediamine. The product gave the following data: NMR
Spectrum: (DMSOd6) 2.18 (s, 3H), 2.65-2.72 (m, 2H), 3.63-3.79 (m, 2H), 6.48 (d, IH),
7.08 (t, IH), 7.2 (m, IH), 7.57 (d, IH), 7.8 (s, IH) 7.88-8.0 (m, 5H), 8.62 (s, IH), 9.52 (s,
20 IH), 10.23 (s. IH); Mass Spectrum: M+H* 415.
(f) The reactants were 6-chloro-N-[2-methyI-5-(4-cyanobenzamido)phenyl]pyridine-
3-carboxamide and 3-morpholinopropylamine. The product gave the following data:
NMR Spectrum: (DMSOd6) 1.62-1.79 (m, 2H), 2.18 (s, 3H), 3.31 (m, 8H), 3.55 (m, 4H),
6.5 (d, IH), 7.05 (t, IH), 7.21 (d, IH), 7.44 (s, IH), 7.52 (d, IH) 7.81 (s, IH), 7.84-8.02
25 (m, 3H), 8.08 (s, IH), .8.64 (s,lH), 9.52 (s,lH), 10.28 (s, IH); Mass Spectrum: M+NH/516.
(g) The reactants were 6-chloro-N-[2-methyl-5-(4-cyanobenzamido)phenyl]pyridine-
3-carboxamide and l-benzyIpiperidin-4-ylamine. The product gave the following data:
Mass Spectrum: M+NH4+ 562.

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(h) The reactants were 6-chloro-N-[2-methyl-5-(2-moipholinopyrid-4-yIcarbonylamino)phenyl]pyridine-3-carboxamide (Example 18) and ethylenediamine. The product gave the following data: Mass Spectrum: M+H+ 476. (i) The reactants were 6-chloro-N-[2-methyl-5-(2-morpholinopyrid-
5 4-ylcarbonylamino)phenyl]pyridine-3-carboxamide and 2-dirnethylaminoethylamine. The product gave the following data: NMR Spectrum: (DMSOd6) 2.17 (s, 6H), 2.19 (s, 3H), 2.41 (t, 2H), 3.32-3.42 (m, 2H), 3.5-3.57 (m, 4H), 3.71 (m, 4H), 6.54 (d, IH), 7.0 (t, IH), 7.1 (d, IH), 7.24 (m, 2H), 7.58 (d, IH), 7.77 (s, IH), 7.85 (d, IH), 8.26 (d, IH), 8.64 (s, IH), 9.51 (s, IH), 10.25 (s, IH); Mass Spectrum: M+HT 504.
10 (j) The reactants were 6-chloro-N-[2-methyl-5-(2-morpholinopyrid-
4-ylcarbonylamino)phenyl]pyridine-3-carboxamideandN-(2-dimethylaminoethyl)-N-methylamine. The product gave the following data: NMR Spectrum: (DMSOd6) 2.18 (s, 6H), 2.19 (s, 3H), 2.42 (t, 2H), 3.07 (s, 3H), 3.50-3.55 (m, 4H), 3.69-3.73 (m, 6H), 6.67 (d, IH), 7.11 (d, IH), 7.22 (m, 2H), 7.58 (d, IH), 7.79 (s, IH), 8.01 (d, IH), 8.26 (d, IH),
15 8.72 (s, IH), 9.57 (s, IH), 10.26 (s, 1H); Mass Spectrum: M+H+ 518. (k) The reactants were 6-chloro-N-[2-methyl-5-(2-morphoIinopyrid-4-ylcarbonyIamino)phenyl]pyridine-3-carboxamide and 2-amino-2-methylpropylamine. The product gave the following data: NMR Spectrum: (DMSOd6) 1.02 (s, 6H), 2.19 (s, 3H), 3.23-3.3 (m, 2H), 3.54 (m, 4H), 3.71 (m, 4H), 6.61 (d, IH), 7.0 (t, IH), 7.1 (d, IH),
20 7.24 (m, 2H), 7.58 (d, IH), 7.78 (s, IH), 7.85 (d, IH), 8.26 (d, IH), 8/61 (s, IH), 9.51 (s, IH), 10.25 (s, IH); Mass Spectrum: M+H+ 504.
(1) The reactants were 6-chloro-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonyIamino)phenyl]pyridine-3-carboxamide and 2-diemylaminoethylarnine. The product gave the following data: NMR Spectrum: (DMSOd6) 0.96 (t, 6H), 2.19 (s, 3H),
25 2.53 (m, 6H), 3.35 (m, 2H), 3.52 (m, 4H), 3.71 (m, 4H), 6.49 (d, IH), 6.96 (t, IH), 7.08 (d, IH), 7.22 (m, 2H), 7.54 (d, IH), 7.78 (s, IH), 7.85 (d, IH), 8.26 (d, IH), 8.64 (s, IH), 9.52 (s, IH), 10.26 (s, IH); Mass Spectrum: M+H+ 532. (m) The reactants were 6-chloro-N-[2^methyl-5-(2-morpholinopyrid-4-ylcarbonyIamino)phenyl]pyridine-3-carboxamide and 1,3-diaminopropane. The product
30 gave the following data: Mass Spectrum: M+H+ 490.

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(n) The reactants were 6-chloro-N-[2-methyI-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-3-carboxamideand 3-dimethyIaminopropyIamine. The product gave the following data: NMR Spectrum: (DMSOd6) 1.65 (m, 2H), 2.13 (s, 6H), 2.19 (s, 3H), 2.26 (t, 2H), 3.32-3.42 (m, 2H), 3.5-3.57 (m, 4H), 3.69-3.73 (m, 4H),
5 6.49 (d, IH), 7.09-7.18 (m, 2H), 7.22 (m, 2H), 7.58 (d, IH), 7.77 (s, IH), 7.85 (d, IH), 8.26 (d, IH), 8.64 (s, IH), 9.51 (s, IH), 10.25 (s, IH); Mass Spectrum: M+H+ 518. (o) The reactants were 6-chloro-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-3-carboxamide and 3-methylaminopropylarnine. The product gave the following data: Mass Spectrum: M+H+ 518.
10 (p) The reactants were 6-chloro-N-[2-methyl-5-(2-morpholinopyrid-
4-ylcarbonylamino)phenyl]pyridine-3-carboxamide and 3-morpholinopropylamine. The product gave the following data: NMR Spectrum: (DMSOd6) 1.64-1.76 (m, 2H), 2.19 (s, 3H), 2.35 (m, 6H), 3.35 (m, 2H), 3.54 (m, 8H), 3.71 (m, 4H), 6.49 (d, IH), 7.04-7.24 (m, 4H), 7.54 (d, IH), 7.78 (s, IH), 7.85 (d, IH), 8.26 (d, IH), 8.64 (s, IH), 9.51 (s, IH), 10.25
15 (s, IH); Mass Spectrum: M+H* 560.
(q) The reactants were 6-chloro-N'[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-3-carboxamideandN-(3-dimethylaminopropyl)-N-methylamine. The product gave the following data: NMR Spectrum: (DMSOd6) 1.65 (m, 2H), 2.13 (s, 6H), 2.19 (s, 3H), 2.19-2.24 (m, 2H), 3.07 (s, 3H), 3.53 (m, 4H), 3.58 (t,
20 2H), 3.71 (m, 4H), 6.68 (d, IH), 7.11 (d, IH), 7.22 (m, 2H), 7.58 (d, IH), 7.79 (s, IH), 8.01 (d, IH), 8.26 (d, IH), 8.72 (s, IH), 9.57 (s, IH), 10.26 (s, IH); Mass Spectrum: M+H+ 532.
(r) The reactants were 6-chloro-N-[2-methyl-5-(2-morpholinopyrid-4-yIcarbonylamino)phenyl]pyridine-3-carboxamide and 2-(N-methylpyrroIidin-
25 2-yl)ethylamine. The product gave the following data: NMR Spectrum: (DMSOdg) 1.38-1.48 (m, 2H), 1.56-1.65 (m, 2H), 1.8-1.96 (m, 2H), 2.0-2.3 (m, 2H), 2.19 (m, 7H), 3.27-3.3 (m, 2H), 3.52 (m, 4H), 3.72 (m, 4H), 6.49 (d, IH), 7.14 (m, 2H), 7.22 (m, 2H), 7.54 (d, IH), 7.78 (s, IH), 7.85 (d, IH), 8.26 (d, IH), 8.64 (s, IH), 9.51 (s, IH), 10.26 (s, IH); Mass Spectrum: M+H+ 544.

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(s) The reactants were 6-chloro-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-3-carboxamide and 1,4-diaminobutane. The product gave the following data: Mass Spectrum: M+H+ 504. (t) The reactants were 6-chloro-N-[2-methyl-5-(2-morpholinopyrid-5 4-ylcarbonyIamino)phenyl]pyridine-3-carboxarnide and l-methylpiperazine. The product gave the following data: Mass Spectrum: M+HT 516. (u) The reactants were 6-chloro-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-3-carboxamide and 1 -ethylpiperazine. The product gave the following data: NMR Spectrum: (DMSOd6) 1.05 (t, 3H), 2.2 (s, 3H), 2.3-2.4 (m, 10 2H), 2.4-2.5 (m, 4H), 3.5-3.55 (m, 4H), 3.55-3.65 (m, 4H), 3.7-3.75 (m, 4H), 6.9 (d, IH), 7.1-7.15 (m, IH), 7.2-7.25 (m, 2H), 7.55-7.6 (m, IH), 7.8 (s, IH), 8.0-8.1 (m, 1H),8.25-8.3 (m, IH), 8.75 (s, IH), 9.65 (s, IH), 10.3 (s, IH); Mass Spectrum: M+H+ 530. (v) The reactants were 6-chioro-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyI]pyridine-3-carboxamide and 1-methylhomopiperazine. The 15 product gave the following data: Mass Spectrum: M+£T 530.
(w) The reactants were 6-chloro-N-[2-methyl-5-(2-morpholinopyrid-4-y3carbonylamino)phenyl]pyridine-3-carboxamide and 1 -(2-hydroxyethyl)piperazine. The product gave the following data: Mass Spectrum: M+H+ 546. (x) The reactants were 6-chloro-N-[2-methyI-5-(2-morpholinopyrid-20 4-yIcarbonylamino)phenyl]pyridine-3-carboxamide and l,3-diamino-2-hydroxypropane. The product gave the following data: Mass Spectrum: M+H+ 506.
(y) The reactants were 2-chloro-N-[2-methyI-5-(3-trifluoromethyIbenzamido)phenyI]-pyridine-4-carboxamide [Example 19(3)] and morpholine. The product gave the following data: NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 3.53 (m, 4H), 3.72 (m, 4H), 7.14 (d, IH), 25 7.27 (d, 2H), 7.58 (d, IH), 7.74-7.82 (m, 2H), 7.94-(d, IH), 8.24-8.29 (m, 3H), 10.03 (s, IH), 10.45 (s, IH); Mass Spectrum: M+H+ 485.
(z) The reactants were 2-chloro-N-[2-methyl-5-(3-trifluoromethylben2amido)phenyl]-pyridine-4-carboxamide and ethylenediamine. The product gave the following data: NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 2.69 (m, 2H), 3.26 (m, 2H), 6.76 (t, IH), 6.92 (d, 2H), 30 7.25 (d, IH), 7.61 (d, IH), 7.77 (m, 2H), 7.95 (d, IH), 8.09 (d, IH), 8.26 (m, 2H), 9.91 (s, 1H), 10.45 (s, 1H); Mass Spectrum: M+H+ 458.

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(aa) The reactants were 2-chloro-N-[2-methyl-5-(4-cyanobenzamido)phenyI]pyridine-4-carboxamide [Example 19(4)] and morpholine. The product gave the following data: NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 3.53 (m, 4H), 3.74 (m, 4H), 7.12 (d, IH), 7.27 (d, 2H), 7.58 (d, IH), 7.82 (s, IH), 8.01 (d, 2H), 8.1 (d, 2H), 8.25 (d, IH), 10.06 (s, IH), 10.43
5 (s, IH); Mass Spectrum: M+H4 442. (bb) The reactants were 2-chloro-N-[2-methyl-5-(4-cyanobenzamido)phenyl]pyridine-4-carboxamide and ethylenediamine. The product gave the following data: NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.7 (m, 2H), 3.26 (m, 2H), 6.8 (t, IH), 6.92 (d, 2H), 7.2-7.3 (m, IH), 7.58 (d, IH), 7.81 (s, IH), 7.9-8.0 (m, 3H), 8.08 (m, 2H), 9.92 (s, IH),
10 10.25 (s. 1H1: Mass Spectrum: M+H* 415.
(cc) The reactants were 2-chloro-N-[2-methyl-5-(4-cyanobenzamido)phenyl]pyridine-4-carboxamide and l-methylpiperazine. The product gave the following data: NMR Spectrum: (DMSOd/) 2.19 (s, 3H), 2.22 (s, 3H), 2.43 (m, 4H), 3.53 (m, 8H), 3.71 (m, 4H), 7.09 (m, 2H), 7.26 (m, 3H)( 7.57 (d, IH), 7.78 (s, IH), 8.26 (m, 2H), 10.01 (s, IH), 10.3 (s,
15 IH): Mass Spectrum: M+H+ 516.
(dd) The reactants were 2-chloro-N-[2-methyl-5-(4-cyanobenzamido)phenyl]pyridine-4-carboxamide and l-(2-hydroxyethyl)piperazine. The product gave the following data: NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.43 (t, 2H), 2.48-2.52 (m, 4H); 3.5-3.56 (m, 10H),.3.69-3.73 (m, 4H), 7.07-7.12 (m, 2H), 7.26 (m, 3H), 7.57 (d, IH), 7.78 (s, IH), 8.26
20 (m, 2H), 10.01 (s, IH), 10.3 (s, IH); Mass Spectrum: M+H+ 546.
Example 23 N-[5-(4-trifluoromethylbenzamido)-2-methylphenyI]quinoIine-6-carboxamide
Using an analogous procedure to that described in Example 4,
25 4-trifluoromethylbenzoyl chloride was reacted with N-(5-amino-2-methylphenyI)-quinoline-6-carboxamide in the presence of triethylamine. The reaction mixture was stirred at ambient temperature for 18 hours and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound in 52%
30 yield: Mass Spectrum: M+H*450.

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Example24 6-chloro-N-[5-(3-f]uoro-5-morpholinobenzamido)-2-rncthylpheny]]pyridine-3-carboxamide
Using an analogous procedure to that described in Example 2 except that the reaction
mixture was heated to 100°C for 4 hours, 6-chloropyridine-3-carbonyl chloride was reacted
5 with N-(3-amino-4-methylphenyl)-3-fluoro-5-morpholinobenzamide to give the title
compound in 74% yield; NMR Spectrum: (DMSOd6): 2.2 (s, 3H), 3.18-3.22 (t, 4H), 3.75-3.85
(t, 4H), 6.9-7.0 (m, 1H), 7.1-7.15 (d, 1H), 7.2-7.3 (m, 2H), 7.55-7.6 (m, 1H), 7.65-7.7 (d, 1H),
7.8 (s, IH), 8.3-8.4 (m, IH), 8.95 (d, IH), .10.15 (s, 1H), 10.17 (s, 1H); Mass Spectrum
M+H+469and471.
10 The N-(3-amino-4-methylphenyf)-3-fluoro-5-morpholinobenzamide used as a starting
material was obtained as follows :-
A solution of 3,5-difluorobenzoyl chloride (2.82 g) in methylene chloride (20 ml) was added to a stirred mixture of 4-methyl-3-nitroaniline (2.28 g), triethylamine (4.35 ml) and methylene chloride (80 ml). The resultant mixture was stirred at ambient temperature for
15 16 hours. The precipitate was isolated, washed with methylene chloride and dried. There was thus obtained N-(4-methyl-3-nitrophenyl)-3,5-difluoroben2amide; NMR Spectrum: (DMSOd6) 2.43 (s, 3H), 7.43'(m, 2H), 7.63 (m, 2H), 7.95 (m, 2H), 8.43 (d, IH), 10.42 (s; IH); Mass Spectrum: M+H+ 293.
A mixture of a portion (1 g) of the material so obtained and morpholine (5 ml) was
20 stirred and heated to 100°C for 48 hours and then to 120°C for 24 hours. The reaction
mixture was cooled and poured into water (100 ml). The resultant solid was isolated, washed with water and dried. The material so obtained was purified by column chromatography on silica using a 1:1 mixture of isohexane and ethyl acetate as eluent. There was thus obtained N-(4-methyl-3-nitrophenyl)-3-fluoro-5-morphoIinoben2amide as a solid (0.53 g); NMR
25 Spectrum: (DMSOd6) 2.46 (s, 3H), 3.22 (t, 4H), 3.75 (t, 4H), 6.98 (m, IH), 7.12 (d, IH), 7.27 (s, IH), 7.46 (d, IH), 7.96 (m, IH), 8.43 (d, IH), 10.48 (s, IH); Mass Spectrum: M+H+ 360.
A portion (0.483 g) of the compound so obtained was dissolved in ethyl acetate (40 ml) and hydrogenated over 10% palladium-on-carbon catalyst (0.6 g) under an atmosphere of hydrogen until the uptake of hydrogen ceased. The catalyst was removed by
30 filtration and the filtrate was evaporated. The residue was triturated under diethyl ether (25 ml). The resultant solid was collected, washed with diethyl ether and dried. There was thus

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obtained the required starting material (0.341 g); NMR Spectrum: (DMSOd6) 1.99 (s, 3H), 3.19 ft 4H), 3.76 ft 4H), 4.8 (s, 2H), 6.75 (d, 1H), 6.82 (d, 1H), 6.9 (d, 1H), 7.02 (s, 1H), 7.04 (d, 1H), 7.23 (s,lH), 9.81 (s,lH).
5 Example 25 6-chIoro-N-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]pyridine-3-carboxamide
Using an analogous procedure to that described in Example 2 except that the reaction mixture was heated to 100°C for 2 hours, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-morpholino-5-trifluoromethylbenzamide. The reaction
10 mixture was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulphate and evaporated. The residue was triturated under a mixture of isohexane and diethyl ether. There was thus obtained the title compound in 63% yield; NMR Spectrum: (DMSOd6): 2.2 (s, 3H), 3.3 (m, 4H) 3.75 (t, 4H), 7.25 (d, 1H), 7.35 (s, 1H), 7.55-7.65 (m, 1H), 7.65 (s, 1H), 7.7-7.75 (m, 2H), 7.8 (d, 1H), 8.35-8.4 (m, 1H), 8.95 (d, 1H), 10.15 (s, 1H),
15 10.33 (s. 1H1; Mass Spectrum M+H+ 519 and 521.
The N-(3-arnino-4-memylphenyl)-3-morpholmo-5-1xifluoromethylberizamide used as a starting material was obtained as follows :-
Ethyl 3-morpholino-5-trifluoromethylbenzoate was prepared from ethyl 3-fluoro-5-trifluoromethylbenzoate by the method described by Brown et ai, Tetrahedron Lett., 1999,
20 40,1219. The material so obtained compound gave the following data :- NMR Spectrum: (CDC13) 1.36 (t, 3H), 3.19 ft 4H), 3.81 ft 4H), 4.34 (m, 2H), 7.22 (d, 1H), 7.72 (d, 1H), 7.76 (s, 1H).
A mixture of ethyl 3-morpholino-5-trifluoromethylben2oate (0.67 g), IN aqueous
sodium hydroxide solution (3.3 ml) and ethanol (6 ml) was stirred and heated to reflux for
25 15 minutes and then left to stand for 16 hours. The ethanol was evaporated and the residue
was dissolved in water (6 ml). Hydrochloric acid (1 M, 3.3 ml) was added and the resultant
solid was isolated, washed with water and dried. There was thus obtained 3-morpholino-
5-trifluoromethylbenzoic acid as a solid (0.464 g); NMR Spectrum: (DMSOd6) 3.25 (t, 4H),
3.73 ft 4H), 7.4 (s, 1H), 7.53 (s, 1H), 7.65 (s, 1H), 13.3 (s, 1H).
30 A solution of 3-morpholino-5-trifluoromethylbenzoyl chloride (11.43 g; obtained by
the reaction of the benzoic acid with oxalyl chloride using a conventional procedure) in

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methylene chloride (200 ml) was added to a stirred mixture of 4-methyl-3-nitroaniline (5.47 g), triethylamine (10 ml) and methylene chloride (200 ml). The resultant mixture was stirred at ambient temperature for 18 hours. The reaction mixture was washed with water and with a saturated aqueous sodium bicarbonate solution, dried (MgS04) and evaporated. The
5 resultant solid was stirred with diethyl ether (300 ml) for 16 hours. The resultant solid was collected, washed with diethyl ether and dried. There was thus obtained N-(4-methyl-3-nitrophenyl)-3-morpholino-5-fluorobenzamide as a solid (10.4 g); NMR Spectrum: (CDC13) 2.58 (s, 3H), 3.22 (t, 4H), 3.83 (t, 4H), 7.21 (s, 2H), 7.32 (d, 1H), 7.41 (s, 1H), 7.58 (s, 1H),7.82 (m, 1H), 8.02 (s, 1H), 8.23 (d, 1H).
10 The compound so obtained was dissolved in ethyl acetate (500 ml) and hydrogenated
over 10% palladium-on-carbon catalyst (1.1 g) under 3 atmospheres pressure of hydrogen until the uptake of hydrogen ceased. The catalyst was removed by filtration and the filtrate was evaporated. The residue was triturated under ethyl acetate to give the required starting material (8.1 g); NMR Spectrum: (CDC13) 2.01 (s, 3H), 3.23 (t, 4H), 3.75 (t, 4H), 4.81 (s, 2H),
15 6.77 (m, 1H), 6.83 (d, 1H), 7.02 (d, 1H), 7.25 (s, 1H), 7.58 (s, 1H), 7.63 (s, 1H), 9.9 (s, 1H).
Example 26
Using an analogous procedure to that described in Example 21, either 6-chloro-N-[5-(3-fluoro-5-morpholinobenzamido)-2-methylphenyl]pyridine-3-carboxamideor
20 6-chloro-N-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]pyridine-3-carboxamide as appropriate was reacted with the appropriate amine to give the compounds described in Table IV.
Table IV


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No. X Y Note
1 2-dimethylaminoethylamino fluoro (a)
2 2-dimethyIaminoethylamino trifluoromethyl (b)
3 N-methyl-N-(2-methylaminoethyl)amino fluoro (c)
4 N-methyl-N-(2-methylaminoetbyl)amino trifluoromethyl (d)
5 N-methyl-N-(2-dimethylaminoethyl)amino fluoro (e)
6 N-methyl-N-(2-dimethyIaminoeLhyl)amino trifluoromethyl (i)
7 2-amino-2-methylpropylarnino fluoro (g)
8 2-amino-2-methylpropylamino trifluoromethyl (h)
9 3-aminopropylamino fluoro 0)
10 3-aminopropylamino trifluoromethyl (i)
11 3-dimethylaminopropylamino trifluoromethyl (k)
12 N-methyI-N-(3-methyIaminopropyl)amino trifluoromethyl 0)
13 N-methyl-N-(3-dimethyiaminopropyl)amino fluoro (m)
14 N-methyl-N-(3-dimethylaminopropyl)amino trifluoromethyl (n)
15 4-aminobutylamino fluoro (o)
16 4-aminobutylamino trifluoromethyl (P)
17 4-dimethyIaminobutylamino trifluoromethyl (q)
18 4-methylpiperazin-1 -yl fluoro (r)
19 4-methyIpiperazin-l -yl trifluoromethyl (s)
20 homopiperazin-1 -yl fluoro (t)
21 homopiperazin-1 -yl trifluoromethyl 00
22 3-morphoIinopropylamino fluoro (v)
23 3 -morpholinopropIamino trifluoromethyl (w)
Notes
(a) The product gave the following data: NMR Spectrum: (DMSOdfi) 2.2-2.25 (rn, 9H), 2.4-2.5 (m, 2H), 3.2-3.3 (m, 4H), 3.4-3.5 (m, 2H), 3.75-3.8 (m, 4H), 6.6 (d, 1H)? 5 6.95-7.05 (m, 2H), 7.1-7.2 (m, 1H), 7.2-7.3 (m, 1H), 7.35 (s, 1H), 7.55-7.6 (m, 1H), 7.8 (s, 1H), 7.9-7.95 (m, 1H), 8.7 (s, 1H), 9.5 (s, 1H), 10.15 (Sj 1H); Mass Spectrum: M+H+ 521.

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(b) The product gave the following data: NMR Spectrum: (DMSOd6) 2.15-2.25 (m, 9H), 2.4-2.5 (m, 2H), 3.4-3.5 (m, 2H), 3.75-3.85 (m, 4H), 6.55-6.6 (m, IH), 7.0-7.05 (m, IH), 7.2-7.3 (m, IH), 7.4 (s, IH), 7.6-7.65 (m, IH), 7.7 (s, IH), 7.75 (s, IH), 7.8 (s, IH),. 7.9-7.95 (m, IH), 8.7 (s, IH), 9.55 (s, IH), 10. 3 (s, 1H); Mass Spectrum: M+H+ 571.
5 (c) The product gave the following data: Mass Spectrum: M+H+ 521.
(d) The product gave the following data: Mass Spectrum: M+H+ 571.
(e) The product gave the following data: NMR Spectrum: (DMSOd6) 2.1 -2.15 (m, 3H), 2.15-2.25 (m, 8H), 2.4-2.5 (m, 2H), 3,1 (s, 3H), 3.2-3.3 (m, 4H), 3.7-3.75 (m, 2H), 3.75-3.8 (m, 4H), 6.7 (d, IH), 6.95-7.0 (m, IH), 7.1-7.2 (m, IH), 7.2-7.3 (m, IH), 7.35 (s,
10 IH), 7.55-7.6 (m, IH), 7.8 (s, IH), 8.0-8.1 (m, IH), 8.75 (m, IH), 9.6 (s, IH), 10.15 (s, IH); Mass Spectrum: M+H 535.
(f) The product gave the following data: NMR Spectrum: (DMSOd6) 2.2-2.3 (m, 9H),
2.4-2.5 (m, 2H), 3.1 (s, 3H), 3.25-3.35 (m, 4H), 3.7-3.8 (m, 2H), 3.8-3.9 (m, 4H), 6.65-
6.75 (m, IH), 7.2-7.3 (m, IH), 7.4 (s, IH), 7.55-7.6 (m, IH), 7.65 (s, IH), 7.75 (s, IH), 7.8
15 (s, IH), 8.0-8.1 (m, IH), 8.75 (s, IH), 9.6 (s, IH), 10. 3 (s, IH); Mass Spectrum: M+H+ 585.
(g) The product gave the following data: NMR Spectrum: (DMSOd«) 1.05 (s, 6H), 2.2
(s, 3H), 3.2-3.4 (m, 4H), 3.75-3.8 (m, 4H), 6.65 (d, IH), 6.95-7.05 (m, 2H), 7.1-7.2 (m,
IH), 7.2-7.3 (m, IH), 7.35 (s, IH), 7.55-7.6 (m, IH), 7.8 (s, IH), 7.9-7.95 (m, IH), 8.65 (s,
20 IH), 9.55 (s, IH), 10.15 (s, 1H1: Mass Spectrum: M+H+521.
(h) The product gave the following data: Mass Spectrum: M+H+ 571.
(i) The product gave the following data: Mass Spectrum: M+H+ 507.
(j) The product gave the following data: Mass Spectrum: M+H+ 557.
(k) The product gave the following data: NMR Spectrum: (DMSOd6) 1.65-1.75 (m,
25 2H), 2.15 (s, 6H), 2.2 (s, 6H), 2.25-2.3 (m, 2H), 3.25-3.35 (m, 4H), 3.75-3.8 (m, 4H), 6.5-
6.55 (m, IH), 7.15-7.2 (m, IH), 7.2-7.3 (m, IH), 7.4 (s, IH), 7.58-7.62 (m, IH), 7.7 (s,
IH), 7.75 (s, IH), 7.8 (s, IH), 7.9-7.95 (m, IH), 8.7 (s, IH), 9.55 (s, IH), 10.3 (s, IH);
Mass Spectrum: M+H+ 585.
(I) The product gave the following data: Mass Spectrum: M+H+ 585.
30 (m) The product gave the following data: NMR Spectrum: (DMSOd6) 1.6-1.7 (m, 2H),
2.1 (s, 6H), 2.1-2.2 (m, 5H), 3.0 (s, 3H), 3.1-3.2 (m, 4H), 3.45-3.55 (m, 2H), 3.6-3.7 (m,

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4H), 6.6-6.65 (m, IH), 6.85-6.9 (m, IH), 7.0-7.05 (m, IH), 7.1-7.15 (m, IH), 7.2 (s, IH), 7.45-7.5 (m, IH), 7.7 (s, IH), 7.95-8.0 (m, IH), 8.65 (s, IH), 9.5 (s, IH), 10.05 (s, IH); Mass Spectrum: M+HT 549.
(n) The product gave the following data: NMR Spectrum: (DMSOdJ 1.65-1.75 (m,
5 2H), 2.15 (s, 6H), 2.2-2.3 (m, 5H), 3.1 (s, 3H), 3.3-3.4 (m, 4H), 3.6-3.7 (m, 2H), 3.75-3.85 (m, 4H), 6.65-6.75 (m, IH), 7.2-7.3 (m, IH), 7.4 (s, IH), 7.55-7.65 (m, IH), 7.7 (s, IH), 7.75 (s, IH), 7.8 (s, IH), 8.0-8.05 (m, IH), 8.75 (s, IH), 9.6 (s, IH), 10.3 (s, IH); Mass Spectrum: M+H+ 599.
(o) The product gave the following data: Mass Spectrum: M+H+ 521.
10 (p) The product gave the following data: Mass Spectrum: M+H+ 571. (q) The product gave the following data: Mass Spectrum: M+JT 599. (r) The product gave the following data: NMR Spectrum: (DMSOd6) 2.2-2.3 (m, 6H), 2.40-2.45 (m, 4H), 3.2-3.3 (m, 4H), 3.6-3.7 (m, 4H), 3.7-3.8 (m, 4H), 6.9 (d, IH), 6.95-7.05 (m, IH), 7.15-7.2 (m, IH), 7.2-7.25 (m, IH), 7.3 (s, IH), 7.55-7.6 (m, IH), 7.8 (s,
15 IH), 8.05-8.1 (m, IH), 8.75 (s, 1H),9.65 (s, IH), 10.15 (s, IH): Mass Spectrum: M+H+ 533.
(s) The product gave the following data: Mass Spectrum: M+H+ 583. (t) The product gave the following data: NMR Spectrum: (DMSOd*) 1.75-1.85 (m, 2H), 2.2 (s, 3H), 2.65-2.75 (m, 4H), 2.85-2.9 (m, 2H), 3.2-3.3 (m, 5H), 3.7-3.85 (m, 9H),
20 6.75 (d, IH), 6.95-7.0 (m, IH),' 7.1-7.2 (m, IH), 7.2-7.3 (m, IH), 7.35 (s, IH), 7.55-7.6 (m, IH), 7.8 (s, IH), 8.0-8.1 (m, IH), 9.6 (s, IH), 10.15 (s, IH); Mass Spectrum: M+H+ 533. (u) The product gave the following data: Mass Spectrum: M-f-H+ 583. (v) The product gave the following data: NMR Spectrum: (DMSOd6) 1.7-1.8 (m, 2H), 2.2 (s, 3H), 2.3-2.4 (m, 6H), 3.2-3.3 (m, 4H), 3.3-3.4 (m, 2H), 3.5-3.6 (m, 4H), 3.75-3.8 25 (m, 4H), 6.5-6.55 (m, IH), 6.95-7.0 (m, IH), 7.1-7.2 (m, 2H), 7.2-7.
25 (m, IH), 7.3 (s, IH), 7.55-7.6 (m, IH), 7.8 (s, IH), 7.9-7.95 (m, IH), 8.7 (s, IH), 9.55 (s, IH), 10.2 (s, IH); Mass Spectrum: M+H+ 577.
(w) The product gave the following data: NMR Spectrum: (DMSOd6) 1.7-1.8 (m, 2H), 2.2 (s, 3H), 2.3-2.45 (m, 7H), 3.5-3.65 (m, 4H), 3.75-3.85 (m, 4H), 6.5-6.55 (m, IH), 7.15-
30 7.2 (m, IH), 7.2-7.3 (m, IH), 7.4 (s, IH), 7.55-7.6 (m, IH), 7.7 (s, IH), 7.75 (s, IH), 7.8

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(s, 1H), 7.9-7.95 (m, 1H), 8.65(s, lH),9.55(s, 1 H), 10.3 (s, lH); Mass Spectrum: M+HT 627.
Example 27 6-chloro-N-[2-chloro-5-(3-fluoro-5
5-morpholinobenzamido)phenyl]pyridine-3-carboxamide
Using an analogous procedure to that described in Example 2, 6-chloropyridine-3-carbonyI chloride was reacted with N-(3-amino-4-chlorophenyl)-3-fluoro-5-morpholinobenzamide to give the title compound in 48% yield; NMR Spectrum: (DMSOd6) 3.23 (rn, 4H), 3.74 (m, 4H), 6.97 (d, 1H), 7.12 (d, 1H), 7.26 (s, IH), 7.54 (d, 1H), 7.71 (d,
10 2H), 8.07 (s, 1H), 8.35 (d, 1H), 8.95 (s, 1H), 10.37 (m, 2H); Mass Spectrum: M+H+ 487.
The N-(3-amino-4-chlorophenyl)-3-fluoro-5-morpholinobenzamide used as a starting material was obtained as follows :-
3,5-Difluorobenzoyl chloride (12.6 ml) was added slowly to a stirred mixture of 2,4-diaminochlorobenzene (14.3 g), triethylamine (15.3 ml) and methylene chloride (150 ml)
15 and the resultant mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was triturated under water. The resultant solid was isolated, washed with a saturated aqueous sodium bicarbonate solution and dried under vacuum. The material so obtained was dissolved in a minimum amount of ethyl acetate and precipitated by the sddition of isohexane. The resultant solid was isolated, washed with one equivalent of
20 dilute aqueous hydrochloric acid and dried under vacuum. There was thus obtained
N-(3-ammo-4-chlorophenyl)-3,5-difluorobenzamide (26.83 g); NMR Spectrum: (DMSOd6) 5.37 (br s, 2H), 6M (d, 1H), 7.13 (d, 1H), 7.32 (d, 1H), 7.46 (m, 1H), 7.63 (d, 2H), 10.16 (s, 1H); Mass Spectrum: M+H+ 283.
A mixture of a portion (10 g) of the material so obtained and morpholine (36 ml) was
25 stirred and heated to 100°C for 15 days. The mixture was poured into a mixture of ice and water and the resultant solid was isolated and washed with water. The solid was dissolved in ethyl acetate and the solution was dried over magnesium sulphate. The filtered solution was reduced in volume by evaporation under vacuum until precipitation was observed. A small quantity of diethyl ether was added followed by isohexane. The resultant solid was isolated
30 and dried under vacuum to give N-(3-amino-4-chlorophenyl)-3-fluoro-
5-morpholinobenzamide (11.23 g); NMR Spectrum: (DMSOd6) 3.21 (m, 4H), 3.73 (m, 4H),

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5.33 (br s, 2H), 6.86 (d, IH), 6.95 (d, IH), 7.09 (t, 2H), 7.24 (s, IH), 7.3 (s, IH), 9.99 (s, IH); Mass Spectrum: M+H+ 350.
Example 28 6-chIoro-N-[2-chIoro-5-(2-morpholinopyrid-
5 4-ylcarbonylamino)phenyl]pyridine-3-carboxamide
Using an analogous procedure to that described in Example 2 except that the reaction mixture was heated to 80°C for 16 hours, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino-4'ChlorophenyI)-2-morpholinopyridine-4-carboxamide. The reaction mixture was evaporated and the residue was triturated under water. The resultant solid was
10 isolated, washed with a saturated aqueous sodium bicarbonate solution and dried in a vacuum oven. The material so obtained was purified by column chromatography on an ion exchange column (isolute CBA column from International Sorbent Technology Limited, Hengoed, Mid-Glamorgan, UK) using methanol as eluent. There was thus obtained the title compound (0.493 g) in 58% yield; NMR Spectrum: (DMSOd6) 3.51 (m, 4H), 3.71 (m, 4H), 7.09 (d, IH),
15 7.23 (s, IH), 7.55 (d, IH), 7.71 (d, 2H), 8.06 (s, IH), 8.27 (d, IH), 8.35 (d, IH), 8.96 (s, IH), 10.39 (s, IH), 10.49 (s, IH); Mass Spectrum: M+JT 472.
The N-(3-amino-4-chloropheny])-2-morphoIinopyridine-4-carboxamide used as a starting material was obtained as follows :-
A solution of 2-chloropyridine-4-carbonyl chloride [obtained by the reaction of oxalyl
20 chloride (2.1 ml) and 2-chloropyridine-4-carboxyIic acid (3.15 g) in a mixture of methylene chloride (50 ml)and DMF (a few drops)] in methylene chloride (10 ml) was added slowly to a stirred mixture of 2,4-diaminochlorobenzene (2.85 g) and triethylamine (7 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate
25 and evaporated. The residue was triturated under methanol and there was thus obtained N-[2-chIoro-5-(2-chIoropyrid-4-ylcarbonylamino)phenyl]-2-chloropyridine-4-carboxamide (1.46 g); NMR Spectrum: (DMSOd.) 7.56 (d, IH), 7.72 (d, IH), 7.87 (m, 2H), 7.98 (s, 2H), 8.10 (s, IH), 8.63 (t, 2H); Mass Spectrum: M+H+ 421.
The filtrate from the trituration was evaporated and the residue was purified by
30 column chromatography on an ion exchange column (isolute SCX column from
International Sorbent Technology Limited, Hengoed, Mid-Glamorgan, UK) using a 99:1

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mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent.
There was thus obtained N-(3-amino-4-chlorophenyl)-2-chIoropyridine-4-"carboxamide
(1.65 g); NMR Spectrum: (DMSOd,) 5.41 (br s, 2H), 6.87 (d, IH), 7.15 (d, IH), 7.33 (s, .
IH), 7.82 (d, IH), 7.94 (s, IH), 8.58 (d, IH), 10.37 (s, IH); Mass Spectrum: M+H+ 282.
5 A mixture of N-(3-amino-4-chlorophenyl)-2-chloropyridine-4-carboxamide
(1.53 g) and morpholine (10 ml) was stirred and heated to 120°C for 16 hours. The reaction mixture was poured into a mixture of ice and water and the resultant solid was isolated, washed with water and dried in a.vacuum oven. There was thus obtained the required starting material as a solid (1.62 g); NMR Spectrum: (DMSOd6) 3.51 (m, 4H), 10 3.72 (m, 4H), 5.36 (br s, 2H), 6M (d, IH), 7.08 (d, IH), 7.15 (d, IH), 7.20'(s, IH), 7.33 (s, IH), 8.25 (d, IH),
10. 13 (s, IH); Mass Spectrum: M+H+ 333.
Example 29 N-[2-chloro-5-(2-morphoimopyrid-4-yIcarbonylamino)phenyI]-6-[N-(3-dimethylaminopropyI)-N-methyIamino]pyridine-3-carboxamide
15 Using an analogous procedure to that described in Example 21, 6-chIoro-N-[2-chloro-
5-(2-morpholinopyrid-4-ylcarbonyIamino)phenyl]pyridine-3-carboxamide was reacted with N-(3-dimethyIaminopropyl)-N-methyIamine to give the title compound in 73% yield; NMR Spectrum: (DMSOd6) 1.67 (m, 2H),2.12 (s, 6H), 2.21 (t, 2H), 3.07 (s, 3H), 3.51 (m, 4H), 3.58 (m, 2H), 3.71 (m, 4H), 6.69 (d, IH), 7.1 (d, IH), 7.23 (s, IH), 7.5 (d, IH), 7.68 (d, IH), 8.04
20 (m, 2H), 8.28 (d, IH), 8.72 (s, IH), 9.7 (s, IH), 10.44 (s, IH); Mass Spectrum: M+H+ 552 and 554.
Example 30 N-[2-chIoro-5-(2-morphoIinopyrid-4-ylcarbonylamino)phenyI]-6-(4-dimethylaminobutyIamino)pyridine-3-carboxamide
25 Using an analogous procedure to that described in Example 21, 6-chloro-N-[2-chloro-
5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-3-carboxamide was reacted with 4-dimethylarninobutylamine to give the title compound in 61% yield; NMR Spectrum: (DMSOd6) 1.49 (m, 4H), 2.09 (s, 6H), 2.19 (t, 2H), 3.51 (m, 4H), 3.71 (m, 4H), 6.49 (d, IH), 7.1 (d, IH), 7.23 (m, 2H), 7.5 (d, IH), 7.68 (d, IH), 7.89 (d, IH), 8.06 (s, IH), 8.27 (d, IH),
30 8.64 (s, IH), 9.64 (s, IH), 10.44 (s, IH); Mass Spectrum: M+H+ 552 and 554.

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Example31 2-chloro-N-I2~chloro-5-(2-morpholmopyrid-4-ylcarbonyIamino)phenyl]pyridine-4-carboxamide
Using an analogous procedure to that described in Example 2, except that the reaction mixture was heated to 80°C for 5 hours, 2-chloropyridine-4-carbonyl chloride was reacted
5 with N-(3-amino-4-chlorophenyl)-2-moipholinopyridine-4-carboxamide to give the title compound in 95% yield; NMR Spectrum: (DMSOd6) 3.53 (m; 4H), 3.75 (m, 4H), l.\ 1 (d, IH), 7.27 (s, IH), 7.56 (d, IH), 7.73 (d, IH), 7.88 (d, IH), 7.98 (s, IH), 8.06 (s, IH), 8.26 (d, IH), 8.64 (d, IH), 10.53 (m, 2H); Mass Spectrum: M+H+ 472.
10 Example 32 N-[2-chloro-5-(2-morphoIinopyrid-4-ylcarbonylamino)phenyl]-2-[N-(3-dimelhylarainopropyl)-N-methyIamino]pyridine-4-carboxamide
Using an analogous procedure to that described in Example 21, 2-chloro-N-[2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give the title compound in 46% yield; NMR
15 Spectrum: (DMSOd6) 1.67 (m, 2H), 2.11 (s, 6H), 2.21 (m, 2H), 3.04 (s, 3H), 3.51 (m, 6H), 3.71 (m, 4H), 6.97 (d, IH), 7.09 (m, 2H), 7.23 (s, IH), 7.54 (d, IH), 7.71 (d, IH), 8.04 (s, IH), 8.20 (d, IH), 8.27 (d, IH), 10.13 (s, IH), 10.47 (s, IH); Mass Spectrum: M+H+ 552.
Example 33 2-[N-(2-dimethylaminoethyI)-N-methyIamino]-N-[2-methyI-20 5-(2-morphoIinopyrid-4-yIcarbonyIamino)phenyI]pyridine-4-carboxamide
Using an analogous procedure to that described in Example 21,2-chloro-N-[2-rnethyl-5-(2-morphoIinopyrid-4-yIcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-(2-dimethy]aminoethyl)-N-methylamine to give the title compound in 44% yield; NMR Spectrum: (DMSOd6) 2.17 (s, 6H), 2.19 (s, 3H), 2.4 (t, 2H), 3.05 (s, 3H), 3.5-3.54 (m, 4H)
25 3.65-3.72 (m, 6H), 6.75 (s, IH), 6.94 (d, IH), 7.02 (s, IH), 7.1 (d, IH), 7.24 (d, 2H), 7.58 (d, IH), 7.78 (s, IH), 8.19 (d, IH), 8.26 (d, IH), 9.96 (s, IH), 10.28 (s, IH); Mass Spectrum: M+JT518.
Example 34 2-[N-(3-dimethylaminopropyI)-N-methylamino]-N-[2-methyI-
30 5-(2-morpholinopyrid-4-yIcarbonylamino)phenyI]pyridine-4-carboxamide

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Using an analogous procedure to that described in Example 21, 2-chloro-N-[2-methyl-5-(2-morpholinopyrid-4-yIcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give the title compound in 56% yield; Mass Spectrum: M+H+ 532.
5 Example 35 N-[2-chioro-5-(2-morphoIinopyrid-4-ylcarbonylamino)phenyll-2-morphoIinopyridine-4-carboxamide
Using an analogous procedure to that described in Example 21, N-[2-chJoro-5-(2-chloropyrid-4-ylcarbonylamino)phenyI]-2-chloropyridine-4-carboxamide was reacted
10 with morpholine to give the title compound.in 84% yield; NMR Spectrum: (DMSOd6) 3.52 (m, 8H), 3.73 (m, 8H), 7.12 (m, 2H), 7.26 (d, 2H), 7.55 (d, IH), 7.73 (d, IH), 8.04 (s, IH), 8.3 (m, 2H), 10.21 (s, IH), 10.48 (s, IH); Mass Spectrum: M+H+ 523.
Example 36 N-[2-chIoro-5-(2-piperidinopyrid-4-ylcarbonylamino)phenyl]-
15 2-piperidmopyridine-4-carboxamide
Using an analogous procedure to that described in Example 21, N-[2-chloro-5-(2-chloropyrid-4-ylcarbpnyIamino)phenyI]-2-chloropyridine-4-carboxamide was reacted with piperidine to give the title compound in 96% yield; NMR Spectrum: (DMSOd6) 1.6 (m, 12H), 3.58 (m, 8H), 7.01 (m, 2H), 7.24 (d, 2H), 7.54 (d, IH), 7.73 (d, IH), 8.02 (s, IH), 8.13
20 (m, 2H), 10.09 (br s, IH), 10.44 (brs, IH); Mass Spectrum: M+H+ 519.
Example 37 N-[2-chIoro-5-(2-morphoIinopyrid-4-yIcarbonylamino)phenyI]-2-(4-methylpiperazin-l-y|)pyridine-4-carboxamide
Using an analogous procedure to that described in Example 21, 2-chloro-N-[2-chloro-
25 5-(2-morphoIinopyrid-4-yIcarbonyIamino)phenyl]pyridine-4-carboxamide was reacted with N-methylpiperazine to give the title compound in 69% yield; NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 2.4 (m, 4H), 3.53 (m, 8H), 3.71 (xn, 4H), 7.09 (m, 2H), 7.25 (d, 2H), 7.53 (d, lH),7.71(d, IH), 8.02 (s, IH), 8.26 (t, IH), 10.19 (s,lH), 10.48 (s, IH): Mass Spectrum: M+H* 536.

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Bxample38 N-[2-chIoro-5-(2-morpholinopyrid-4-yIcarbonyIamino)phenyl]-2-[4-(2-hydroxycthyl)piperazin-l-yl]pyridine-4-carboxamide
Using an analogous procedure to that described in Example 21,2-chloro-N-[2-chloro-5-(2-morphoIinopyrid-4-ylcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with
5 N-(2-hydroxyethyl)piperazine to give the title compound in 62% yield; NMR Spectrum: (DMSOd6) 2.45 (m, 8H), 3.53 (m, 8H), 3.71 (m, 4H), 4.4 (t, IH), 7.07 (t, 2H), 7.25 (d, 2H), 7.54 (d, IH), 7.71 (d, IH), 8.02 (s, 1H),. 8.26 (t, 2H), 10.19 (s, IH), 10.47 (s, IH); Mass Spectrum: M+H4 566.
10 Example 39 N-[5-(3-dimethylaminobenzamido)-2-methyIphenyl]quinoHne-6-carboxamide
Diisopropylethylamine (0.174 ml) was added to a stirred mixture of 3-morphoIinobenzoic acid (0.104 g), N-(5-amino-2-methyIphenyl)quinoline-6-carboxaraide (0.14 g), 2-(7-a2abenzotriazoI-I-yl)-l>l,3,3-tetramethyIuronium hexafluorophosphate(V)
15 (0.23 g) and DMF (1 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The reaction mixture was poured into water and the resultant solid was isolated, washed with a saturated aqueous sodium bicarbonate solution and dried in a vacuum oven. There was thus obtained the title compound (0.216 g); NMR Spectrum: (DMSOd6) 2.25 (s, 3H), 3.18 (m, 4H), 3.75 (m, 4H), 7.14 (d, IH), 7.25 (d, IH), 7.36 (m, 2H), 7.44 (s, IH), 7.62
20 (m, 2H), 7.86 (s, IH), 8.13 (d, IH), 8.28 (d, IH), 8.52 (d, IH), 8.65 (s, IH), 9.0 (s, IH), 10.14 (m,-2H); Mass Spectrum: M+HM67.
Example 40 Pharmaceutical compositions
The following illustrate representative pharmaceutical dosage forms of the invention
25 as defined herein (the active ingredient being termed "Compound X"), for therapeutic or prophylactic use in humans:
30

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(a) Tablet I mg/tablet
Compound X 100
Lactose Ph.Eur 182.75
Croscarmellose sodium 12.0
5 Maize starch paste (5% w/v paste) 2.25
Magnesium stearate 3.0
(b) Tablet II mg/tablet
Compound X 50
10 Lactose Ph.Eur..... .\ 223.75
Croscarmellose sodium 6.0
Maize starch 15.0
Polyvinylpyrrolidone (5% w/v paste) 2.25
Magnesium stearate 3.0
15
(c) Tablet III mg/tablet
Compound X ; 1.0
Lactose Ph.Eur 93.25
Croscarmellose sodium 4.0
20 Maize starch paste (5% w/v paste) 0.75
Magnesium stearate......: 1.0
(d) Capsule mg/capsule
Compound X 10
25 Lactose Ph.Eur 488.5
Magnesium 1.5
30

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(e) Injection I (50 mg/ml)
Compound X 5.0% w/v
IM Sodium hydroxide solution 15.0% v/v
O.IM Hydrochloric acid (to adjust pH to 7.6)
5 Polyethylene glycol 400 4.5% w/v
Water for injection to 100%
(f) Injection II (10 mg/ml)
Compound X 1.0% w/v
10 Sodium phosphate BP 3.6% w/v
0.1M Sodium hydroxide solution 15.0% v/v
Water for injection to 100%
(g) Injection III (1 mg/ml, buffered to pH6)
15 Compound X : 0.1% w/v
Sodium phosphate BP 2.26% w/v
Citric acid 0.38% w/v
Polyethylene glycol 400 3.5% w/v
Water for injection to 100% 20
(h) Aerosol I mg/ml
Compound X 10.0
Sorbitan trioleate 13.5
Trichlorofluoromethane 910.0
25 Dichlorodifluoro methane 490.0
30

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(i) Aerosol II mg/ml
Compound X 0.2
Sorbitan trioleate 0.27
Trichlorofluoromethane 70.0
5 Dichlorodifluoromethane 280.0
Dichlorotetrafluoroethane 1094.0
(j) Aerosol III mg/ml
Compound X 2.5
10 Sorbitan'trioleate 3.38
Trichlorofluoromethane 67.5
Dichlorodifluoromethane 1086.0
Dichlorotetrafluoroethane 191.6
15 (k) Aerosol IV mg/ml
Compound X 2.5
Soya lecithin 2.7
Trichlorofluoromethane 67.5
Dichlorodifluoromethane 1086.0
20 Dichlorotetrafluoroethane 191.6
(1) Ointment ml
Compound X 40 mg
Ethanol 300^1
25 Water ; 300^1
1 -Dodecylazacycloheptan-2-one 50 ^il
Propylene glycol to 1 ml
30

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Note
The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. The aerosol formulations (h)-(k)
5 may be used in conjunction with standard, metered dose aerosol dispensers, and the suspending agents sorbitan trioleate and soya lecithin may be replaced by an alternative suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.

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CLAIMS
1. An amide derivative of the Formula I


I

5 wherein R3 is (1 -6C)alkyl or halogeno; Q1 is heteroaryl which is optionally substituted with 1, 2, 3 or 4 substituents selected from hydrox-y, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (l-6C)alkyl, (2-6C)alkenyI, (2-6C)alkynyl, (l-6C)alkoxy, (l-3C)alkylenedioxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyI, (l-6C)alkylamino, 10 di-[(l-6C)alky]]amino, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl,
N)N-di-[(l-6C)alkyl]carbamoyl) (2-6C)alkanoyl, (2-6C)alkanoyloxy, (l-6C)alkanoylamino, N-(l-6C)alkylsulphamoyl)N,N-di-[(l-6C)alkyl]sulphamoyl, (l-6C)aIkanesulphonylamino, N-( 1 -6C)alkyl-(l -6C)alkanesulphonylamino, halogeno-( 1 ~6C)alkyl, hydroxy-( 1 -6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)aIkyIarnmo-15 (l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, carboxy-(l-6C)alkyls (l-6C)alkoxycarbonyl-(l-6C)alkyl, carbaraoyl-(l-6C)alkyl, N-(l-6C)alkylcarbamoyl-(l-6C)alkyl, N}N-di-[(l-6C)alkyl]carbamoyI-(l-6C)a]kyl,halogeno-(2-6C)alkoxy,hydroxy-(2-6C)aIkoxy, (l-6C)alkoxy-(2-6C)alkoxy, cyano-(l-6C)alkoxy> carboxy-(l-6C)alkoxy, (l-6C)alkoxycarbonyl-(l-6C)alkoxy, carbamoyl-(l-6C)alkoxy,N-(l-6C)alkylcarbamoyI-20 (l-6C)alkoxy, N3N-di-[(l-6C)alky]]carbamoyl-(l-6C)alkoxy> amino-(2-6C)alkoxy, (l-eQalkylammo-(1-6C)alkoxy-(1-6C)alkyllamino-eQalkoxy.halogeno-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (l-6C)alkoxy-(2-6C)alkylamino, cyano-(l-6C)alkylamino, carboxy-(l-6C)alkylamino, (l-6C)alkoxycarbonyI-(l-6C)alkylamino, carbamoyl-(l-6C)alkylamino, N-(l-6C)alkylcarbamoyl-(l-6C)alkylamino, 25 N,N-di-[(l-6C)alkyl]carbamoyl-(l-6C)alkylamino, amino-(2-6C)alkylamino, (1 -6C)alkylamino-(2-6C)alkylamino? di-[( 1 -6C)alkyl]amino-(2-6C)alkylamino, N^l-eOalkyl-halogeno-Cl-eQalkylamino.N-d-eQalkyl-hydroxy-eQalkylamino,

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N-(l-6C)alkyl-(l-6C)alkoxy-(2-6C)alkylamino,N-(l-6C)alkyl-cyano-(l-6C)alkylamino5 Nha]ogeno- ' (2-6C)alkanoyIamino, hydroxy-(2-6C)alkanoylamino, (1 -6C)alkoxy-(2-6C)alkanoylamino, cyano-(2-6C)aIkanoylamino, carboxy-(2-6C)alkanoylamino, (l-6C)alkoxycarbonyl-(2-6C)alkanoyIamino, carbamoyl-(2-6C)alkanoyIamino)N-(l-6C)alkylcarbamoyl-10 (2-6C)alkanoylamino)N,N-di-[(1-6C)alkyl]carbamoyl-(2-6C)alkanoylamino>
arnino-(2-6C)alkanoylamino, (l-6C)alkylamino-(2-6C)alkanoylaminoJ di-[(l-6C)alkyl]amino-(2-6C)alkanoylamino, aryl, aryl-(l-6C)alkyl, aryl-(l-6C)alkoxy, aryloxy, arylamino, N-(l -6C)alkyl-arylamino, aryl-(l -6C)alkylamino, N-(l -6C)alkyl-aryl-(l -6C)alkylamino, aroylamino, arylsulphonylamino, N-arylsulphamoyl, aryl-(2-6C)alkanoylamino, heteroaryl, 15 heteroaryI-(l-6C)alkyl, heteroaryloxy, heteroaryl-(l~6C)alkoxy, heteroarylarnino,
N-(1-6C)alkyl-heteroarylamino, heteroaryl-( 1 -6C)alky 1 amino, N-(l -6C)alkyl-heteroaryl-(l-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino, heterocyclyl, heterocyclyl-(l-6C)alkyl, heterocyclyloxy, heterocycly!-(l-6C)alkoxy, heterocyclylamino, N-(l-6C)alkyl-20 heterocyclylamino, heterocycIyl-(]-6C)alky]amino, N-(l-6C)alkyl-heterocydyl-(l-6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino, N-heterocyclylsulphamoyl and heterocyclyl-(2-6C)alkanoylamino,
and wherein any of the substituents on Q1 defined hereinbefore which comprise a CH2 group which is attached to 2 carbon atoms or a CH3 group which is attached to a carbon atom may 25 optionally bear on each said CH2 or CH3 group a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and heterocyclyl; and wherein any aryl, heteroaryl or heterocyclyl group in a substituent on Q1 may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (l-6C)alkyl, (l-6C)aIkoxy, carboxy, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl,N,N-di-[(l-6C)alkyl]carbamoyI, 30 (2-6C)alkanoyl, amino, (l-6C)alkylamino, di-[(I-6C)alkyl]amino, halogeno-(l-6C)alkyl,

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hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)a]kyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, aryl and aryl-(l-6C)alkyl; R2 is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, (l-6C)alkoxycarbonyl, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)aIkoxy, 5 (l-6C)alkylamino or di-[(l-6C)alkyl]amino; p is 0, 1 or 2; q is 0, 1,2, 3 or 4; and
Q2 is aryl, aryl-(l-6C)alkoxy, aryloxy, arylamino, N-(l-6C)alkyl-arylamino, aryl-(l-6C)alkylamino, N-(l-6C)alkyl-aryl-(l-6C)alkylamino, aroylamino, arylsulphonylamino, 10 N-arylsulphamoyl, aryl-(2-6C)aIkanoylamino, cycloalkyl, heteroaryl, heteroaryloxy, heteroaryl-(l-6C)aIkoxy, heteroarylamino, N-(l -6C)alkyI-heteroarylamino, heteroaryl-(1 -6C)alky lamino, N-( 1 -6C)alkyl-heteroaryl-( 1 -6C)alkylamino, heteroarylcarbonylamino, heteroaiylsulphonylammoJN-heteroarylsulphamoyl)heteroalyl-(2-6C)alkanoylarnino, heterocyclyl, heterocyclyloxy, heterocyclyl-(l-6C)aikoxy, heterocyclylamino, N-(l-6C)alkyl-15 heterocyclylamino, heterocyclyl-(l-6C)alkylarnino, N-(l-6C)alkyl-heterocyclyl-(1 -6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino, N-beterocyclylsulphamoyl or heterocyclyl-(2-6C)alkanoylamino and Q2 is optionally substituted with 1, 2, 3 or 4 substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (l-6C)alkyl, (2-6C)alkenyl, 20 (2-6C)alkynyl, (l-6C)alkoxy, (l-3C)alkylenedioxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyI, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, (l-6C)aIkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (l-6C)alkanoylamino, N-(l-6C)alkylsulphamoyl, N,N-di-[(l-6C)alkyl]sulphamoyl,(l-6C)alkanesuIphonylamino,N-(l-6C)alky 25 (l-6C)alkanesulphonyIamino, halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, amino-(l-6C)alkyl, (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl,carboxy-(l-6C)alkyl, (l-6C)alkoxycarbonyl-(l-6C)alkyl, carbamoyKl-6C)alkyl,N-(l-6C)alkylcarbamoyl-(l-6C)alkyl,
N,N-di-[(l-6C)alkyl]carbamoyl-(l-6C)alkyl,haIogeno-(2-6C)alkoxy,hydroxy-(2-6C)alkoxy, 30 (l-6C)alkoxy-(2-6C)alkoxy, cyano-(l-6C)alkoxy, carboxy~(l-6C)alkoxy,
(l-6C)alkoxycarbonyl-(l-6C)alkoxy, carbamoyl-(l-6C)alkoxy, N-(l-6C)alkylcarbamoy]-

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(l-6C)alkoxy, N>N-di-[(l-6C)aIkyl]carbamoyl-(l-6C)alkoxy> amino-(2-6C)alkoxy, (l-6C)alkylamino-(2-6C)a!koxy, di-[(l-6C)alkyl]amino-(2-6C)alkoxy3 halogeno-(2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (] -6C)a!koxy-(2-6C)alkylaminoJ cyano-(l-6C)alkylamino,carboxy-(l-6C)alkylarnino, (l-6C)alkoxycarbonyl-5 (1 -6C)alkylamino, carbamoyl-(l-6C)alkylamino, N-(l -6C)alkyIcarbamoyI-(l –6C)alkylamino, N)N-di-[(l-6C)alkyl]carbamoyl"(]-6C)alkylamino3 amino-(2-6C)aIkyIaminoJ (l-6C)alky]amino-(2-6C)alkylamino, di-[(l-6C)alkyl]ammo-(2-6C)alkylarnino, N-(l-6C)alkyl-halogeno-(l-6C)alkylamino, N-(l-6C)alkyl-hydroxy-(2-6C)alkylamino, N-(l-6C)alkyl-(l-6C)alko>cy-(2-6C)a^^^ 10 N-(l-6C)alkyl-carboxy-(l-6C)alkylamino,N-(l-6C)alkyl-(l-6C)aIkoxycarbo (l-6C)alkylamino,N-(l-6C)alkyl (1 -6C)alkylamino, N-(l-6C)alkyl-amino-(2-6C)alkylamino, N-(l-6C)alkyl-(l-6C)alkylamino-(2-6C)alkylamino,N-(l-6C)alkyl-di-K^ 15 (2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino, (l-6C)alkoxy-(2-6C)alkanoylammo, cyano-(2-6C)alkanoylamino, carboxy-(2-6C)alkanoylamino, (1 -6C)alkoxycarbonyI-(2-6C)alkanoylamino, carbamoyl-(2-6C)alkanoylamino3 N-(l-6C)alkylcarbamoyI-(2-6C)aIkanoy3amino,IiN-di4(l-6C)alkyl]carbamoyl-(2-6C)alkanoylamino, amino-(2-6C)alkanoylamino, (l-6C)alky]amino-(2-6C)alkanoylamino> di-[(l-6C)aIky]]amino-20 (2-6C)alkanoylamino, aryl, aryl-(l-6C)alkyl, aryI-(l-6C)alkoxy, aryloxy, arylamino, N-(l-6C)alkyl-arylarainoJaryN(l-6C)aIkyIaminoJN-(l-6C)alkyl-ai7l-(l-6Q^^ aroylamino, arylsulphonylamino, N-arylsulphamoyl, aryI-(2-6C)alkanoylamino., heteroaryl, heteroaryl-(l-6C)alkyl, heteroaryloxy, heteroaryl-(l-6C)aIkoxy, heteroaryl amino, N-(l-6C)alkyl-heteroarylamino, heteroaryl^l^Qalkylamino^^l^Qalkyl-heteroaryl-25 (l-6C)alkylaminoJ heteroarylcarbonylamino, heteroarylsulphonylamino,
N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino, heterocyclyl, heterocyclyl-(l-6C)alkyl, heterocyclyloxy, heterocyclyl-(l-6C)alkoxy, heterocyclylamino, N-(l-6C)alkyl-heterocyclylamino, heterocydyl-(l -6C)alkylamino, N-(l -6C)alkyl-heterocycIyl-(I -6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino, 30 N-heterocydylsulphamoyl and heterocyclyI-(2-6C)alkanoylamino,

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and wherein any of the substituents on Q2 defined hereinbefore which comprise a CH2 group which is attached to 2 carbon atoms or a CH3 group which is attached to a carbon atom may optionally bear on each said CH2or CH3 group a substituent selected from hydroxy, amino, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and heterocyclyl;
5 and wherein any aryl, heteroaryl or heterocyclyl group in a substituent on Q2 may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (l-6C)alkyl, (l-6C)a!koxy, carboxy, (1 -6C)alkoxycarbonyl, N-( 1 -6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (l-6C)alkylamino,.di-[(l-6C)alkyl]amino, halogeno-(l-6C)alkyl, hydroxy-(l-6C)alkyl, (l-6C)alkoxy-(l-6C)alkyl, cyano-(l-6C)alkyl, ammo-(l-6C)alkyl,
10 (l-6C)alkylamino-(l-6C)alkyl, di-[(l-6C)alkyl]amino-(l-6C)alkyl, aryl and aryl-(l-6C)alkyl; or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof; except that N-[5-(3-cyclohexylpropionamido)-2-rnethylphenyl]pyridme-3-carboxamide and N-[5-(3-cyclohexylpropionarnido)-2-methylphenyl]pyridine-4-carboxamide are excluded.
15 2. An amide derivative of the Formula I according to claim 1
wherein R3 is methyl, ethyl, chloro or bromo;
Q1 is furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl,
benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl,
20 isoquinolyl, quinazolinyl, quinoxalinyl or naphthyridinyl which optionally bears 1 or 2
substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, methyl, ethyl,
methoxy and ethoxy;
pisO;
q is 0; and
25 Q2 is phenyl which bears 1 or 2 substituents selected from hydroxy, fluoro, chloro,
trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy,
methylamino, ethylamino, dimethylamino, diethylamino, acetyl, propionyl, chloromethyl,
methoxymethyl,
2-methoxyethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,
30 diethylaminomethyl, 2-chIoroethoxy, 3-chloropropoxy, 2-hydroxyethoxy, 3-hydroxypropoxy,
2-methoxyethoxy. 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, cyanomethoxy,

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carboxymethoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, tert-butoxycarbonylmethoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethyIaminopropoxy, 2-dimethylaminoethoxy7 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,
5 2-chloroethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 2-arninoethyIamino, 2-methylaminoethylamino, 2-ethylaminoethylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino,N-(2-chloroethyl)-N-methylamino) N-(2-hydroxyemyl)-N-methylamino, N-(2TmethoxyethyI)-N-methylamino)N-(2-ethoxyemyI)-N-methylamino,N-(2-aminoethyl)-N-^
10 methylamino,
N-(2-dimethylaininoethyI)-N-methylamino)N-(3-aminopropyl)-N-methylam N-(3-methylaminopropyl)-N-methylamino, N-(3-ethylaminopropyl)-N-methylamino, N-(3-dimethylarninopropyl)-N-methylamino, N-(3-diethy]aminopropyl)-N-methylamino, phenyl, benzyl, benzyloxy, 2-pyridyImethoxy, 2-(imidazol-l-yl)ethoxy, 3-(imidazol-
15 l-yl)propoxy, pyrrolidin-1-yl, pipendino, morpholino, piperazin-1-yl, 4-methyIpiperazin-l-yl, 4-acetylpiperazin-l-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-
1-ylmethyl, 4~methylpiperazin-l-ylmethyl, 4-acetylpiperaziii-l-ylmethyl, piperidin-4-yloxy, 1 -methylpiperidin-4-yIoxy, 2-(pyrrolidin-1 -yI)ethoxy, 3-(pyrrolidin-1 -yl)propoxy,
20 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-l-ylethoxy, 3-piperazin-l-ylpropoxy, 2-(4-methylpiperazin-l-yl)ethoxy, 3-(4-methylpiperazin-1 -yl)propoxy, 2-(4-acetyIpiperazin-1 -yl)ethoxy and 3-(4-acetylpiperazin-1 -yl)propoxy,
or Q2 is oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, benzofuranyl, benzothienyl,
25 benzothiazolyl, quinolyl, quinazolinyl, quinoxalinyl or 1,8-naphthyridinyl which optionally bears 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, methyl, ethyl, methoxy and ethoxy; or a pharmaceutically-acceptable salt thereof.
30 3. An amide derivative of the Formula I according to claim 1

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wherein Q1 is substituted by a basic substituent selected from the substituents for Q1 defined in claim 1.
4. An amide derivative of the Formula I according to claim 1
5 wherein Q1 is substituted by a basic substituent selected from the substituents for Q1 defined in claim 1 and Q2 is a phenyl or heteroaryl group as defined in claim ] which also bears a basic substituent selected from the substituents for Q2 defined in claim 1.
5. An amide derivative of the Formula I according to claim 1
10 wherein R3 is methyl, ethyl, chloro or bromo;
Ql is 2-, 3- or 4-pyridyl which bears 1 basic substituent selected from amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-arninoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylamiriopropoxy, 3-ethylaminopropoxy,
15 2-dimethyIaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-arninoethylamino, 3-aminopropyIamino, 2-amino-2-methylpropyIamino, 4-aminobutyJamino, 3-methylaminopropylarnino, 2-dimethyIaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 4-dimethyIaminobutylamino, N-(2-dimethylaminoethyl)-N-methylamino,
20 N-(3-dimethylaminopropyl)-N-methylamino, 4-pyridyl, 2-pyridylmethyl, 2-pyridylmethoxy, pyrrolidin-l-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, 4-acetylpiperazin-l-yI, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinorriethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methyIpiperazin-l-yImethyl, 4-acetylpiperazin-l-ylmethyl, 4-(2-hydroxyethyI)piperazin-
25 1-yI, piperidin-4-yloxy, l-methylpiperidin-4-yloxy, 2-pyrrolidin-l-ylethoxy, 3-pyrrolidin-l-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-l-ylethoxy, 3-piperazin-l-ylpropoxy, 2-(4-methyIpiperazin-1 -yl)ethoxy, 3-(4-methylpiperazin-1 -yl)propoxy, 2-(4-acetylpiperazin-l-yl)ethoxy, 3-(4-acetylpiperazin-l-yl)propoxy, l-benzylpiperidin-4-yIamino, 2-pyrrolidin-
30 1-ylethylamino, 3-pyrroIidin-l-ylpropylamino, 2-morpholinoethylamino,
3-morpholinopropylamino, 2-piperidinoethyIamino, 3-piperidinopropylamino, 2-piperazin-

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l-ylethylamino, 3-piperazin-l-ylpropylamino, 2-(4-methylpiperazin-l-yI)ethylamino, 3-(4-methylpiperazin-l-yl)propylamino, 2-(l-methylpyrroIidm-2-yl)ethylamino, 3-(l-methylpyrrolidin-2-yl)propylamino, 3-amino-2-hydroxypropoxy, 2-hydroxy-3-methylaminopropoxy, 3-dimethylamino-2-hydroxypropoxy,
5 3-amino-2-hydroxypropylaminoJ 2-hydroxy-3-methylaminopropylamino, 3-dimethyIamino-2-hydroxypropylamino, 3-[N-(3-dimethylaminopropyl)-N-methylarnino]-2-hydroxypropoxy, 2-hydroxy-3-pyrrolidin-1 -ylpropoxy, 2-hydroxy-3-piperidinopropoxy, 2-hydroxy-3-morpholinopropoxy, 2-hydroxy-3-pyrrolidin-l-ylpropylamino, 2-hydroxy-3-piperidinopropylamino, 2-hydroxy-3-morphoIinopropylamino,
10 3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-hydroxypropylamino,
2-aminoethyIaminomethyl, 3-aminopropylaminomethyl, 2-methyIaminoethylaminomethyl, 3-methylaminopropylamiriomethyl, 2-dimethyIaminoethylaminomethyl, 3-dimethylaminopropyIaminomethyl, 2-pyrroHdin-l -ylethylaminomethyl, 3-pyrrolidin-1 -ylpropylaminomethyl, 2-piperidmoethylarninomethyl, 3-piperidinopropylaminomethyl,
15 2-morpholinoethylaminomethyI, 3-morpholinopropylaminornethyI, 2-piperazin-1-ylethylaminomethyl, 3-piperazin-l-ylpropylaminomethyl, 2-(4-methylpiperazin-l-yl)ethylaminomethyl and 3-(4-methylpiperazin-l-yl)propylarninomethyl, and wherein Q1 may optionally bear 1 further substituent selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, methyl, ethyl, methoxy and ethoxy;
20 p is 0; q is 0; and
Q2 is phenyl, 5-isoxazoIyl or 3- or 4-pyridyl which optionally bears 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylamino. dimethylamino, aminomethyl, methylaminomethyl,
25 dimethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 3-methylaminopropoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 2-aminoethyIamino, 3-aminopropyIamino, 4-aminobutyIamino, 3-methylaminopropylarnino, 2-dimethyIaminoethylamino, 3-dimethylaminopropylamino, 4-dimethyIaminobutylamino, N-(2-dimethylaminoethyl)-N-methyIamino, N-(3-dimethyIaminopropyl)-N-methyIamino,
30 4-pyridyl, 2-pyridylmethoxy, pyrrolidin-1-yl, morpholino, piperidino, piperazin-l-yl, 4-methyIpiperazin-l-yl, 4-ethylpiperazin-l-yI, 4-acetyipiperazin-l-yl, homopiperazin-'l-yl,

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4-methylhomopiperazin-l-yl, pyrrolidin-l-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methyipiperazin-l-ylmethyl, 2-pyrrolidin-l-ylettioxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morphoIinopropoxy, 2-piperazin-l -ylethoxy, 3-piperazin-1 -ylpropoxy,
5 2-(4-methylpiperazin-l-yl)ethoxy) 3-(4-methylpiperazin-l-yl)propoxy, 2-pyrrolidin-1-ylethylamino, 3-pyrrolidin-l-yIpropylamino, 2-morpholinoethyl amino, 3-morpholinopropylarnino, 2-piperidinoethylamino, 3-piperidinopropyIamino, 2-piperazin-l-ylethylamino, 3-piperazin-l-ylpropylamino, 2-(4-methylpiperazin-l-yl)ethylamino and 3 -(4-methylpiperazin-1 -y l)propyIamino;
10 or a pharmaceutically-acceptable salt thereof.
6. An amide derivative of the Formula I according to claim 1
wherein R3 is methyl or chloro;
Q1 is 3-pyridyI or 4-pyridyl .which bears a substituent selected from 2-aminoethylamino, 15 3-aminopropylamino, 2-amino-2-methyIpropylamino, 4-aminobutyIamino,
3-methylaminopropylamino, 2-dimethylammoethylamino, 2-diethyIaminoethyIamino, 3-dimethylaminopropylamino, 4-dimethylaminobutyIarnino,N-(2-dimethylarninoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1 -yl, morpholino, piperidino, piperazin-1-yl, 4-methyIpiperazin-l-yl, 4-ethylpiperazin-l-yl,
20 4-(2-hydroxyethyl)piperazin-l~yl, 4-methylhomopiperazin-l-yI, l-benzylpiperidin-4-ylamino, 2-pyrrolidin-lylethylamino, 3-pyiToIidm-lylpropylarnino, 2-morpholinoethylamino, 3-morpholinopropylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 2-piperazin-I-ylethylamino, 3-piperazin-l-ylpropyIammo, 2-(4-methylpiperazin-l-yl)ethylaminoJ 3-(4-methylpiperazin-l-yl)propylamino, 2-(l-methylpyrrolidin-2-yl)ethylamino,
25 3-(l-methylpyrrolidin-2-yl)propylamino or 3-amino-2-hydroxypropylamino; p is 0; q is 0; and
Q2 is phenyl or 4-pyridyl which bears a substituent selected from pyrrolidin-1 -yl, morpholino and piperidino;
30 or a pharmaceutically-acceptable salt thereof.

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7. An amide derivative of the Formula 1 according to claim 1
wherein R3 is methyl or chloro;
Q1 is 3-pyridyl or 4-pyridyl which bears a substituent selected from 2-aminoethylamino, .
3-aminopropylamino, 2-amino-2-methylpropyIamino, 4-aminobutyIamino,
5 3-memylaminopropyIamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino,
3-dimethylaminopropylamino,4-dimethylaminobutylamino, N-(2-dimethylaminoethyl)-
N-rnethylamino, N-(3-dimethylaminopropyI)-N-methyIamino, pyrrolidin-l -yl, morpholino,'
piperidino, piperazin-1-yl, 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl, 4-(2-hydroxyethyl)piperazin-1 -yl, homopiperazin-1 -yl, 4-methylhomopiperazin-1 -yl,
10 1-benzylpiperidin-4-yIamino, 2-pyrrolidin-lylethylamino, 3-pyrrolidin-lylpropyIamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 2-piperidinoethylamino, 3 -piperidinopropylamino, 2-piperazin-1 -ylethylamino, 3-piperazin-1 -ylpropylamino, 2-(4-methylpiperazin-l-yl)ethylamino, 3-(4-methylpiperazin-l-ylpropylamino, 2-(l-methylpyrrolidiri-2-yl)ethylamino, 3-(l-methylpyrrolidin-2-yl)propylamino or 3-amino-
15 2-hydroxypropylamino; p is 0; q is 0; and
Q2 is phenyl or 4-pyridyl which bears a substituent selected from pyrrolidin-l-yl, morpholino and piperidino and which optionally bears a further substituent selected from fluoro and
20 trifluoromethyl;
or a pharmaceutically-acceptable salt thereof.
8. An amide derivative of the Formula I according to claim 1 selected from :-
6-[N-(2-dimemylaminoemyl)-N-memylamino]-N-[2-methyl-5-(2-morphoIinopyrid-25 4-ylcarbonylamino)phenyl]pyridine-3-carboxamide,
6-(2-amino-2-methylpropylamino)-N-[2-methyl-5-(2-morphoIinopyrid-
4-ylearbonylamino)phenyI]pyridine-3-carboxamide,
6-(2-diethylaminoethylamino)-N-[2-methyl-5-(2-morphoIinopyrid-
4-ylcarbonyIamino)phenyl]pyridine-3-carboxamide,
30 6-(3-dimemylarninopropylamino)-N-[2-rnethyl-5-(2-morpholinopyrid-
4-ylcarbonyIamino)phenyl]pyridine-3-carboxarnide,

WO 00/07991 PCT/GB99/0^fio
111
6-[2-(I-rnethyipyiroIidin-2-yi)ethylamino]-N-[2-methyI-5-(2-morpholinopyrid-
4-ylcarbonylamino)phenyl]pyridme-3-carboxamide,
6-(3-morpholinopropylamino)-N-[2-methyl-5-(2-morpholinopyrid-
4-yIcarbonylamino)phenyl]pyridine-3-carboxamideJ
5 6-(4-dimethyIaminobutyIamino)-N-[2-rnethyl-5-(2-morpholinopyrid-
4-ylcarbonylamino)phenyI]pyridine-3-carboxamide>
2-(4-methylpiperazin-l-yI)-N-[2-methyI-5-(2-morpholinopyrid^-yIcarb6nylamino)phenyI]~
pyridine-4-carboxamide,
2-[4-(2-hydroxyethyl)pipera2in-l-yI]-N-[2-methyI-5-'(2-niorphoIinopyrid-10 4-ylcarbony]amino)phenyl]pyridine-4-:carboxaniide,
6-(3-morphoIinopropylammo)-N-r2-m'emyI-5-(3^ pyridine-3-carboxamide,
6-(4-methylpipera-l-yl)-N-[2-methyl-5-(3^ pyridine-3-carboxamide,
15 6-(4-ethylpiperazin-l-yI)-N-[2-methyI-5-(2-moiphoIinopyrid-ylcarbonyIamm pyridine-3 -carboxamide,
N-[2-chJoro-5-(2-morpholinopyrid-4-yIcarbonyJamino)phenyIj-2-(4-methylpiperazin-l-yl)pyridine-4-carboxamide and
N-[2-chIoro-5-(2-morpholinopyrid-4-ylcarbonyIamino)phenyl]-;
20 2-[4-(2-bydroxyethyl)piperazin-I-yI]pyridine-4-carboxamide; or a pharmaceutically-acceptable salt thereof.
9 A pharmaceutical composition which comprises an amide derivative of the Formula I,
20 or a pharmaceutically-acceptable or in-vivo-cleavable ester thereof, according to claim 1 in association with a pharmaceutically-acceptable diluent or carrier.
10. An amide derivative substantially as hereinbefore described with reference to the foregoing examples
11. A pharmaceutical composition substantially as hereinbefore described with reference to the foregoing examples

Documents:

00351-mumnp-2005-abstract(11-07-2007).pdf

00351-mumnp-2005-cancelled pages(11-07-2007).pdf

00351-mumnp-2005-claims(granted)-(11-07-2007).pdf

00351-mumnp-2005-correspondence(22-08-2007).pdf

00351-mumnp-2005-correspondence(ipo)-(20-07-2006).pdf

00351-mumnp-2005-form 1(11-07-2007).pdf

00351-mumnp-2005-form 1(29-04-2005).pdf

00351-mumnp-2005-form 13(12-07-2007).pdf

00351-mumnp-2005-form 13(17-02-2009).pdf

00351-mumnp-2005-form 18(28-10-2005).pdf

00351-mumnp-2005-form 2(granted)-(11-07-2007).pdf

00351-mumnp-2005-form 3(11-07-2007).pdf

00351-mumnp-2005-form 3(28-04-2005).pdf

00351-mumnp-2005-form 5(28-04-2005).pdf

00351-mumnp-2005-form-pct-ipea-409(29-04-2005).pdf

00351-mumnp-2005-form-pct-isa-210(29-04-2005).pdf

00351-mumnp-2005-petition under rule 137(12-07-2007).pdf

00351-mumnp-2005-petition under rule 138(12-07-2007).pdf

00351-mumnp-2005-power of authority(02-01-2001).pdf

00351-mumnp-2005-power of authority(06-06-2005).pdf

00351-mumnp-2005-power of authority(11-07-2007).pdf

351-mumnp-2005-abstract(11-07-2007).doc

351-mumnp-2005-claims(granted)-(11-07-2007).doc

351-mumnp-2005-claims.pdf

351-mumnp-2005-correspondence-others.pdf

351-mumnp-2005-correspondence-received-ver-260905.pdf

351-mumnp-2005-correspondence-received-ver-261005.pdf

351-mumnp-2005-correspondence-received-ver-280405.pdf

351-mumnp-2005-description (complete).pdf

351-mumnp-2005-form 2(granted)-(11-07-2007).doc

351-mumnp-2005-form-1.pdf

351-mumnp-2005-form-18.pdf

351-mumnp-2005-form-2.pdf

351-mumnp-2005-form-3.pdf

351-mumnp-2005-form-5.pdf

351-mumnp-2005-form-pct-ib-304.pdf

351-mumnp-2005-form-pct-ib-306.pdf

351-mumnp-2005-form-pct-ib-308.pdf

351-mumnp-2005-form-pct-ipea-409.pdf

351-mumnp-2005-form-pct-ipea-416.pdf

351-mumnp-2005-form-pct-ro-101.pdf

351-mumnp-2005-form-pct-separate sheet-409.pdf

351-mumnp-2005-pct-search report.pdf


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Patent Number 229456
Indian Patent Application Number 351/MUMNP/2005
PG Journal Number 13/2009
Publication Date 27-Mar-2009
Grant Date 17-Feb-2009
Date of Filing 29-Apr-2005
Name of Patentee ASTRAZENECA AB
Applicant Address S-151 85 SODERTALJE, SWEDEN
Inventors:
# Inventor's Name Inventor's Address
1 DEARG SUTHERLAND BROWN ALDERLEY PARK, MACCLESFIELD, CHESHIRE SK 10 4TG , GREAT BRITAIN
2 GEORGE ROBERT BROWN Alderley Park Macclesfield, Cheshire SK10 4TG
PCT International Classification Number C07D 213/82
PCT International Application Number PCT/GB99/02489
PCT International Filing date 1999-07-29
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 9824939.4 1998-11-13 U.K.
2 9816838.8 1998-08-04 U.K.