WO2007025575A1

WO2007025575A1 - O-hydroxy- and o-amino benzamide derivatives as ikk2 inhibitors

Info

Publication number: WO2007025575A1
Application number: PCT/EP2006/003534
Authority: WO
Inventors: James Vaughan Morey; John Andrew Christopher
Original assignee: Smithkline Beecham Corporation
Priority date: 2005-04-08
Filing date: 2006-04-06
Publication date: 2007-03-08
Also published as: GB0507200D0

Abstract

A compound of Formula (I).

Description

O-HYDROXY- AND O-AMINO BENZAMIDE DERIVATIVES AS IKK2 INHIBITORS

BACKGROUND OF THE INVENTION

The present invention relates to benzamide derivatives, pharmaceutical compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments. Such benzamide carboxamide derivatives are useful in the treatment of diseases associated with inappropriate IKK2 (also known as IKKβ) activity, in particular in the treatment and prevention of disease states mediated by IKK2 activity including inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease); osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin damage; autoimmune diseases including systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restonosis, diabetes, glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation associated with infection and certain viral infections, including acquired immune deficiency syndrome (AIDS), adult respiratory distress syndrome, and Ataxia Telangiestasia.

An important large family of enzymes is the protein kinase enzyme family. Currently, there are about 500 different known protein kinases. However, because three to four percent of the human genome is a code for the formation of protein kinases, there may be many thousands of distinct and separate kinases in the human body. Protein kinases serve to catalyze the phosphorylation of an amino acid side chain in various proteins by the transfer of the γ-phosphate of the ATP-Mg²⁺ complex to said amino acid side chain. These enzymes control the majority of the signaling processes inside cells, thereby governing cell function, growth, differentiation and destruction (apoptosis) through reversible phosphorylation of the hydroxyl groups of serine, threonine and tyrosine residues in proteins. Studies have shown that protein kinases are key regulators of many cell functions, including signal transduction, transcriptional regulation, cell motility, and cell division. Several oncogenes have also been shown to encode protein kinases, suggesting that kinases play a role in oncogenesis. These processes are highly regulated, often by complex intermeshed pathways where each kinase will itself be regulated by one or more kinases. Consequently, aberrant or inappropriate protein kinase activity can contribute to the rise of disease states associated with such aberrant kinase activity. Due to their physiological relevance, variety and ubiquitousness, protein kinases have become one of the most important and widely studied family of enzymes in biochemical and medical research.

The protein kinase family of enzymes is typically classified into two main subfamilies: Protein Tyrosine Kinases and Protein Serine/Threonine Kinases, based on the amino acid residue they phosphorylate. The serine/threonine kinases (PSTK), includes cyclic AMP- and cyclic GMP-dependent protein kinases, calcium and phospholipid dependent protein kinase, calcium- and calmodulin-dependent protein kinases, casein kinases, cell division cycle protein kinases and others. These kinases are usually cytoplasmic or associated with the particulate fractions of cells, possibly by anchoring proteins. Aberrant protein serine/threonine kinase activity has been implicated or is suspected in a number of pathologies such as rheumatoid arthritis, psoriasis, septic shock, bone loss, many cancers and other proliferative diseases. Accordingly, serine/threonine kinases and the signal transduction pathways which they are part of are important targets for drug design. The tyrosine kinases phosphorylate tyrosine residues. Tyrosine kinases play an equally important role in cell regulation. These kinases include several receptors for molecules such as growth factors and hormones, including epidermal growth factor receptor, insulin receptor, platelet derived growth factor receptor and others. Studies have indicated that many tyrosine kinases are transmembrane proteins with their receptor domains located on the outside of the cell and their kinase domains on the inside. Much work is also under progress to identify modulators of tyrosine kinases as well.

Nuclear factor KB (NF-KB) belongs to a family of closely related dimeric transcription factor complexes composed of various combinations of the Rel/NF-κB family of polypeptides. The family consists of five individual gene products in mammals, ReIA (p65), NF-κB1 (p50/ p105), NF-κB2 (p49/ p100), c-Rel, and ReIB, all of which can form hetero- or homodimers. These proteins share a highly homologous 300 amino acid "ReI homology domain" which contains the DNA binding and dimerization domains. At the extreme C-terminus of the ReI homology domain is a nuclear translocation sequence important in the transport of NF-κB from the cytoplasm to the nucleus. In addition, p65 and cRel possess potent transactivation domains at their C-terminal ends.

The activity of NF-κB is regulated by its interaction with a member of the inhibitor IKB family of proteins. This interaction effectively blocks the nuclear localization sequence on the NF-κB proteins, thus preventing migration of the dimer to the nucleus. A wide variety of stimuli activate NF-κB through what are likely to be multiple signal transduction pathways. Included are bacterial products (LPS), some viruses (HIV-1 , HTLV-1 ), inflammatory cytokines (TNFα, IL-1), environmental and oxidative stress and DNA damaging agents. Apparently common to all stimuli however, is the phosphorylation and subsequent degradation of IKB. IKB is phosphorylated on two N-terminal serines by the recently identified IKB kinases (IKK-α and IKK-β). IKK-β is also known as IKK2. Site- directed mutagenesis studies indicate that these phosphorylations are critical for the subsequent activation of NF-κB in that once phosphorylated the protein is flagged for degradation via the ubiquitin-proteasome pathway. Free from IKB, the active NF-κB complexes are able to translocate to the nucleus where they bind in a selective manner to preferred gene-specific enhancer sequences. Included in the genes regulated by NF-κB are a number of cytokines and chemokines, cell adhesion molecules, acute phase proteins, immunoregulatory proteins, eicosanoid metabolizing enzymes and anti-apoptotic genes.

It is well-known that NF-κB plays a key role in the regulated expression of a large number of pro-inflammatory mediators including cytokines such as TNF, IL-1 β, IL-6 and IL-8, cell adhesion molecules, such as ICAM and VCAM, and inducible nitric oxide synthase (iNOS). Such mediators are known to play a role in the recruitment of leukocytes at sites of inflammation and in the case of iNOS, may lead to organ destruction in some inflammatory and autoimmune diseases.

The importance of NF-κB in inflammatory disorders is further strengthened by studies of airway inflammation including asthma, in which NF-κB has been shown to be activated. This activation may underlie the increased cytokine production and leukocyte infiltration characteristic of these disorders. In addition, inhaled steroids are known to reduce airway hyper responsiveness and suppress the inflammatory response in asthmatic airways. In light of the recent findings with regard to glucocorticoid inhibition of NF-κB, one may speculate that these effects are mediated through an inhibition of NF-κB.

Further evidence for a role of NF-κB in inflammatory disorders comes from studies of rheumatoid synovium. Although NF-κB is normally present as an inactive cytoplasmic complex, recent immunohistochemical studies have indicated that NF-κB is present in the nuclei, and hence active, in the cells comprising rheumatoid synovium. Furthermore, NF- KB has been shown to be activated in human synovial cells in response to stimulation with TNF-α or IL-1 β. Such a distribution may be the underlying mechanism for the increased cytokine and eicosanoid production characteristic of this tissue. See Roshak, A. K., et al., J. Biol. Chem., 271 , 31496-31501 (1996). Expression of IKK-β has been shown in synoviocytes of rheumatoid arthritis patients and gene transfer studies have demonstrated the central role of IKK-β in stimulated inflammatory mediator production in these cells. See Aupperele et al. J. Immunology 1999. 163:427-433 and Aupperle et al. J. Immunology 2001 ; 166:2705-11. More recently, the intra-articular administration of a wild type IKK-β adenoviral construct was shown to cause paw swelling while intra-articular administration of dominant-negative IKKβ inhibited adjuvant-induced arthritis in rat. See Tak et al. Arthritis and Rheumatism 2001 , 44: 1897-1907.

The NF-κB/Rel and IKB proteins are also likely to play a key role in neoplastic transformation and metastasis. Family members are associated with cell transformation in vitro and in vivo as a result of over expression, gene amplification, gene rearrangements or translocations. In addition, rearrangement and/or amplification of the genes encoding these proteins are seen in 20-25% of certain human lymphoid tumors. Further, NF-κB is activated by oncogenic ras, the most common defect in human tumors and blockade of NF-κB activation inhibits ras mediated cell transformation. In addition, a role for NF-κB in the regulation of apoptosis has been reported strengthening the role of this transcription factor in the regulation of tumor cell proliferation. TNF₁ ionizing radiation and DNA damaging agents have all been shown to activate NF-κB which in turn leads to the upregulated expression of several anti-apoptotic proteins. Conversely, inhibition of NF-κB has been shown to enhance apoptotic-killing by these agents in several tumor cell types. As this likely represents a major mechanism of tumor cell resistance to chemotherapy, inhibitors of NF-κB activation may be useful chemotherapeutic agents as either single agents or adjunct therapy. Recent reports have implicated NF-κB as an inhibitor of skeletal cell differentiation as well as a regulator of cytokine-induced muscle wasting (Guttridge et al. Science; 2000; 289: 2363-2365.) further supporting the potential of NFKB inhibitors as novel cancer therapies.

We have now found benzamide compounds, which are inhibitors of kinase activity, in particular inappropriate IKK2 activity. Such benzamide derivatives are therefore potentially useful in the treatment of disorders associated with inappropriate kinase activity, in particular inappropriate IKK2 activity especially in the treatment and prevention of disease states mediated by IKK2 activity including inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease); osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UV)- induced skin damage; autoimmune diseases including systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restonosis, diabetes, glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation associated with infection and certain viral infections, including acquired immune deficiency syndrome (AIDS), adult respiratory distress syndrome, and Ataxia Telangiestasia.

BRIEF SUMMARY OF THE INVENTION

In one aspect of the present invention, there is provided a compound of Formula (I):

(I) wherein:

Z is NH₂ or OH;

R¹ represents phenyl (optionally substituted by halogen, -SO₂C_1-3 alkyl, C_1-6 alkoxy,

CONR³R⁴) or pyridinyl;

R³ and R⁴ are independently C_1-3 alkyl or H;

R² represents:

(a) halogen

(b) H

(c) pyridinyl

wherein p is 0 or 1 ,

X represents a bond (i.e. is absent), Ci_-3 alkylene, -NH-,

R⁵ represents C_1-6 alkyl, NR⁶R⁷;

R⁶ and R⁷ indepently represent H, C_1-6 alkyl (optionally substituted by C_1-6 alkoxy), C₃-₇ cycloalkyl, C_1-6 alkylene NR⁸R⁹; or R⁵ and R⁶ together with the nitrogen to which they are joined form a 5 or 6 membered heterocyclic ring

(optionally containing a further heteroatam selected from N or O and optionally being substituted by C_1-3 alkyl);

R⁸ and R⁹ are independently H, C_1-3 alkyl, C_1-3 alkoxy, -COC _1-3 alkyl, or R⁸ and R⁹ together with the nitrogen atom to which they are joined form a 5 or

6 membered heterocyclic ring (optionally containing a further heteroatom selected from N or O and optionally substituted by C_1-3 alkyl);

One of R¹¹ and R¹² is NHCOC_1-6 alkyl, CN, halogen; the other is H or halogen,

N(CHa)₂,

(g) CONH₂

alkyl J₂

R¹² is , -C_1-6 alkoxy;

with the proviso that when Z is OH, R 2 : is, not H or halogen;

or a salt, solvate, or physiologically functional derivative thereof.

In a second aspect of the present invention, there is provided a compound of formula (I), or a salt, solvate, or a physiologically functional derivative thereof for use in therapy.

In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a salt, solvate, or a physiologically functional derivative thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.

In a fourth aspect of the present invention, there is provided a method of treating a disorder in a mammal, said disorder being mediated by inappropriate IKK2 activity, comprising administering to said mammal a compound of formula (I) or a salt, solvate or a physiologically functional derivative thereof. In a fifth aspect of the present invention, there is provided the use of a compound of formula (I), or a salt, solvate, or a physiologically functional derivative thereof in the preparation of a medicament for use in the treatment of a disorder mediated by inappropriate IKK2 activity.

In a sixth aspect there is provided a method of treating inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease); osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UV)- induced skin damage; autoimmune diseases including systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restonosis, diabetes, glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation associated with infection and certain viral infections, including acquired immune deficiency syndrome (AIDS), adult respiratory distress syndrome, and Ataxia Telangiestasia, comprising administering to a mammal a compound of formula (I), or a salt, solvate or pharmaceutically functional derivative thereof.

In a seventh aspect there is provided the use of a compound of formula (!) or a salt, solvate or physiologically functional derivative thereof in the manufacture of a medicament for the treatment of inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease); osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin damage; autoimmune diseases including systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restonosis, diabetes, glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation associated with infection and certain viral infections, including acquired immune deficiency syndrome (AIDS), adult respiratory distress syndrome, and Ataxia Telangiestasia.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

As used herein "a compound of the invention" or "a compound of formula (I)" means a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

As used herein the term "alkyl" refers to a straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms, so for example, as used herein, the terms "C_1-C₃ alkyl" and "C_1-C₆ alkyl" refer to an alkyl group, as defined above, containing at least 1 , and at most 3 or 6 carbon atoms respectively. Examples of such branched or straight- chained alkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, isopentyl, and n-hexyl.

As used herein, the term "alkylene" refers to a straight or branched chain divalent hydrocarbon radical having the specified number of carbon atom, so for example, as used herein, the terms "C_1-C₃ alkylene" and "C_1-C₆ alkylene" refer to an alkylene group, as defined above, which contains at least 1 , and at most 3 or 6, carbon atoms respectively.

Examples of "C_1-C₆ alkylene" and "C₁-C₆ alkylene" groups useful in the present invention include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, isopentylene, and the like.

As used herein, the term "alkenyl" (and "alkenylene") refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least one and up to 3 carbon-carbon double bonds. Examples include ethenyl (and ethenylene) and propenyl (and propenylene).

As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) and the term "halo" refers to the halogen radicals: fluoro (-F), chloro (-Cl), bromo(-Br), and iodo(-l). As used herein, the term "Ci-C₆ haloalkyl" refers to a straight or branched chain alkyl group as defined above containing at least 1 , and at most 6 carbon atoms respectively substituted with at least one halo group, halo being as defined herein. Examples of such branched or straight chained haloalkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more halos, e.g., fluoro, chloro, bromo and iodo.

As used herein, the term "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring containing the specified number of carbon atoms so, for example, the term "C_5-C₇ cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from five to seven carbon atoms. Exemplary "C₅-C₇ cycloalkyl" groups useful in the present invention include, but are not limited to, cyclopentyl, cyclohexyl and cycloheptyl.

As used herein, the term "cycloalkenyl" refers to a non-aromatic monocyclic carboxycyclic ring having the specified number of carbon atoms and up to 3 carbon-carbon double bonds. "Cycloalkenyl" includes by way of example cyclopentenyl and cyclohexenyl.

As used herein, the term "heterocyclic" or the term "heterocyclyl" refers to a non-aromatic heterocyclic ring containing the specified number ring atoms being saturated or having one or more degrees of unsaturation, containing one or more heteroatom substitutions selected from O and/or N. Such a ring may be optionally fused to one or more other "heterocyclic" ring(s) or cycloalkyl ring(s). Examples of "heterocyclic" moieties include, but are not limited to, tetrahydrofuran, pyran, 1 ,4-dioxane, 1 ,3-dioxane, piperidine, piperazine, 2,4-piperazinedione, pyrrolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.

As used herein, the term "aryl" refers to monocyclic carbocyclic groups and fused bicyclic carbocyclic groups having the specified number of carbon atoms and having at least one aromatic ring. Examples of aryl groups include phenyl and naphthyl.

As used herein, the term "heteroaryl" refers to an aromatic monocyclic ring, or to a fused bicyclic or tricyclic ring system wherein at least one ring is aromatic, having the specified number of ring atoms and containing at least one heteratom selected from N, O, and/or S. Examples of "heteroaryl" groups used herein include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo- pyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl.

As used herein, the term "alkoxy" refers to the group R₃O-, where R₃ is alkyl as defined above and the terms "Ci-C₃ alkoxy" and "Ci-C₆ alkoxy" refer to an alkoxy group as defined herein wherein the alkyl moiety contains at least 1 , and at most 3 or 6, carbon atoms. Exemplary "C_1-C_S aIkOXy" and "C_1-C₆ alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.

As used herein, the term "haloalkoxy" refers to the group R₃O-, where R₃ is haloalkyl as defined above and the term "C_1-C₆ haloalkoxy" refers to a haloalkoxy group as defined herein wherein the haloalkyl moiety contains at least 1 , and at most 6, carbon atoms. Exemplary Ci-C₆ haloalkoxy groups useful in the present invention include, but is not limited to, trifluoromethoxy.

In one embodiment, Z is NH₂.

In one embodiment of the invention, R¹ is phenyl (substituted by chloro, fluoro SO₂CH₃, OCH₃ or CONH₂), phenyl or pyridinyl.

In one embodiment R¹ is phenyl (substituted in the para position by SO₂CH₃, OCH₃, CONH₂, Cl or F), phenyl or pyridinyl.

In one embodiment R² is

(wherein X and R⁵ are as defined for formula (I) above), Br, pyridinyl,

(wherein R¹⁰ is as defined for formula (I) above).

In one embodiment, R is

(wherein R⁵ and X are as defined above in formula (I)).

In one embodiment, X is a bond (i.e. is absent).

In one embodiment, R⁵ is methyl or NR⁶R⁷ wherein R⁶ and R⁷ are independently H, cyclopropyl, C_1-3 alkyl, (CH₂)₂-3N(CH₃)2, (CH₂J_2-3NHCOCH₃, (CHa)_2-3NH₂, (CH₂)₂N(CH₃)₂,

^CH₂) _2.3— N p ^CH₂) ₂.₃__N N-CH,

or R⁵ and R⁶ together with the nitrogen to which they are joined form a pyrrolidyl, or morpholino ring.

In one embodiment there is provided a compound of formula 2:

(2) wherein:

R^a represents phenyl (optionally substituted by halogen, SO₂C_1-3 alkyl, OC_1-3 alkyl) or pyridinyl; R^b represents

R^c represents C_1-6 alkyl, NR^dR^e;

R^d and R^e independently represent H, C_1-6 alkyl, C_3-7 cycloalkyl, C_1-6 alkylene NR^fR⁹; or R^d and R^e together with the nitrogen to which they are joined form a 5 or 6 membered heterocyclic ring (optionally containing a further heteroatam selected from N or O and optionally being substituted by C_1-3 alkyl);

R^f and R⁹ are independently H, C_1-3 alkyl, C_1-3alkoxy, -COC_1-3 alkyl, or R^f and R⁹ together with the nitrogen atom to which they are joined form a 5 or 6 membered heterocyclic ring (optionally containing a further heteroatom selected from N or O and optionally substituted by C_1-3 alkyl);

In one embodiment R^a represents phenyl (optionally substituted by fluoro, chloro, SO₂CH₃ or OCH₃) or pyridinyl.

In one embodiment R^a represents phenyl (substituted in the para position by fluoro, chloro, SO₂CH₃ or OCH₃) phenyl or pyridinyl.

In one embodiment R^c is CH₃, or NR^dR^e wherein R^d and R^e are independently H, cyclopropyl, C_1-3 alkyl, (CH₂J_2-3NH₂, (CH₂)_2-3N(CH₃)_2l (CH₂)_2-3NHCOCH₃

-(CH₂)₂, N p -(CH₂), , N N-CH

or R^d and R^e together with the Nitrogen to which they are joined form a pyrrolidyl or morpholino ring or a salt, solvate or physiologically functional derivative thereof.

While embodiments for each variable have generally been listed above separately for each variable, preferred compounds of this invention include those in which several or each variable in formula (I) and (2) is selected from all embodiments for each variable. Therefore, this invention is intended to include all combinations of embodiments for each variable.

Specific examples of compounds of the present invention include the following:

4'-Amino-4^ll-(aminosulfonyl)-4-chloro-1 ,1^l:3',1"-terphenyl-5'-carboxamide;

6'-Amino-4-{[(2-aminoethyl)amino]sulfonyl}-1 ,1^l:3^l,1"-terphenyl-5'-carboxamide;

4-({[2-(Acetylamino)ethyl]amino}sulfonyl)-6'-amino-1 ,1':3',1"-terphenyl-5'-carboxamide;

6'-Amino-4-({[2-(4-morpholinyl)ethyl]amino}sulfonyl)-1 ,1^l:3',1"-terphenyl-5'-carboxamide; 6'-Amino-4-({[2-(1-pyrrolidinyl)ethyl]amino}sulfonyl)-1 ,1':3',1"-terphenyl-5'-carboxamide;

6^l-Amino-4-({[3-(methyloxy)propyl]amino}sulfonyl)-1 ,1^I:3^I,1"-terphenyl-5'-carboxamide;

6'-Amino-4-({[3-(4-morpholinyl)propyl]amino}sulfonyl)-1 ,1':3',1"-terphenyl-5^I-carboxamide; e'-Amino^-KcyclopropylaminoJsulfonylj-i .i'^IMerphenyl-S'-carboxamide;

6'-Amino-4-{[(1-methylethyl)amino]sulfonyl}-1 ,1':3',1"-terphenyl-5^l-carboxamide; 4'-Amino-4-ch!oro-4"-[(dimethylamino)su!fonyl]-1 ,1¹:3¹,1"-terpheny!-5'-carboxamide;

4'-Amino-4"-(aminosulfonyl)-4-fluoro-1 ,1':3',1"-terphenyl-5^l-carboxamide;

4^l-Amino-4"-[(dimethylamino)sulfonyl]-4-fluoro-1 ,1':3'_l1"-terphenyl-5'-carboxamide;

2-Amino-4'-(aminosulfonyl)-5-(4-pyridinyl)-3-biphenylcarboxamide;

6'-Amino-4-({[2-(4-methyl-1 -piperazinyl)ethyl]amino}sulfonyl)-1 , 1 ':3\ 1 "-terphenyl-5¹- carboxamide;

6'-Amino-4-[(dimethylamino)sulfonyl]-1 ,1^l:3',rⁱ-terphenyl-5'-carboxamide;

2-Amino-4'-[(dimethylamino)sulfonyl]-5-(4-pyridinyl)-3-biphenylcarboxamide;

6'-Amino-4-(4-morpholinylsulfonyl)-1 ,1':3',rⁱ-terphenyl-5'-carboxamide;

6'-Amino-4-({[3-(dimethylamino)propyl]amino}sulfonyl)-1 , 1 ':3', 1 "-terphenyl-5¹- carboxamide;

4'-Amino-4-chloro-4"-(1-pyrrolidinylsulfonyl)-1 ,r:3',rⁱ-terphenyl-5^I-carboxamide;

2-Amino-5-(4-pyridinyl)-4'-(1-pyrrolidinylsulfonyl)-3-biphenylcarboxamide;

4^I-Amino-4-fluoro-4"-(1-pyrrolidinylsulfonyl)-1 ,1':3',1"-terphenyl-5^l-carboxamide;

6'-Amino-4-(aminosulfonyl)-1 ,1':3',1"-terphenyl-5^l-carboxamide; 6'-Amino-4-({[2-(dimethylamino)ethyl]amino}sulfonyl)-1 , 1 ':3\ 1 "-terphenyl-5'-carboxamide ;

6'-Amino-4-(1 -pyrrolidinylsulfonyl)-1 , 1 ':3', 1 "-terphenyl-δ'-carboxamide; 6'-Amino-4-(methylsulfonyl)-1 ,1':3^l,1"-terphenyl-5^l-carboxamide;

4-Amino-5-{1-[(4-cyanophenyl)sulfonyl]-1 ,2,3,6-tetrahydro-4-pyridinyl}-4'-fluoro-3- biphenylcarboxamide;

4-Amino-4'-fluoro-5-(1 ,2,3,6-tetrahydro-4-pyridinyl)-3-biphenylcarboxamide; 4-Amino-5-(4-pyridinyl)-3-biphenylcarboxamide;

4-Amino-4',5-dibromo-3-biphenylcarboxamide;

2-Amino-3-bromo-5-(4-pyridinyl)benzamide;

6^l-Amino-4-[(methylsulfonyl)amino]-1 ,1^I:3^l,1"-terphenyl-5'-carboxamide;

4-Amino-5-bromo-4'-chloro-3-biphenylcarboxamide; 5-(1-{[4-(Acetylamino)phenyl]sulfonyl}-1 ,2,3,6-tetrahydro-4-pyridinyl)-4-amino-4'-fluoro-3- biphenylcarboxamide;

2-Amino-4'-[(methylsulfonyl)amino]-5-(4-pyridinyl)-3-biphenylcarboxamide;

4-Amino-4'-fluoro-5-(4-pyridinyl)-3-biphenylcarboxamide;

4-Amino-5-{1-[(4-cyanophenyl)sulfonyl]-1 ,2,3,6-tetrahydro-4-pyridinyl}-3- biphenylcarboxamide;

4^l-Amino-4-fluoro-4^I'-[(methylsulfonyl)amino]-1 ,1':3',1"-terphenyl-5^l-carboxamide;

4-Amino-5-{1-[(3,4-difluorophenyl)sulfonyl]-1 ,2,3,6-tetrahydro-4-pyridinyl}-4'-fluoro-3- biphenylcarboxamide;

4-Amino-5-bromo-3-biphenylcarboxamide; 4^Amino-4-chloro-4^ll-[(rnethylsulfonyl)amino]-1 _l1':3'_!1^II-terphenyl-5'-carboxamide;

4^I-Amino-4"-[(arninosulfonyl)methyl]-4-fluoro-1 ,1':3',1'^l-terphenyl-5'-carboxarnide;

6'-Amino-1 , 1 ':3\ 1 "-terphenyl-4,5'-dicarboxamide;

6'-Amino-3-[(dimethylamino)sulfonyl]-1 , 1 ':3', 1 "-terphenyl-5'-carboxamide;

6'-Amino-4-[(aminosulfonyl)methyl]-1 ,1^l:3^l,1'^l-terphenyl-5^I-carboxamide; 2-Amino-5-(4-pyridinyl)-3-biphenylcarboxamide;

4-Amino-4'-chloro-5-(4-pyridinyl)-3-biphenylcarboxamide;

2-Amino-5-(4-pyridinyl)-3,4'-biphenyldicarboxamide;

2-Amino-4'-[(aminosulfonyl)methyl]-5-(4-pyridinyl)-3-biphenylcarboxamide;

6^I-Amino-4"-fluoro-1 ,1':3'_l1"-terphenyl-4,5^l-dicarboxamide; 6^l-Amino-Λ/⁴-[4-(methyloxy)-3-(4-methyl-1-piperazinyl)phenyl]-1 _l1':3^I,1^I'-terphenyl-4,5'- dicarboxamide;

4-Amino-5-bromo-4'-fluoro-3-biphenylcarboxamide;

2-Amino-5-(4-pyridinyl)benzamide;

1 , 1 -Dimethylethyl 4-[4-amino-5-(aminocarbonyl)-3-biphenylyl]-3,6-dihydro-1 (2H)- pyridinecarboxylate;

6'-Amino-3-[(methylsulfonyl)amino]-1 ,1':3',1"-terphenyl-5'-carboxarnide; 6^I-Amino-3-(aminosulfonyl)-1 ,1':3',1"-terphenyl-5^l-carboxamide;

6'-Amino-Λ/⁴-[4-(1 H-imidazol-1 -ylmethyl)phenyl]-1 ,1 ':3',1 "-terphenyl-4,5'-dicarboxamide;

2-Amino-3,5-di-4-pyridinylbenzamide;

5-{1 -[(1 -Acetyl-4-piperidinyl)carbonyl]-1 ^.S.Θ-tetrahydro^-pyridinylM-amino^'-fluoro-S- biphenylcarboxamide;

6'-Amino-Λ/⁴ _lΛ/⁴-dimethyl-1 ,1^l:3'_I1"-terphenyl-4,5'-dicarboxamide;

4-Amino-5-(1-{[4-(dimethylamino)phenyl]carbonyl}-1 ,2,3,6-tetrahydro-4-pyridinyl)-4'-fluoro-

3-biphenylcarboxamide;

4-Amino-5-[2,6-bis(methyloxy)-3-pyridinyl]-3-biphenylcarboxamide; 1 ,1-Dimethylethyl 4-[4-amino-5-(aminocarbonyl)-4'-fluoro-3-biphenylyl]-3,6-dihydro-1 (2H)- pyridinecarboxylate;

6^I-Amino-4"-fluoro-Λ/⁴,Λ/⁴-dimethyl-1 ,1^l:3^l,1"-terphenyl-4,5'-dicarboxamide;

6'-Amino-4-[(Λ/,Λ/-dimethylglycyl)amino]-1 _l1':3',1"-terphenyl-5^I-carboxamide;

4-amino-3-biphenylcarboxamide; 4'-Amino-4"-[(dimethylamino)sulfonyl]-4-(methylsulfonyl)-1 ,1':3^l,1"-terphenyl-5'- carboxamide;

4-Amino-5-(4-pyridinyl)-3,4'-biphenyldicarboxamide;

4'-Amino-4-(methyloxy)-4"-(1-pyrrolidinylsulfonyl)-1 ,1^I:3^l,1"-terphenyl-5'-carboxamide;

2-Amino-4¹-[(dimethylamino)sulfonyl]-5-(3-pyridinyl)-3-biphenylcarboxamide; 4-Amino-4^I-(methy!sulfony!)-5-(4-pyridinyl)-3-biphenylcarboxamide;

4^l-Amino-4-(methyloxy)-4"-(methylsulfonyl)-1 ,1^l:3',1"-terphenyl-5^I-carboxamide;

4^l-Amino-4"-(aminosulfonyl)-4-(methyloxy)-1 ,1^l:3',1"-terphenyl-5'-carboxamide;

4'-Amino-4"-(aminosulfonyl)-4-(methylsulfonyl)-1 ,1':3',1"-terphenyl-5'-carboxamide;

4'-Amino-4"-[(dimethylarriino)sulfonyl]-4-(methyloxy)-1 ,1':3',1^l'-terphenyl-5^l-carboxamide; 4'-Amino-4-(methylsulfonyl)-4"-(1-pyrrolidinylsulfonyl)-1 ,1':3^I,1"-terphenyl-5'-carboxamide;

4-Amino-4'-(methyloxy)-5-(4-pyridinyl)-3-biphenylcarboxamide;

2-Amino-5-(3-pyridinyl)-4'-(1-pyrrolidinylsulfonyl)-3-biphenylcarboxamide;

4^l-amino-4"-[(dimethylamino)sulfonyl]-1 ,1':3',1"-terphenyl-4,5'-dicarboxamide;

4'-amino-4"-(aminosulfonyl)-1 ,1':3',1"-terphenyl-4,5^l-dicarboxamide; 4'-amino-4"-(methylsulfonyl)-1 ,1':3',1"-terphenyl-4,5'-dicarboxamide;

4-[(Dimethylamino)sulfonyl]-6'-hydroxy-1 ,1^I:3^l,1"-terphenyl-5'-carboxamide;

6'-Hydroxy-4-[(methylsulfonyl)amino]-1 ,1':3^l,1"-terphenyl-5^l-carboxamide;

4"-(Aminosulfonyl)-4-chloro-4'-hydroxy-1 ,1^l:3^I,1"-terphenyl-5^I-carboxamide;

4-Chloro-4"-[(dimethylamino)sulfonyl]-4^l-hydroxy-1 ,r:3',1"-terphenyl-5'-carboxamide; 4-Hydroxy-5-(4-pyridinyl)-3-biphenylcarboxamide;

4'-[(Dimethylamino)sulfonyl]-2-hydroxy-5-(4-pyridinyl)-3-biphenylcarboxamide; 6^l-Hydroxy-4-(1-pyrrolidinylsulfonyl)-1 ,1^l:3^l,1"-terphenyl-5'-carboxamide;

As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur.

As used herein, the term "physiologically functional derivative" refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof. Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5^th Edition, Vo1 1 : Principles and Practice, which is incorporated herein by reference to the extent that it teaches physiologically functional derivatives.

As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt or physiologically functional derivative thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.

As used herein, the term "substituted" refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.

Certain of the compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers. The compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formula (I) above as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted. Also, it is understood that any tautomers and mixtures of tautomers of the compounds of formula (I) are included within the scope of the compounds of formula (I).

The present invention also covers salts of the compounds of formula (I). Typically, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen on a substituent in the compound of formula (I). Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N- methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium and valerate. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these form a further aspect of the invention.

While it is possible that, for use in therapy, a compound of formula (I), as well as salts, solvates and physiological functional derivatives thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions, which includes a compound of formula (I) and salts, solvates and physiological functional derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of formula (I) and salts, solvates and physiological functional derivatives thereof, are as described above. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I), or salts, solvates and physiological functional derivatives thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5mg to 1g, preferably 1 mg to 700mg, more preferably 5mg to 100mg of a compound of the formula (I), depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage compositions are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association a compound of formal (I) with the carrier(s) or excipient(s).

Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

For instance, for oral administration in the form of a tablet or capsule, a compound of formula (I) can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.

Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar- agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of a compound of formula (I). Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.

Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit pharmaceutical compositions for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.

The compounds of formula (I), and salts, solvates and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of formula (I) and salts, solvates and physiological functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide -phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, a compound of formula (I) may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For treatments of the eye or other external tissues, for example mouth and skin, the pharmaceutical compositions are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, a compound of formula (I) may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical compositions adapted for topical administrations to the eye include eye drops wherein a compound of formula (I) is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.

Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or as enemas.

Pharmaceutical compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasa! passage from a container of the powder held close up to the nose. Suitable compositions wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.

Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurised aerosols, nebulizers or insufflators.

Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The pharmaceutical compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

It should be understood that in addition to the ingredients particularly mentioned above, the pharmaceutical compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

A therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. However, an effective amount of a compound of formula (I) for the treatment of neoplastic growth, for example colon or breast carcinoma, will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70kg adult mammal, the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same. An effective amount of a salt or solvate, or physiologically functional derivative thereof, may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.

The compounds of formula (I) and salts, solvates and physiological functional derivatives thereof, are believed to have utility in inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease); osteoarthritis.osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin damage; autoimmune diseases including systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation associated with infection and certain viral infections, including acquired immune deficiency syndrome (AIDS), adult respiratory distress syndrome, and Ataxia Telangiestasia.

The present invention thus also provides a compound of formula (I) and pharmaceutically acceptable salts or solvates thereof, or physiologically functional derivatives thereof, for use in medical therapy, and particularly in the treatment of disorders mediated by IKK2 activity.

The inappropriate IKK2 activity referred to herein is any IKK2 activity that deviates from the normal IKK2 activity expected in a particular mammalian subject. Inappropriate IKK2 activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of IKK2 activity. Such inappropriate activity may result then, for example, from overexpression or mutation of the protein kinase leading to inappropriate or uncontrolled activation.

The present invention is directed to methods of regulating, modulating, or inhibiting IKK2 for the prevention and/or treatment of disorders related to unregulated IKK2 activity. In particular, the compounds of the present invention can also be used in the treatment of certain forms of renal and cardiovascular disease as well as congestive heart failure.

A further aspect of the invention provides a method of treatment of a mammal suffering from a disorder mediated by IKK2 activity, which includes administering to said subject a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or a physiologically functional derivative thereof. In a preferred embodiment, the disorder is a susceptible cancer.

A further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, in the preparation of a medicament for the treatment of a disorder characterized by inappropriate IKK2 activity.

Particular disorders characterised by inappropriate IKK2 activity include inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease);osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin damage; autoimmune diseases including systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation associated with infection and certain viral infections, including acquired immune deficiency syndrome (AIDS), adult respiratory distress syndrome, and Ataxia Telangiestasia as a result of inhibition of the protein kinase IKK2.

Particular disorders are an inflammatory or tissue repair disorder, most particularly rheumatoid arthritis, inflammatory bowel disease, asthma, and COPD (chronic obstructive pulmonary disease).

In a still further aspect, the disorder is selected from the group consisting of autoimmune diseases; tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes, glomerulonephritis, osteoarthritis, osteoporosis, and Ataxia Telangiestasia. Most particularly the disorder is an autoimmune disease including systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, or alkylosing spondylitis, diabetes.

In a still further aspect, the disease is cachexia or cancer, more particularly Hodgkins disease.

The compound and pharmaceutical compositions according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from anti-inflammatory agents, anticholinergic agents (particularly an M₁ZM₂ZM₃ receptor antagonist), β₂-adrenoreceptor agonists, antiinfective agents such as antibiotics or antivirals, or antihistamines. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with one or more other therapeutically active agents, for example selected from an anti-inflammatory agent such as another corticosteroid or an NSAID, an anticholinergic agent, a β₂-adrenoreceptor agonist, an antiinfective agent such as an antibiotic or an antiviral, or an antihistamine. Combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a β₂- adrenoreceptor agonist, andZor an anticholinergic, andZor a PDE-4 inhibitor are preferred.

Preferred combinations are those comprising one or two other therapeutic agents. It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates, to optimise the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.

A combination comprising of compound of the invention together with a β₂-adrenoreceptor agonist is particularly preferred.

Examples of β₂-adrenoreceptor agonists include salmeterol (which may be a racemate or a single enantiomer, such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline and salts thereof, for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol. Long-acting β₂-adrenoreceptor agonists are preferred, especially those having a therapeutic effect over a 24 hour period, such as salmeterol or formoterol.

Preferred long acting β₂-adrenoreceptor agonists include those described in WO02/66422A, WO02/270490, WO02/076933, WO03/024439, WO03/072539, WO 03/091204, WO04/016578, WO04/022547, WO04/037807, WO04/037773, WO04/037768, WO04/039762, WO04/039766, WO01/42193 and WO03/042160.

Especially preferred long-acting β₂-adrenoreceptor agonists are:

3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino) hexyl]oxy}butyl)benzenesulfonamide;

3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}- amino)heptyl]oxy}propyl)benzenesulfonamide; 4-{(1 R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1 -hydroxyethyl}-2-

(hydroxymethyl)phenol;

4-{(1 R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-

(hydroxymethyl)phenol;

N-[2-hydroxyl-5-[(1 R)-1 -hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2- phenylethyl]amino]phenyl]ethyl]amino]ethyl]phenyl]foramide, and N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1/-/)- quinolinon-5-yl)ethylamine.

Suitable anti-inflammatory agents include corticosteroids. Suitable corticosteroids which may be used in combination with the compounds of the invention are those oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α,9α-difluoro-11β- hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1 ,4-diene-17β-carbothioic acid S- (2-oxo-tetrahydro-furan-3S-yl) ester, 6α,9α-difluoro-11 β-hydroxy-16α-methyl-17α-(1 - methylcylopropylcarbonylJoxy-S-oxo-androsta-i ,4-diene-17β-carbothioic acid S- fluoromethyl ester, 6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo -17α-(2, 2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid cyanomethyl ester, beclomethasone esters (such as the 17-propionate ester or the 17,21-dipropionate ester), budesonide, flunisolide, mometasone esters (such as the furoate ester), triamcinolone acetonide, rofleponide, ciclesonide, (16α,17-[[(R)- cyclohexylmethylene]bis(oxy)]-11 β,21 -dihydroxy-pregna-1 ,4-diene-3,20-dione), butixocort propionate, RPR-106541 , and ST-126. Preferred corticosteroids include fluticasone propionate, 6α,9α-difluoro-11 β-hydroxy-16α-methyi-17α-[(4-methyi-1 ,3-thiazole-5- carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester and 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4- diene-17β-carbothioic acid S-fluoromethyl ester, more preferably 6α,9α-difluoro-17α-[(2- furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester.

Non-steroidal compounds having glucocorticoid agonism that may possess selectivity for transrepression over transactivation and that may be useful in combination therapy include those covered in the following patents: WO03/082827, WO01 /10143, WO98/54159, WO04/005229, WO04/009016, WO04/009017, WO04/018429, WO03/104195, WO03/082787, WO03/082280, WO03/059899, WO03/101932, WO02/02565, WO01/16128, WO00/66590, WO03/086294, WO04/026248, WO03/061651 , WO03/08277. Suitable anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID¹S).

Suitable NSAID's include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (for example, theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (for example, montelukast), iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (for example, adenosine 2a agonists), cytokine antagonists (for example, chemokine antagonists, such as a CCR3 antagonist) or inhibitors of cytokine synthesis, or 5-lipoxygenase inhibitors. Suitable other β₂- adrenoreceptor agonists include salmeterol (for example, as the xinafoate), salbutamol (for example, as the sulphate or the free base), formoterol (for example, as the fumarate), fenoterol or terbutaline and salts thereof. An iNOS (inducible nitric oxide synthase inhibitor) is preferably for oral administration. Suitable iNOS inhibitors include those disclosed in WO93/13055, WO98/30537, WO02/50021 , WO95/34534 and WO99/62875. Suitable CCR3 inhibitors include those disclosed in WO02/26722.

Of particular interest is use of the compounds of formula (I) in combination with a phosphodiesterase 4 (PDE4) inhibitor, especially in the case of a formulation adapted for inhalation. The PDE4-specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family, such as PDE3 and PDE5, as well as PDE4.

Compounds of interest include c/s-4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-1-carboxylic acid, 2-carbomethoxy-4-cyano-4-(3- cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1 -one and c/s-[4-cyano-4-(3- cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]. Another compound of interest is c/s-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1 -carboxylic acid (also known as cilomilast) and its salts, esters, pro-drugs or physical forms, which is described in U.S. patent 5,552,438 issued 03 September, 1996; this patent and the compounds it discloses are incorporated herein in full by reference.

AWD-12-281 from Elbion (Hofgen, N. et_aj. 15th EFMC lnt Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering- Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, L.J. et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a pthalazinone (WO99/47505, the disclosure of which is hereby incorporated by reference) from Byk-Gulden; Pumafentrine, (-)-p-[(4aR*,106S^*)-9-ethoxy-1 ,2,3,4,4a, 10b-hexahydro-8-methoxy-2- methylbenzo[c][1 ,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide which is a mixed PDE3/PDE4 inhibitor which has been prepared and published on by Byk-Gulden, now Altana; arofylline under development by Almirall-Prodesfarma; VM554/UM565 from Vemalis; or T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1): 162), and T2585.

Further compounds of interest are disclosed in the published international patent application WO04/024728 (Glaxo Group Ltd), PCT/EP2003/014867 (Glaxo Group Ltd) and PCT/EP2004/005494 (Glaxo Group Ltd).

Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptors, in particular those compounds which are antagonists of the Mi or M₃ receptors, dual antagonists of the M₁ZM₃ or M₂/M₃, receptors or pan-antagonists of the M₁ZM₂ZM₃ receptors. Exemplary compounds for administration via inhalation include ipratropium (for example, as the bromide, CAS 22254-24-6, sold under the name Atrovent), oxitropium (for example, as the bromide, CAS 30286-75-0) and tiotropium (for example, as the bromide, CAS 136310-93-5, sold under the name Spiriva). Also of interest are revatropate (for example, as the hydrobromide, CAS 262586-79-8) and LAS- 34273 which is disclosed in WO01/04118. Exemplary compounds for oral administration include pirenzepine (for example, CAS 28797-61-7), darifenacin (for example, CAS 133099-04-4, or CAS 133099-07-7 for the hydrobromide sold under the name Enablex), oxybutynin (for example, CAS 5633-20-5, sold under the name Ditropan), terodiline (for example, CAS 15793-40-5), tolterodine (for example, CAS 124937-51-5, or CAS 124937- 52-6 for the tartrate, sold under the name Detrol), otilonium (for example, as the bromide, CAS 26095-59-0, sold under the name Spasmomen), trospium chloride (for example, CAS 10405-02-4) and solifenacin (for example, CAS 242478-37-1 , or CAS 242478-38-2, or the succinate also known as YM-905 and sold under the name Vesicare). Other suitable anticholinergic agents include compounds of formula (XXI), which are disclosed in US patent application 60/487981 :

in which the preferred orientation of the alkyl chain attached to the tropane ring is endo;

R³¹ and R³² are, independently, selected from the group consisting of straight or branched chain lower alkyl groups having preferably from 1 to 6 carbon atoms, cycloalkyl groups having from 5 to 6 carbon atoms, cycloalkyl-alkyl having 6 to 10 carbon atoms, 2-thienyl, 2-pyridyl, phenyl, phenyl substituted with an alkyl group having not in excess of 4 carbon atoms and phenyl substituted with an alkoxy group having not in excess of 4 carbon atoms;

X^" represents an anion associated with the positive charge of the N atom. X^" may be but is not limited to chloride, bromide, iodide, sulfate, benzene sulfonate, and toluene sulfonate, including, for example:

(S-enαfoJ-S^^-di^-thienylethenyO-δ.δ-dimethyl-δ-azoniabicyclofS^.1 ]octane bromide;

(3-e/7c/o)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide; (3-eπαfo)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane 4- methylbenzenesulfonate;

(3-eA7cfo)-8,8-dimethyl-3-[2-phenyl-2-(2-thienyl)ethenyl]-8-azoniabicyclo[3.2.1]octane bromide; and/or

(3-enc⁽o)-8,8-dimethyl-3-[2-phenyl-2-(2-pyridinyl)ethenyl]-8-azoniabicyclo[3.2.1]octane bromide.

Further suitable anticholinergic agents include compounds of formula (XXII) or (XXIII), which are disclosed in US patent application 60/511009: (XXII) (XXIII)

wherein:

the H atom indicated is in the exo position;

-.41-

R represents an anion associated with the positive charge of the N atom. R1^" may be but is not limited to chloride, bromide, iodide, sulfate, benzene sulfonate and toluene sulfonate;

R⁴² and R⁴³ are independently selected from the group consisting of straight or branched chain lower alkyl groups (having preferably from 1 to 6 carbon atoms), cycloalkyl groups (having from 5 to 6 carbon atoms), cycloalkyl-alkyl (having 6 to 10 carbon atoms), heterocycloalkyl (having 5 to 6 carbon atoms) and N or O as the heteroatom, heterocycloalkyl-alkyl (having 6 to10 carbon atoms) and N or O as the heteroatom, aryl, optionally substituted aryl, heteroaryl, and optionally substituted heteroaryl:

-.44

R is sleeted from the group consisting of (C₁-C₆JaIkVl, (C₃-C₁₂)cycloalkyl, (C₃- C₇)heterocycloalkyl, (d-C₆)alkyl(C₃-C₁₂)cycloalkyl, (d-C₆)alkyl(C₃-C₇)heterocycloalkyl, ryl, (d-C₆)alkyl-aryl, (CrC₆)alkyl-heteroaryl, -OR ,4⁴5 i45 aryl, heteroa ⁰, -CH₂OR , -CH₂OH, -CN,

,47 -CF₃, -CH₂O(CO)R⁴⁶, -CO₂R⁴', -CH₂NH₂, -CH₂N(R⁴⁷)SO₂R , -SO₂N(R⁴')(R ⁸), -

CON(R⁴⁷XR⁴⁸), -CH₂N(R⁴⁸)CO(R⁴⁶), -CH₂N(R⁴⁸JSO₂(R⁴⁶), -CH₂N(R⁴⁸)CO₂(R⁴⁵), CH₂N(R⁴⁸)CONH(R⁴⁷);

R is selected from the group consisting of (C₁-C₆JaIkVl, (d-C₆)alkyl(C₃-C₁₂)cycloalkyl, (d-CeJalkyKCa-CyJheterocycloalkyl, (d-C₆)alkyl-aryl, (C_rC₆)alkyl-heteroaryl;

-.46

R is selected from the group consisting of (C₁-C₆JaIkVl, (C₃-C₁₂)cycloalkyl, (C₃- Cyjheterocycloalkyl, (d-C₆)alkyl(C₃-C₁₂)cycloalkyl, (d-CeJalkyKCs-CyJheterocycloalkyl, aryl, heteroaryl, (d-QsJalkyl-aryl, (d-CeJalkyl-heteroaryl; R⁴⁷ and R⁴⁸ are, independently, selected from the group consisting of H, (Ci-C₆)alkyl, (C₃-

C₁₂)cycloalkyl, (C₃-C₇)heterocycloalkyl, (Ci-C₆)alkyl(C₃-C₁₂)cycloalkyl, (d-C₆)alkyl(C3-

C₇)heterocycloalkyl, (CrC₆)alkyl-aryl_F and (Ci-C₆)alkyl-heteroaryl, including, for example:

(Endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-δ,δ-dimethyl-δ-azonia- bicyclo[3.2.1]octane iodide;

3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionitrile;

(Endo)-8-methyl-3-(2,2,2-triphenyl-ethyl)-8-aza-bicyclo[3.2.1]octane;

3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide;

3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionic acid; (Endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide;

(Endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide;

3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propan-1-ol;

Λ/-Benzyl-3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide; (Endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide;

1 -Benzyl-S-β-^endoJ-δ-methyl-δ-aza-bicyclotS^.1 ]oct-3-yl)-2,2-diphenyl-propyl]-urea;

1-Ethyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;

Λ/-[3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-acetamide; ^-^-((EndoVδ-methyl-δ-aza-bicyclotS^.IJoct-S-yl^^-diphenyl-propyll-benzamide;

3-((Endo)-8-methyl-δ-aza-bicyclo[3.2.1]oct-3-yl)-2,2-di-thiophen-2-yl-propionitrile;

(Endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-δ,δ-dimethyl-δ-azonia-bicyclo[3.2.1]octane iodide;

Λ/-[3-((Endo)-δ-methyl-δ-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]- benzenesulfonamide;

^-((EndoJ-δ-methyl-δ-aza-bicyclotS^.IJoct-S-yl^^-diphenyl-propyll-urea;

^-^-((EndoJ-δ-methyl-δ-aza-bicyclofS^.iloct-S-yO^^-diphenyl-propyl]- methanesulfonamide; and/or

(Endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-δ,δ-dimethyl-δ-azonia- bicyclo[3.2.1]octane bromide.

More preferred compounds useful in the present invention include:

(Endo)-3-(2-cyano-2,2-diphenyl-ethyl)-δ,δ-dimethyl-δ-azonia-bicyclo[3.2.1]octane iodide; (Endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide;

(Endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide; (Endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide; and/or

(Endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane bromide.

Suitable antihistamines (also referred to as H1-receptor antagonists) include any one or more of the numerous antagonists known which inhibit H 1 -receptors, and are safe for human use. First generation antagonists, include derivatives of ethanolamines, ethylenediamines, and alkylamines, such as diphenylhydramine, pyrilamine, clemastine, chlorpheniramine. Second generation antagonists, which are non-sedating, include loratidine, desloratidine, terfenadine, astemizole, acrivastine, azelastine, levocetirizine fexofenadine and cetirizine.

Examples of preferred anti-histamines include loratidine, desloratidine, fexofenadine and cetirizine.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a β₂-adrenoreceptor agonist.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an antihistamine. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor and a β₂-adrenoreceptor agonist.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic and a PDE-4 inhibitor.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.

The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Preferably, the individual compounds will be administered simultaneously in a combined pharmaceutical composition. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.

The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the Working Examples.

Compounds of general formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991 ) Protecting Groups in Organic Synthesis. John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of Formula (I). Those skilled in the art will recognize if a stereocenter exists in compounds of Formula (I). Accordingly, the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

Compounds of Formula I wherein Z is NH₂ can be prepared for example according to the general scheme depicted below and the Examples section following:

NaOH (aq)

Suzuki reaction Aryl or heteroaryl or alkenyl boronic acid or ester,

PdCI₂(dppf)-CH₂CI₂, Na₂CO₃. 1 ,4-Dιoxane / Water

Compounds of Formula I wherein Z is OH can be prepared for example according to the general scheme depicted below and the Examples section following: EtOH

(ι) Suzuki reaction (ιv) Suzuki reaction (H) NBS₁ AcOH (v) LiI, Pyridine

Suzuki reaction Aryl or heteroarγl or alkenyl boronic acid or ester, PdCI^dPPf)¹CH₂CI₂₁ Na₂CO₃, 1,4-Dιoxaπe / Water

Reaction conditions will be apparent to a skilled person and Examples of suitable conditions are further exemplified in the Examples Section below. It will also be evident from the above scheme that a compound of formula (I) may be converted into another compound of formula (I) using conventional procedures.

Certain embodiments of the present invention will now be illustrated by way of example only. The physical data given for the compounds exemplified is consistent with the assigned structure of those compounds.

EXAMPLES

As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configu ration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification.

As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:

g (grams); mg (milligrams);

L (liters); mL (milliliters); μl_ (microliters); M (molar); mM (millimolar); Hz (Hertz);

MHz (megahertz); mol (moles); mmol (millimoles); rt (room temperature); min (minutes); h (hours);

MeOH (methanol); DMSO (dimethylsulfoxide); THF (tetrahydrofuran); NBS (Λ/-bromosuccinimide);

MeCN (acetonitrile); AcOH (acetic acid);

BSA (bovine serum albumin)

ATP (adenosine triphosphate);

HPLC (high pressure liquid chromatography); HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid);

EDTA (ethylenediaminetetraacetic acid);

LCMS (liquid chromatography - mass spectrometry);

MS (mass spectrometry); dppf (bis(diphenylphosphino)ferrocene) DBU (1 ,8-diazabicyclo[5.4.0]undec-7-ene)

All references to ether are to diethyl ether; brine refers to a saturated aqueous solution of NaCI. Unless otherwise indicated, all temperatures are expressed in ⁰C (degrees Centigrade). All reactions are conducted under an inert atmosphere at room temperature unless otherwise noted.

¹H NMR spectra were recorded on a Bruker DPX400 spectrometer using the specified solvent. Chemical shifts are expressed in parts per million (ppm, δ units). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint, (quintet), sext. (sextet) m (multiplet), br (broad), c (complex). Low-resolution mass spectra (MS) were recorded on a JEOL JMS-AX505HA, JEOL SX- 102, or a SCIEX-APIiii spectrometer; LCMS were recorded on Waters ZQ spectrometers.

Preparative HPLC refers to methods where the material was purified by High Performance Liquid Chromatography on a HPLC ABZ+ 5μm column (10 cm x 21.2 mm i.d.) with water (containing 0.1 % formic acid) and acetonitrile (containing 0.05% formic acid) utilising gradient elution at a flow rate of 8 mL/min and UV detection at 254 nm.

Mass-directed HPLC refers to methods where the material was purified by HPLC comprised of the following apparatus: Waters 600 gradient pump, Waters 2700 sample manager, Waters reagent manager, Micromass ZQ mass spectrometer, Gilson 202 - fraction collector, Gilson 202 - waste collector, Gilson 115 post-fraction UV detector.

Detection is by UV and fraction collection is triggered by observation of the programmed mass ion for the compound of interest. Software used is Micromass Masslynx version 3.5. Two columns are used: For polar (< 1.8 min analytical RT) compounds, an Optimal ODS-

L is used, whose dimensions are 20mm internal diameter by 100mm in length. The stationary phase particle size is 5 μm. For all other compounds, a Supelco LCABZ++ column is employed, whose dimensions are 20mm internal diameter by 100 mm in length.

The stationary phase particle size is 5μm. Eluting solvents are: water + 0.1% formic acid and acetonitrile: water 95:5+0.05% formic acid; using a runtime of 14 minutes and a flow rate of 20 mL/min .

Reactions requiring microwave irradiation were performed using a Personal Chemistry SmithCreator or SmithSynthesizer microwave.

Pre-adsorbtion onto an inert sorbent refers to the use of Bulk lsolute Sorbent HM-N (40- 70 micron mean particle size), supplied by International Sorbent Technology Ltd., Dyffryn Business Park, Hengoed, Mid Glam., CF82 7RJ, UK.

The use of silica cartridges and aminopropyl functionalised silica cartridges refer to prepacked cartridges supplied by International Sorbent Technology Ltd., Dyffryn Business Park, Hengoed, Mid Glam., CF82 7RJ, UK.

Unless otherwise stated, silica column chromatography refers to the purification of material using Redisep™ pre-packed silica flash columns on an ISCO sq16x machine with the stated solvent systems. Intermediates and Examples wherein Z is NH?: INTERMEDIATES

Intermediate 1 : 6-lodo-2H-3,1-benzoxazine-2,4(1H)-dione

Triphosgene (10.1 g, 34.0 mmol) was added to a solution of 2-amino-5-iodobenzoic acid (25.5 g, 96.9 mmol) in THF (900 ml.) and the resulting pink suspension was stirred at rt under N₂ for 1 h. Cyclohexane (1.0 L) was added, and the resulting precipitate (14.7 g) was isolated by filtration. A second crop of the precipitate (13.8 g) was isolated from the filtrate, to give a total yield of the title compound of 28.5 g as a pale-pink solid.

MS [M-1]^" 288.21 ; ¹H NMR <5H (400.13 MHz, Cf₆-DMSO, TMS): 11.82 (br s, 1 H), 8.13 (br s, 1 H), 8.02 (d, J = 8.3Hz, 1 H), 6.96 (d, J = 8.5 Hz, 1 H).

Intermediate 2 : 2-Amino-5-iodobenzamide

Ammonia (0.5M solution in 1 ,4-dioxane, 250 ml.) was added to a suspension of 6-iodo- 2/-/-3,1-benzoxazine-2,4(1H)-dione (Intermediate 1 , 13.8 g, 47.6 mmol) in THF (200 mL) and the resulting pink suspension stirred at rt under N₂ for 3 h. The suspension was then concentrated in vacuo to yield the title compound (12.5 g, 47.3 mmol) which was used without purification.

MS [M+1]⁺ 263.18; ¹H NMR S_n (400.13 MHz, Cf₆-DMSO, TMS): 7.83 (br s, 1 H), 7.81 (d, J = 2.0 Hz, 1 H), 7.37 (dd, J = 8.7, 1.9 Hz, 1 H), 7.14 (br s, 1 H), 6.71 (br s, 2H), 6.54 (d, J = 8.5 Hz, 1 H). Intermediate 3 : 4-Amino-4'-chloro-3-biphenylcarboxamide

A mixture of 2-amino-5-iodobenzamide (Intermediate 2, 3.27 g, 12.5 mmol), (4- chlorophenyl)boronic acid (2.93 g, 18.8 mmol), dichloro(1 ,1'- bis(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (915 mg, 1.25 mmol) and sodium carbonate (2M aqueous solution, 38.0 ml_, 76.0 mmol) in 1 ,4-dioxane (50 ml.) and water (12 ml.) was heated at 8O⁰C under N₂ for 15 h. After cooling to rt the mixture was partially concentrated in vacuo to remove the 1 ,4-dioxane. Water (100 mL) and CHCI₃ (200 mL) were added, the phases were separated, and the aqueous phase was extracted with CHCI₃ (2 x 100 mL). The organic phases were combined and concentrated in-vacuo with pre-adsorbtion onto an inert sorbent (approximately 40 g). Purification by column chromatography (SiO₂, 30-60% ethyl acetate in cyclohexane gradient over 40 mins) yielded the title compound (1.24 g, 5.03 mmol) as a white solid.

MS [M+1]⁺ 247.29 / 249.28 (- 3:1 ratio); ¹H NMR <5H (400.13 MHz, Cf₆-DMSO, TMS): 7.96 (br s, 1 H), 7.86 (d, J = 2.0 Hz, 1 H), 7.68 (d, J = 8.5 Hz, 2H), 7.50 (dd, J = 8.7, 2.1 Hz, 1 H), 7.44 (d, J = 8.5 Hz, 2H), 7.15 (br s, 1 H), 6.77 (d, J = 8.5 Hz, 1 H), 6.75 (br s, 2H).

Intermediate 4 : 4-Amino-5-bromo-4'-chloro-3-biphenylcarboxamide

Λ/-Bromosuccinimide (939 mg, 5.28 mmol) was added to a solution of 4-amino-4'-chloro- 3-biphenylcarboxamide (Intermediate 3, 1.24 g, 5.03 mmol) in acetic acid (100 mL) at rt. After stirring for 45 min, the solution was concentrated in vacuo. Water (150 mL) was added, the mixture was sonicated, and the title compound (1.60 g, 4.91 mmol) was isolated by filtration as a yellow solid.

MS [M+1]⁺ 325.22 / 327.20 (-1 :1 ratio); ¹H NMR & (400.13 MHz, Of₆-DMSO, TMS): 8.16 (br s, 1 H), 7.91 (br s, 1 H)₁ 7.89 (d, J = 1.8 Hz, 1 H), 7.73 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.3Hz, 2H), 7.43 (br s, 2H), 6.82 (br s, 1 H).

Intermediate 5 : 4-Amino-3-biphenylcarbonitrile

A well-stirred solution of 2-amino-5-bromobenzonitrile (2.35 g, 11.9 mmol), phenylboronic acid (2.18 g, 17.9 mmol), sodium carbonate (7.63 g, 72 mmol) and dichloro(1 ,1'- bis(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (0.98 g, 1.3 mmol) in 1 ,4-dioxane (100 ml.) and water (100 mL) was heated at 70 ⁰C for 17 h. The solution was allowed to cool to rt and the 1 ,4-dioxane removed by concentration in vacuo. The resulting slurry was diluted with water (100 mL) and shaken with chloroform (2 x 200 mL). The combined organic phases were concentrated in vacuo to give a black oil which was dissolved in methanol (200 mL) and concentrated in vacuo with pre-adsorbtion onto an inert sorbent (20 g). Purification by column chromatography (SiO₂, 15-25% ethyl acetate in cyclohexane gradient) afforded the title compound as an off-white solid. (1.80 g, 9.27 mmol).

MS, no m/z seen for a common adduct; ¹H NMR δπ (400.13 MHz, Cf₆-DMSO, TMS): 7.71 (d, J = 2.0 Hz, 1 H), 7.66 (dd, J = 8.8, 2.3Hz, 1 H), 7.59 (d, J = 7.3Hz, 2H), 7.40 (t, J = 7.5 Hz₁ 2H), 7.27 (t, J = 7.3Hz, 1 H), 6.88 (d, J = 8.5 Hz, 1 H), 6.18 (s, 2H).

Intermediate 6 : 4-amino-3-biphenylcarboxamide

To a stirred suspension of 4-amino-3-biphenylcarbonitrile (Intermediate 5, 1.59 g, 8.19 mmol) in ethanol (100 ml_) and aqueous sodium hydroxide (2M, 50 mL) at 0 ⁰C was added 30 % w/w hydrogen peroxide solution (20 mL) dropwise over 15 mins. The homogeneous solution was allowed to warm up to ambient temperature and stirred for 24 h. Addition of water (100 mL) caused a thick white precipitate to form which was recovered by suction filtration, washed well with cold water and dried under suction in air to afford the title compound as a white solid (1.70 g, 98.01 mmol).

MS [M+1]⁺ 213.18; ¹H NMR δ* (400.13 MHz, Cf₆-DMSO, TMS): 7.94 (br s, 1 H), 7.85 (s, 1 H), 7.64 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 8.5 Hz, 1 H), 7.39 (t, J = 7.5 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1 H), 7.12 (br s, 1 H), 6.68 (s, 2H), 6.77 (d, J = 8.5 Hz, 1 H).

Intermediate 7 : 4-Amino-5-bromo-3-biphenylcarboxamide

A solution of 4-amino-3-biphenylcarboxamide (Intermediate 6, 1.00 g, 4.7 mmol) and N- bromosuccinimide (0.80 g, 4.5 mmol) in glacial acetic acid (20 mL) was stirred at rt for 3 h. The reaction mixture was diluted with methanol (50 mL) and concentrated in vacuo.

The resulting crude solid was dissolved in methanol (100 mL) and concentrated in vacuo with pre-adsorbtion onto an inert sorbent (10 g). Purification by column chromatography

(SiO₂, 30-75% ethyl acetate in cyclohexane gradient) afforded the title compound as a beige solid. (0.96 g, 3.30 mmol). MS [M+1]⁺ 291.02, 293.00 (approximately 1 :1 ratio); ¹H NMR S_n (400.13 MHz, Gf₆-DMSO, TMS): 8.14 (br s, 1 H), 7.91 (d, J = 2.0 Hz, 1 H), 7.87 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 7.3 Hz, 2H), 7.42 (complex t, J = 7.7 Hz, 3H), 7.29 (t, 1H, J = 7.0 Hz), 6.76 (br s, 2H).

Intermediate 8 : Pentaflυorophenyl 4-bromobenzenesulfonate

To a solution of pentafluorophenol (82.0 g, 0.45 mol) in CH₂CI₂ (3.5 L) was added triethylamine (135 g, 1.34 mol). The mixture was stirred at rt for 10 minutes; during which time a change of colour occurred from pale yellow to an intense orange. A solution of 4- bromobenzenesulphonyl chloride (114 g, 0.45 mol) in CH₂CI₂ was then added. The reaction mixture was allowed to stir at rt for 1 h, before concentration in vacuo. Acetone was added to the resulting white solid, and the mixture was filtered; concentration in vacuo of the filtrate yielded a white solid. Purification by re-crystallisation from ether- hexane gave the title compound (171 g, 0.42 mmol) as a white solid.

19

¹H NMR 4_H (400 MHz, CDCI₃): 7.83 (d, J = 4.6 Hz, 2H), 7.79 (d, J = 4.6 Hz, 2H). F NMR (400 MHz, CDCI₃ + CFCI₃): δ 150.45 (d, J = 6.3), 155.21 (d, J = 6.3), 160.90 (d, J = 6.3).

Intermediate 9 : Pentafluorophenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzenesulfonate

To a solution of pentafluorophenyl 4-bromobenzenesulfonate (Intermediate 8, 20.0 g, 49.6 mmol) in 1 ,4-dioxane (700 ml.) were added 4,4,4',4',5,5,5¹,5'-octamethyl-2,2¹-bi- 1 ,3,2-dioxaborolane (13.9 g, 54.6 mmol), dichloro(1 ,1'- bis(diphenylphosphino)ferrocene)palladium(ll) (1.22 g, 1.48 mmol), 1 ,1'- bis(diphenylphosphino)ferrocene (825 mg, 1.48 mmol) and sodium acetate (24.4 g, 297 mmol), and the mixture was heated at reflux for 16 h. After cooling to rt, the inorganic residue was removed by filtration through celite and washed with CH₂CI₂ (3 x 200 ml_). The organic filtrate was concentrated in vacuo to give a dark residue which was purified by column chromatography (SiO₂, using a gradient of hexane / CH₂CI₂ (100:0) to hexane / CH₂CI₂ (60:40)). Further purification by crystallisation from ether-hexane gave the title compound (16.0 g, 35.5 mmol) as a white solid.

¹H NMR δπ (400 MHz, CDCI₃): 8.01 (d, J = 5.4Hz, 2H), 7.94 (d, J = 5.2Hz, 2H)₁ 1.38 (s,

19 12H). F NMR (400 MHz₁ CDCI₃ + CFCI₃): δ 150.39 (d, J = 6.3 Hz), 155.28 (d, J = 6.3 Hz)₁ 160.99 (d, 2 J = 6.3 Hz).

Intermediate 10 : Pentafluorophenyl 6^>-amino-5^>-(aminocarbonyl)-1,1':3',1^>>- terphenyl-4-sulfonate

To a solution of pentafluorophenyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzenesulfonate (Intermediate 9, 5.56 g, 12.4 mmol) in 1 ,4-dioxane / ethanol (180 mL, 5:1 ) were added dichloro(1 ,1'-bis(diphenylphosphino)ferrocene)palladium(ll) (841 mg, 1.03 mmol), sodium tetraborate (12.5 g, 61.8 mmol), and 4-amino-5-bromo-3- biphenylcarboxamide (Intermediate 7, 3.00 g, 10.3 mmol), and the reaction was heated at reflux for 16 h. After cooling to rt, the inorganic residue was removed by filtration through celite and washed with CH₂CI₂ (3 x 50 mL). The organic filtrate was concentrated in vacuo to give a dark residue which was purified by column chromatography (CH₂CI₂ / hexane; gradient elution - 0% to 20% CH₂CI₂ over 12 mins, 20% CH₂CI₂ for 5 mins, 20% to 50% CH₂CI₂ over 18 min, 50% CH₂CI₂ for 4 min). Further purification by crystallisation from ether / hexane yielded the title compound as a pale yellow solid (3.60 g, 6.74 mmol).

¹H NMR δ_H (400 MHz, CDCI₃): 8.12 (d, J = 8.3 Hz₁ 2H)₁ 7.77 (d, J = 8.5 Hz₁ 2H)₁ 7.69 (d, J = 2.0 Hz₁ 1 H)₁ 7.54 (d, J = 7.0 Hz, 2H)₁ 7.48-7.42 (m, 3H), 7.34 (t, J = 7.4 Hz₁ 1 H), 5.91 (S, 2H). ¹⁹F NMR (400 MHz, CDCI₃ + CFCI₃): £ 150.51 (d, J = 6.3 Hz), 154.92 (d, J = 6.3 Hz), 160.74 (d, J = 6.3 Hz).

Intermediate 11 : 4-Amino-4'-fluoro-3-biphenylcarbonitrile

A suspension of 2-amino-5-bromobenzonitrile (5.16 g, 26.2 mmol), (4- fluorophenyl)boronic acid (5.50 g, 39.3 mmol), sodium carbonate (16.7 g, 157.1 mmol) and dichloro(1 ,1'-bis(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (0.96 g, 1.31 mmol) in 1 ,4-dioxane (100 ml.) and water (100 mL) was heated at 8O⁰C under N₂ for 22.5 h. The solution was allowed to cool to rt and the 1 ,4-dioxane removed by concentration in vacuo. The resultant slurry was diluted with water (150 mL) and shaken with chloroform (200 mL). The phases were separated, and the aqueous phase extracted with chloroform (2 x 200 mL). The combined organic phases were concentrated in vacuo with pre-adsorbtion onto an inert sorbent (20 g). Purification by column chromatography (SiO₂, 15-35% ethyl acetate in cyclohexane gradient over 45 min) afforded the title compound (5.11 g, 24.1 mmol) as a light-beige solid.

MS [M-1]- 211.28; ¹H NMR S_n (400.13 MHz, Cf₆-DMSO, TMS): 7.70 (d, J = 2.0 Hz, 1 H), 7.64-7.61 (m, 3H), 7.22 (t, J = 8.9 Hz, 2H), 8.87 (d, J = 8.8 Hz, 1 H), 6.19 (s, 2H).

Intermediate 12 : 4-Amino-4'-fluoro-3-biphenylcarboxamide

To a stirred suspension of 4-amino-4'-fluoro-3-biphenylcarbonitrile (Intermediate 11 , 13.7 g, 64.5 mmol) in ethanol (400 mL) and 2M aqueous sodium hydroxide (400 ml.) at 0 ⁰C (ice/water bath) was added 30 % w/w hydrogen peroxide solution (100 mL) dropwise. The mixture was allowed to warm up to ambient temperature and stirred for 17 h. After suction filtration, the filtrate was reduced in volume under a gentle vacuum until a precipitate began to form. Water (1 L) was added, and the resulting precipitate collected by suction filtration, washed well with water (1 L in three equal portions) and dried under suction in air to afford the title compound as a white solid (11.24 g, 48.8 mmol).

MS [M+1]⁺ 231.27; ¹H NMR <5H (400.13 MHz, cfe-DMSO, TMS): 7.95 (br s, 1 H), 7.82 (s, 1 H), 7.67 (br t, J = 6.4Hz, 2H), 7.46 (d, J = 8.3Hz, 1 H), 7.22 (t, J = 8.4Hz, 2H), 7.13 (br s, 1 H), 6.77 (d, J = 8.5 Hz, 1 H), 6.69 (br s, 2H).

Intermediate 13 : 4-Amino-5-bromo-4'-fluoro-3-biphenylcarboxamide

To a well stirred suspension of 4-amino-4'-fluoro-3-biphenylcarboxamide (Intermediate 12, 6.22 g, 27 mmol) in glacial acetic acid (100 mL) was added Λ/-bromosuccinimide (4.81 g, 27 mmol). After 1 h the solution was diluted with methanol (100 mL) and concentrated in vacuo. The crude solid was re-dissolved in methanol (300 mL) and pre-adsorbed onto an inert sorbent (10 g). Purification by column chromatography (SiO₂, 25-75% ethyl acetate in cyclohexane) yielded an impure solid, which was sonicated in water (500 mL), and the resulting suspension filtered under suction through a sintered frit. The recovered solid was washed well with water (100 mL) and dried under suction in air to afford the title compound as a white solid (8.37 g, 27.1 mmol).

MS [M+1]⁺ 309.18 / 31 1.19 (approximately 1 :1 ratio); ¹H NMR S_n (400.13 MHz, cfe-DMSO, TMS): 8.16 (br s, 1 H), 7.89 (d, J = 2.0 Hz₁ 1 H), 7.86 (d, J = 2.0 Hz, 1 H), 7.72 (dd, J = 9.0, 6.0 Hz, 2H), 7.42 (br s, 1 H), 7.24 (t, 2H, J = 9 Hz), 6.77 (br s, 2H).

Intermediate 14 : 2-Amino-5-(4-pyridinyl)benzonitrile

A suspension of 2-amino-5-bromobenzonitrile (5.08 g, 25.8 mmol), 4-pyridinylboronic acid (4.75 g, 38.7 mmol), sodium carbonate (16.4 g, 155 mmol) and dichloro(1 ,T- bis(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (0.94 g, 1.29 mmol) in 1 ,4-dioxane (100 ml_) and water (100 ml.) was heated at 8O⁰C under N₂ for 20 h. The solution was allowed to cool to rt and the 1 ,4-dioxane removed by concentration in vacuo. The resultant slurry was diluted with water (100 ml_) and extracted with chloroform (3 x 200 ml_). The combined organic phases were concentrated in vacuo with pre- adsorbtion onto an inert sorbent (approximately 30 g). Purification by column chromatography (SiO₂, 60-100% ethyl acetate in cyclohexane gradient over 60 min) afforded the title compound as a light-brown solid. (2.58 g, 13.2 mmol).

MS [M+1]⁺ 196.10; ¹H NMR 3» (400.13 MHz, cfe-DMSO, TMS): 8.54 (d, J = 6.0 Hz, 2H), 7.95 (d, J = 2.0 Hz, 1 H), 7.82 (dd, J = 8.8, 2.3Hz, 1H), 7.65 (d, J = 6.0 Hz, 2H)₁ 6.90 (d, J = 8.8 Hz, 1 H), 6.45 (br s, 2H).

Intermediate 15 : 2-Amino-5-(4-pyridinyl)benzamide

To a suspension of 2-amino-5-(4-pyridinyl)benzonitrile (Intermediate 14, 2.58 g, 13.2 mmol) in ethanol (100 ml_) and 2M aqueous sodium hydroxide (100 mL) was added 30 % w/w hydrogen peroxide solution (50 mL) and the mixture stirred at rt for 16 h. After suction filtration, the filtrate was reduced in volume under a gentle vacuum until a precipitate began to form. Water (100 mL) was added, and the resulting precipitate collected by suction filtration, washed well with water (100 ml_) and dried under suction in air to afford the title compound as a dark orange solid (2.34 g, 11.0 mmol).

MS [M+1]⁺ 214.11 ; ¹H NMR δ» (400.13 MHz₁ Cf₆-DMSO, TMS): 8.52 (d, J = 6.0 Hz, 2H), 8.04 (d, J = 1.8 Hz, 2H), 7.69 (d, J = 6.0 Hz, 2H), 7.65 (d, J = 2.0 Hz, 1 H), 7.21 (br s, 1 H), 6.97 (br s, 2H), 6.81 (d, J = 8.8 Hz, 1H).

Intermediate 16 : 2-Amino-3-bromo-5-(4-pyridinyl)benzamide

A slurry of 2-amino-5-(4-pyridinyl)benzamide (Intermediate 15, 2.00 g, 9.34 mmol) and N- bromosuccinimide (1.75 g, 9.85 mmol) in glacial acetic acid (100 ml_) was ultrasonicated, and then stirred at rt for 2 h. The suspension was dispersed by adding methanol (50 mL) and the clear solution concentrated in vacuo. The resulting solid was dissolved in methanol (300 mL) and pre-adsorbed onto an inert sorbent (10 g). Purification by column chromatography (SiO₂, 60-100% ethyl acetate in cyclohexane gradient, followed 100% methanol) yielded a thick slurry after partial concentration in vacuo of product containing fractions. The slurry was filtered through a sintered frit under suction, the residue washed well with cyclohexane (100 mL) and dried under suction in air to afford the title compound as a cream powder (2.10 g, 7.19 mmol).

MS [M+1]⁺ 292.01 / 293.99 (Approximate 1 :1 ratio); ¹H NMR ^ (400.13 MHz, Cf₆-DMSO, TMS): 8.56 (d, J = 5.8 Hz, 2H), 8.21 (br s, 1 H), 8.07 (s, 1 H), 8.06 (s, 1 H), 7.75 (d, J = 6.0 Hz, 2H), 7.49 (br s, 1 H), 7.03 (br s, 2H).

Intermediate 17 : 1,1-Dimethylethyl 4-[4-amino-5-(aminocarbonyl)-4'-fluoro-3- biphenylyl]-3,6-dihydro-1(2W)-pyridinecarboxylate

A mixture of 4-amino-5-bromo-4'-fluoro-3-biphenylcarboxamide (Intermediate 13, 3.40 g, 11.0 mmol), 1 ,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro- 1(2/-/)-pyridinecarboxylate (5.00 g, 16.5 mmol), sodium carbonate (7.00 g, 66.0 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (805 mg, 1.10 mmol) in 1 ,4-dioxane (75 ml_), and water (75 ml.) was heated at 8O⁰C under N₂ for approximately 16 h. The solution was allowed to cool to rt and the 1 ,4-dioxane removed by concentration in vacuo. Water (75 mL) and chloroform (100 mL) were added, and the phases were separated. The aqueous phase was extracted with chloroform (2 x 100 mL), and the combined organic phases were concentrated in vacuo. Methanol (200 mL) was added, and the resulting solution was concentrated in vacuo, with pre-adsorbtion onto an inert sorbent (~ 30 g). Purification by column chromatography (SiO₂, 40-60% ethyl acetate in cyclohexane gradient over 45 min, followed by 100% ethyl acetate for 10 mins) afforded the title compound as a yellow solid. (2.50 g, 6.08 mmol).

MS [M+1]⁺ 412.40; ¹H NMR 4_H (400.13 MHz, Cf₆-DMSO, TMS): 8.00 (br s, 1 H), 7.77 (d, J = 1.8 Hz, 1 H), 7.69 (dd, J = 8.8, 5.5 Hz, 2H), 7.30 (d, J = 2.0 Hz, 1 H), 7.21 (t, J = 8.8 Hz, 3H), 6.39 (br s, 2H), 5.74 (br s, 1 H), 3.97 (br s, 2H), 3.58 (br t, J = 5.0 Hz, 2H), 2.32 (br s, 2H), 1.44 (s, 9H).

Intermediate 18 4-Amino-4'-fluoro-5-(1,2,3,6-tetrahydro-4-pyridinyl)-3- biphenylcarboxamide

A mixture of 1 ,1-dimethylethyl 4-[4-amino-5-(aminocarbonyl)-4¹-fluoro-3-biphenylyl]-3,6- dihydro-1 (2H)-pyridinecarboxylate (1.00 g, 2.43 mmol) and HCI in 1 ,4-dioxane (4M, 0.67 ml_, 2.67 mmol) in 1 ,4-dioxane (75 ml_) was stirred at rt for approximately 16 h. Ethanol (50 ml_ and HCI in 1 ,4-dioxane (4M, 1.00 ml_, 4.00 mmol) were added, and after stirring at rt for 24H, further HCI in 1 ,4-dioxane (4M, 1.00 ml_, 4.00 mmol) was added and the solution stirred for 3 d. Aqueous sodium carbonate solution (2M) was added until neutral pH was obtained, and the mixture was then partially concentrated in vacuo to remove the ethanol and 1 ,4-dioxane. The resulting slurry was filtered, and the solid obtained rinsed with water. The crude brown solid (850 mg) obtained was dissolved in ethyl acetate and purified by passing through a short silica column, eluting with ethyl acetate, and then methanol. Concentration in vacuo of product containing fraction yielded the title compound (577 mg, 1.85 mmol, approximately 80% pure by ¹H NMR) as a brown solid.

MS [M+1]⁺ 312.20; ¹H NMR δ» (400.13 MHz, Cf₆-DMSO, TMS): (Approximately 80% pure) 7.98 (br s, 1 H), 7.74 (d, J = 2.0 Hz, 1 H), 7.68 (dd, J = 8.5, 5.5 Hz, 2H), 7.24-7.19 (m, 4H), 6.32 (s, 2H), 5.74 (s, 1 H), 2.93 (t, J = 5.5 Hz, 2H), 2.17 (br s, 2H).

Intermediate 19 : 1,1-Dimethylethyl 4-[4-amino-5-(aminocarbonyl)-3-biphenylyl]-3,6- dihydro-1(2H)-pyridinecarboxylate

A mixture of 4-amino-3-biphenylcarboxamide (Intermediate 6, 340 mg, 1.17 mmol), 1 ,1- dimethylethyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-1 (2H)- pyridinecarboxylate (540 mg, 1.75 mmol), sodium carbonate (742 mg, 7.00 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (85 mg, 0.12 mmol) in 1 ,4-dioxane (5 ml.) and water (5 mL) was heated at 8O⁰C under N₂ for approximately 16 h. After cooling to rt, water (25 mL) and chloroform (30 mL) were added and the phases were separated. The aqueous phase was extracted with chloroform (2 x 30 mL), and the combined organic phases were concentrated in vacuo. After dissolution in methanol, the solution was concentrated in vacuo, with pre-adsorbtion onto an inert sorbent (~ 10 g). Purification by column chromatography (SiO₂, 40-70% ethyl acetate in cyclohexane gradient over 45 min) yielded the title compound (430 mg, 1.09 mmol). MS [M+1]⁺ 394.41 ; ¹H NMR δ* (400.13 MHz, Cf₆-DMSO, TMS): (approximately 80% pure) 8.00 (br s, 1 H)₁ 7.79 (s, 1 H), 7.65 (d, J = 7.8 Hz₁ 2H)₁ 7.39 (t, J = 7.5 Hz₁ 2H), 7.82 (s, 1 H)₁ 7.26-7.19 (m, 2H)₁ 6.38 (s, 2H)₁ 5.74 (s, 1 H)₁ 3.98 (br s, 1H)₁ 3.93 (s, 1 H)₁ 3.64-3.55 (m, 2H)₁ 2.37-2.39 (m, 2H)₁ 1.44 (s, 9H).

Intermediate 20 : 4-Amino-5-(1 ,2,3,6-tetrahydro-4-pyridinyl)-3-biphenylcarboxamide

A mixture of 1 ,1-dimethylethyl 4-[4-amino-5-(aminocarbonyl)-3-biphenylyl]-3,6-dihydro- 1 (2/-/)-pyridinecarboxylate (Intermediate 19, 430 mg, 1.09 mmol) and palladium hydroxide on carbon (100 mg) in ethanol (15 mL) and HCI in 1 ,4-dioxane (4M₁ 5 ml.) was stirred at rt under an atmosphere of hydrogen for 20 h. The mixture was filtered, and the filtrate concentrated in vacuo to yield a yellow solid which was partitioned between aqueous hydrochloric acid (2M, 50 mL) and chloroform (50 mL). The phases were separated, and the aqueous phase was taken to pH 12 by the cautious addition of sodium carbonate. The resulting suspension was extracted with chloroform (3 x 50 mL), and the combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo to yield the title compound as a cream solid. The bulk of the solid was used without further purification. For the purposes of characterization, 40 mg of the crude solid was purified by preparative HPLC using a 0-20 % MeCN (aq) gradient; spectroscopic data confirmed the structure as the title compound, ie reduction of the alkene had not occurred.

MS [M+1]⁺ 294.36; ¹H NMR <5H (400.13 MHz₁ cfe-DMSO, TMS): 7.99 (br s, 1 H)₁ 7.77 (d, J = 1.8 Hz₁ 1 H)₁ 7.64 (d, J = 7.5 Hz, 2H)₁ 7.39 (t, J = 7.7 Hz₁ 2H)₁ 7.27-7.23 (m, 2H), 7.20 (br s, 1 H), 6.33 (s, 2H), 5.75 (s, 1 H), 2.93 (t, J = 5.4Hz₁ 2H)₁ 2.18 (br s, 2H).

Intermediate 21 : 4-Amino-4'-(methylsulfonyl)-3-biphenylcarbonitrile

A mixture of 2-amino-5-bromobenzonitrile (5.00 g, 25.4 mmol), [4- (methylsulfonyl)phenyl]boronic acid (7.50 g, 37.5 mmol), sodium carbonate (16.0 g, 150 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (1.02 g, 1.25 mmol) in 1 ,4-dioxane (200 mL) and water (200 ml.) was heated at 100⁰C under N₂ for 1 h. The mixture was partially concentrated in vacuo to remove the 1 ,4-dioxane and the resulting slurry was diluted with water (500 mL) and chloroform (200 mL). The phases were separated, and the aqueous phase extracted with chloroform (2 x 200 mL). The combined organic phases were concentrated in vacuo to yield a black solid, which was re-dissolved in methanol (200 mL) and concentrated in vacuo with pre- adsorbtion onto an inert sorbent. Purification by column chromatography (SiO₂, 35-60% ethyl acetate in cyclohexane gradient over 45 min; followed by 100% ethyl acetate for 10 min) afforded the title compound (1.30 g, 4.77 mmol) as a beige solid.

MS [M-I]^" 271.36; ¹H NMR δ_ri (400.13 MHz, Cf₆-DMSO, TMS): 7.95-7.84 (m, 5H), 7.77 (dd, J = 8.8, 2.0 Hz, 1 H), 6.91 (d, J = 8.8 Hz, 1 H), 6.40 (s, 2H), 3.23 (s, 3H).

Intermediate 22 : 4-Amino-4'-(methylsulfonyl)-3-biphenylcarboxamide

To a suspension of 4-amino-4'-(methylsulfonyl)-3-biphenylcarbonitrile (Intermediate 21 , 1.31 g, 4.79 mmol) in ethanol (125 mL) and 2M aqueous sodium hydroxide (25 mL) at O⁰C was added 30 % w/w hydrogen peroxide solution (20 mL) dropwise. The suspension was allowed to warm to rt with stirring, and further 30 % w/w hydrogen peroxide solution (20 mL) was added after 2 h. The suspension was stirred at rt for 3 d before dropwise addition to aqueous sodium sulfite solution (1M₁ 500 mL) over 10 min. The title compound (1.25 g, 4.31 mmol) was isolated by filtration as a light-yellow solid.

MS [M+1]⁺ 291.21 ; ¹H NMR <fc (400.13 MHz, Gf₆-DMSO₁ TMS): 8.07-7.85 (m, 6H)₁ 7.61 (dd, J = 8.5, 2.0 Hz₁ 1 H)₁ 7.19 (br s, 1H), 6.90 (s, 2H), 6.81 (d, J = 8.8 Hz, 1 H), 3.22 (s, 3H).

Intermediate 23 : 4-Amino-5-bromo-4'-(methylsulfonyl)-3-biphenylcarboxamide

A suspension of 4-amino-4'-(methylsulfonyl)-3-biphenylcarboxamide (Intermediate 22, 1.24 g, 4.28 mmol) and Λ/-bromosuccinimide (799 mg, 4.49 mmol) in glacial acetic acid (40 mL) was stirred at rt for 3 h. Concentration in vacuo yielded an orange-yellow solid to which was added water (100 mL). The mixture was ultrasonicated, and the title compound (1.52 g, 4.12 mmol) isolated by filtration as a yellow solid.

MS [M+1]⁺ 369.12, 371.16 (approximately 1 :1 ratio); ¹H NMR & (400.13 MHz₁ cfe-DMSO, TMS): 8.20 (br s, 1 H), 8.06-8.00 (m, 2H), 7.98 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.48 (br s, 1 H), 6.96 (br s, 2H), 3.24 (s, 3H).

Intermediate 24 : 4'-Amino-3'-cyano-4-biphenylcarboxamide

A mixture of 2-amino-5-bromobenzonitrile (10.7 g, 54.4 mmol), [4- (aminocarbonyl)phenyl]boronic acid (13.5 g, 81.6 mmol), sodium carbonate (34.6 g, 326 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (4.44 g, 5.44 mmol) in 1 ,4-dioxane (250 ml.) and water (250 mL) was heated at 10O⁰C under N₂ for approximately 2 h. The mixture was partially concentrated in vacuo to remove the 1 ,4-dioxane and the resulting slurry was diluted with water (500 mL) and chloroform (500 mL). The phases were separated, and the aqueous extracted with chloroform (2 x 250 mL). The combined organic fractions were concentrated in vacuo and purified by column chromatography (SiO₂, 0-20% methanol (with 1 % added concentrated ammonia) in dichloromethane gradient over 60 min; followed by 20-100% methanol (with 1 % added concentrated ammonia) in dichloromethane gradient over 10 min) to yield the title compound (3.30 g, 13.9 mmol) as a brown solid.

MS [M+1]⁺ 238.18; ¹H NMR δ» (400.13 MHz, c/₄-MeOD): 7.91 (d, J = 8.5 Hz, 2H), 7.71- 7.61 (m, 4H), 6.91 (d, J = 8.5 Hz, 1 H).

Intermediate 25 : 4-Amino-3,4'-biphenyldicarboxamide

To a suspension of 4'-amino-3'-cyano-4-biphenylcarboxamide (Intermediate 24, 3.30 g, 13.91 mmol) in ethanol (400 mL) and 2M aqueous sodium hydroxide (100 mL) at O⁰C was added 30 % w/w hydrogen peroxide solution (70 mL) dropwise over 20 min. The suspension was allowed to warm to rt with stirring, and stirred for 16.5 h. Dropwise addition of the resulting suspension to stirred aqueous sodium sulfite solution (2M, 500 mL) was followed by partial concentration in vacuo to remove ethanol. The title compound (2.80 g, 11.0 mmol) was isolated as a brown solid by filtration of the resulting suspension, rinsing with water (2 x 100 mL).

MS [M+1]⁺ 256.04; ¹H NMR S_n (400.13 MHz, Cf₆-DMSO, TMS): 8.04-7.88 (m, 5H), 7.74 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 1 H), 7.30 (s, 1 H), 7.16 (br s, 1 H), 6.80 (s, 2H), 6.78 (s, 1 H).

Intermediate 26 : 4-Amino-5-bromo-3,4¹-biphenyldicarboxamide

A suspension of 4-amino-5-bromo-3,4'-biphenyldicarboxamide (Intermediate 25, 2.80 g, 11.0 mmol) and Λ/-bromosuccinimide (2.05 g, 11.5 mmol) in glacial acetic acid (100 ml_) was stirred at rt for 17.5 h. The mixture was concentrated in vacuo and water (100 ml_) was added, and the title compound (> 5 g crude mass) was isolated as a brown solid and used without further purification.

MS [M+1]⁺ 333.95, 335.96 (approximate 1 :1 ratio); ¹H NMR δn (400.13 MHz, Of₆-DMSO, TMS): 8.19 (br S₁ 1 H), 8.02-7.95 (m, 3H), 7.92 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.44 (S₁ 1 H), 7.34 (s, 1 H), 6.87 (s, 2H).

Intermediate 27 : 4-Amino-4'-(methyloxy)-3-biphenylcarboxamide

A mixture of 2-amino-5-iodobenzamide (Intermediate 2, 3.64 g, 13.9 mmol), [4- (methyloxy)phenyl]boronic acid (3.17 g, 20.1 mmol), sodium carbonate (8.85 g, 83.5 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (1.02 g, 1.39 mmol) in 1 ,4-dioxane (70 mL) and water (70 mL) was heated at 8O⁰C under N₂ for 18.5 h. After partial concentration in vacuo to remove the 1 ,4-dioxane, water (100 mL) and chloroform (250 mL) were added and the phases were separated. The aqueous phase was extracted with chloroform (2 x 100 mL) and the combined organic phases were concentrated in vacuo, with pre-adsorbtion onto silica (approximately 40 g). Purification by column chromatography (SiO₂, 10% solvent B in solvent A (10 min); 20% solvent B in solvent A (10 min); 30% solvent B in solvent A (10 min); 40% solvent B in solvent A (10 min); 50% solvent B in solvent A (10 min); 100% solvent B (5 min) where solvent A = cyclohexane, solvent B = ethyl acetate / triethylamine (99:1 )) yielded the title compound (787 mg, 3.25 mmol) as a brown solid.

MS [M+1]⁺ 243.13; ¹H NMR Sn (400.13 MHz, CDCI₃, TMS): 7.53 (d, J = 2.0 Hz, 1 H), 7.48- 7.41 (m, 3H)₁ 6.96 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.5 Hz, 1 H), 5.68 (s, 2H), 3.85 (s, 3H).

Intermediate 28 : 4-Amino-5-bromo-4¹-(methyloxy)-3-biphenylcarboxamide

A solution of 4-amino-4'-(methyloxy)-3-biphenylcarboxamide (Intermediate 27, 787 mg, 3.25 mmol) and Λ/-bromosuccinimide (578 mg, 3.25 mmol) in glacial acetic acid (20 mL) was stirred at rt for 17.5 h. Further Λ/-bromosuccinimide (116 mg, 0.65 mmol) was added, and the solution stirred at rt for 2 d before the addition of Λ/-bromosuccinimide (174 mg, 0.98 mmol). After stirring at rt for 1.5 h, the solution was concentrated in vacuo and water (100 mL) was added. The mixture was ultrasonicated, and the title compound (603 mg, 1.88 mmol) was isolated as a brown solid by filtration.

MS [M+1]⁺ 213.10, 323.12 (approximately 1 :1 ratio); ¹H NMR δ» (400.13 MHz, ^₆-DMSO, TMS): 8.13 (s, 1 H), 7.84 (d, J = 2.0 Hz, 1 H), 7.80 (d, J = 2.0 Hz, 1 H), 7.61 (d, J = 9.0 Hz, 2H), 7.39 (s, 1 H), 6.98 (d, J = 8.8 Hz, 2H), 6.67 (s, 2H), 3.78 (s, 3H).

Intermediate 29 : 2-Amino-5-(3-pyridinyl)benzamide

A mixture of 2-amino-5-iodobenzamide (Intermediate 2, 3.68 g, 14.0 mmol), 3- pyridinylboronic acid (2.59 g, 21.1 mmol), sodium carbonate (8.93 g, 84.3 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (1.03 g, 1.41 mmol) in 1 ,4-dioxane (70 mL) and water (70 ml.) was stirred at 8O⁰C under N₂ for 20 h. After partial concentration in vacuo to remove the 1 ,4-dioxane, water (100 mL) and chloroform (250 mL) were added and the phases were separated. The aqueous phase was extracted with chloroform (2 x 100 mL) and the combined organic phases were concentrated in vacuo with pre-adsorbtion onto silica (approximately 40 g). Purification by column chromatography (SiO₂, 25% solvent B in solvent A (10 min); 45% solvent B in solvent A (10 min); 65% solvent B in solvent A (10 min); 75% solvent B in solvent A (10 min); 100% solvent B (10 min) where solvent A = dichloromethane and solvent B = dichloromethane / methanol / concentrated aqueous ammonia (90:10:1 )) yielded the title compound (2.05 g, 9.61 mmol) as a brown solid.

MS [M+1]⁺ 214.3; ¹H NMR S_n (400.13 MHz, CDCI₃): 8.79 (s, 1 H), 8.54 (d, J = 3.8 Hz, 1 H), 7.80 (dt, J = 8.0, 1.8 Hz, 1 H), 7.60 (d, J = 2.0 Hz, 1 H), 7.48 (dd, J = 8.4, 2.1 Hz, 1 H), 7.34 (dd, J = 7.5, 4.8 Hz, 1 H), 6.81 (d, J = 8.5 Hz, 1 H), 5.84 (br s, 2H).

Intermediate 30 : 2-Amino-3-bromo-5-(3-pyridinyl)benzamide

A solution of 2-amino-5-(3-pyridinyl)benzamide (2.04 g, 9.58 mmol) and N- bromosuccinimide (1.79 g, 10.1 mmol) in glacial acetic acid (60 mL) was stirred at rt for 30 min before concentration in vacuo. Water (100 mL) was added and the title compound (2.19 g, 7.50 mmol) was isolated by filtration as a brown solid.

MS [M+1]⁺ 292.04, 294.06 (approximately 1 :1 ratio); ¹H NMR S_n (400.13 MHz, CZ₆-DMSO₁ TMS): 8.93 (d, J = 2.0 Hz, 1 H), 8.49 (dd, J = 4.8, 1.3 Hz, 1 H), 8.16 (br s, 1 H), 8.10 (dt, J = 8.0, 1.9 Hz, 1 H), 7.98 (dd, J = 5.0, 2.0 Hz, 2H), 7.47-7.41 (m, 2H), 6.89 (s, 2H).

EXAMPLES

Example 1 : 4^I-Amino-4"-(aminosulfonyl)-4-chloro-1,1':3^I,1"-terphenyl-5^I- carboxamide

4-Amino-5-bromo-4'-chloro-3-biphenylcarboxamide (Intermediate 4, 31 mg, 0.10 mmol), 4-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)benzenesulfonamide (29 mg, 0.10 mmol), sodium carbonate (61 mg, 0.58 mmol) and dichloro(1 ,1'-bis- (diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (7 mg, 0.10 mmol) were slurried with 1 ,4-dioxane (1 ml.) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (500 mg silica), rinsing with MeOH, and the eluent concentrated in vacuo. The crude solid was dissolved in 1 :1 DMSO / MeOH, and purified by preparative HPLC using a 30-80% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (1 1.7 mg).

MS [M+1]⁺ 402.23 / 404.25 (approximately 3:1 ratio); ¹H NMR S_H (400.13 MHz, d₆-DMSO, TMS): 8.13 (br s, 1 H), 7.94-7.93 (m, 2H), 7.90 (s, 1 H), 7.75 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.3Hz, 2H), 7.46-7.42 (m, 5H), 7.35 (br s, 1 H), 6.59 (br s, 2H).

Example 2 : 6^I-Amino-4-{[(2-aminoethyl)amino]sulfonyl}-1,1':3^l,1"-terphenyl-5¹- carboxamide and Example 3 : 4-({[2-(Acetylamino)ethyl]amino}sulfonyl)-6¹-amino- i.i'iS'.T-terphenyl-S'-carboxamide

Example 2

A solution of pentafluorophenyl 6^l-amino-5'-(aminocarbonyl)-1 ,1^l:3',1"-terphenyl-4- sulfonate (Intermediate 10, 83 mg, 0.16 mmol) and Λ/-(2-aminoethyl)acetamide (0.24 mL, 0.62 mmol) in THF (5 mL) was heated at reflux under N₂ for 17 h. After cooling to rt, concentration in vacuo, dissolution in DMSO / MeOH (1 :1 , 1 mL) and filtration; purification by mass-directed HPLC yielded title compounds Example 2 (13.3 mg) and Example 3 (34.2 mg) as light-yellow solids.

Example 2 data: MS [M+1]⁺411.27; ¹H NMR & (400.13 MHz, Cy₆-DMSO₁ TMS): 8.31 (br s, 2H)₁ 8.12 (br s, 1 H), 7.94 (d, J = 2.0 Hz, 1 H), 7.89 (d, J = 8.3Hz, 2H), 7.72 (t, J = 7.5 Hz, 4H), 7.44 (d, J = 2.0 Hz, 1 H), 7.41 (t, J = 7.7 Hz, 2H), 7.34 (br s, 1 H), 7.27 (t, J = 7.4Hz, 2H), 6.48 (br s, 2H)₁ 2.93 (d, J = 6.4Hz, 2H), 2.75 (d, J = 6.3Hz, 2H).

Example 3 data : MS [M+1]⁺ 453.27; ¹H NMR S_n (400.13 MHz, Of₆-DMSO, TMS): 8.12 (br s, 1 H), 7.94 (d, J = 2.0 Hz, 1 H)₁ 7.90-7.86 (m, 1 H)₁ 7.87 (d, J = 8.3Hz, 2H)₁ 7.71 (d, J = 8.0 Hz, 4H), 7.44 (d, J = 2.3Hz, 1 H), 7.40 (t, J = 7.8 Hz, 2H), 7.83 (br s, 1 H), 7.27 (t, J = 7.4Hz, 1 H), 6.48 (br s, 2H), 3.09 (q, J = 6.4Hz₁ 2H), 6.84 (t, J = 6.8 Hz, 2H), 1.76 (s, 3H).

Example 4 : 6'-Amino-4-({[2-(4-morpholinyl)ethyl]amino}sulfonyl)-1,1':3',1"- terphenyl-5'-carboxamide

A solution of pentafluorophenyl 6^l-amino-5'-(aminocarbonyl)-1 ,1^l:3',1"-terphenyl-4- sulfonate (Intermediate 10, 83 mg, 0.16 mmol) and [2-(4-morpholinyl)ethyl]amine (0.33 mL, 0.62 mmol) in THF (5 mL) was heated at reflux under N₂ for 17 h. After cooling to rt, concentration in vacuo, dissolution in DMSO / MeOH (1 :1 , 1 mL) and filtration; purification by mass-directed HPLC yielded the title compound (61.5 mg) as a yellow oil. MS [M+1]⁺ 481.31 , ¹H NMR S_n (400.13 MHz₁ Cf₆-DMSO₁ TMS): 8.12 (br s, approximately 1 H)₁ 7.93 (d, J = 1.8 Hz₁ 1 H)₁ 7.89 (d, J = 8.3Hz₁ 2H)₁ 7.70 (d, J = 8.3Hz, 4H), 7.64 (br t, J = 5.5 Hz₁ 1 H)₁ 7.43-7.39 (m, 3H), 7.34 (br s, approximately 1 H), 7.27 (t, J = 7.3Hz₁ 1 H), 6.46 (br s, approximately 1 H)₁ 6.43 (br s, approximately 1 H)₁ 3.51 (t, J = 4.5 Hz, 4H), 2.96-2.88 (m, 2H), 2.35 (t, J = 6.8 Hz, 2H), 2.32-2.25 (br m, 4H). Example 5 : 6'-Amino-4-({[2-(1-pyrrolidinyl)ethyl]amino}sulfonyl)-1,1^I:3^l,1¹¹- terphenyl-5'-carboxamide

A solution of pentafluorophenyl 6'-amino-5^l-(aminocarbonyl)-1 ,1':3',1"-terphenyl-4- sulfonate (Intermediate 10, 83 mg, 0.16 mmol) and [2-(1-pyrrolidinyl)ethyl]amine (284 mg, 0.62 mmol) in THF (5 ml.) was heated at reflux under N₂ for 17 h. After cooling to rt, concentration in vacuo, dissolution in DMSO / MeOH (1 :1 , 1 ml.) and filtration; purification by mass-directed HPLC yielded the title compound (57.2 mg) as a yellow oil.

MS [M+1]⁺ 465.33; ¹H NMR S_n (400.13 MHz, O₄-MeOD): 8.39 (br s, 1 H), 7.99 (d, J = 8.3Hz, 2H), 7.89 (d, J = 2.0 Hz, 1 H), 7.73 (d, J = 8.3Hz₁ 2H), 7.60 (d, J = 7.3Hz, 2H), 7.44 (d, J = 2.3Hz, 1 H), 7.38 (t, J = 7.7 Hz, 2H), 7.26 (t, J = 7.4Hz, 1 H), 3.45-3.28 (m, 6H), 3.23 (t, J = 5.8 Hz, 2H)₁ 2.11-2.07 (m, 4H).

Example 6 : 6'-Amino-4-({[3-(methyloxy)propyl]amino}sulfonyl)-1,1^l:3',1"-terphenyl- 5'-carboxamide

A solution of pentafluorophenyl 6'-amino-5'-(aminocarbonyl)-1 ,1':3^I,1"-terphenyl-4- sulfonate (Intermediate 10, 83 mg, 0.16 mmol) and [3-(methyloxy)propyl]amine (0.254 ml_, 0.62 mmol) in THF (5 mL) was heated at reflux under N₂ for 17 h. After cooling to rt, concentration in vacuo, dissolution in DMSO / MeOH (1 :1 , 1 mL) and filtration; purification by mass-directed HPLC yielded the title compound (31.4 mg) as a yellow oil.

MS [M+1]⁺ 440.20; ¹H NMR S_n (400.13 MHz, Cf₄-MeOD): 7.97 (d, J = 8.3Hz, 2H), 7.90 (d, J = 2.3Hz, 1 H)₁ 7.71 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 7.3Hz₁ 2H), 7.47 (d, J = 2.3Hz, 1 H), 7.40 (t, J = 7.7 Hz₁ 2H), 7.27 (t, J = 7.3Hz₁ 1 H), 3.43 (t, J = 6.1Hz, 2H), 3.30 (s, 3H), 3.00 (t, J = 6.9 Hz, 2H), 1.75 (quint., J = 6.5 Hz, 2H).

Example 7 : 6^I-Amino-4-({[3-(4-morpholinyl)propyl]amino}sulfonyl)-1,1':3^I,1"- terphenyl-5'-carboxamide

A solution of pentafluorophenyl 6'-amino-5'-(aminocarbonyl)-1 ,1':3\1"-terphenyl-4- sulfonate (Intermediate 10, 83 mg, 0.16 mmol) and [3-(4-morpholinyl)propyl]amine (0.40 ml_, 0.62 mmol) in THF (5 mL) was heated at reflux under N₂ for 17 h. After cooling to rt, concentration in vacuo, dissolution in DMSO / MeOH (1 :1 , 1 mL) and filtration; purification by mass-directed HPLC yielded the title compound (58.4 mg) as a light-yellow oil.

MS [M+1]⁺ 495.30; ¹H NMR <5H (400.13 MHz, Cf₄-MeOD): 8.33 (br s, 1 H), 7.95 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 2.3Hz, 1 H), 7.69 (d, J = 8.3Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 2.3Hz, 1 H), 7.38 (t. J = 7.7 Hz, 2H), 7.25 (t, J = 7.4Hz, 1 H), 3.78 (t, J = 4.4Hz, 4H), 3.31-3.29 (m, 2H), 2.99 (t, J = 6.4Hz, 2H), 2.93-2.83 (m, 4H), 1.83 (br quint., J = 7.3Hz, 2H).

Example 8 : 6^l-Amino-4-[(cyclopropylamino)sulfonyl]-1,1^I:3',1"-terphenyl-5^>- carboxamide

A solution of pentafluorophenyl 6^l-amino-5'-(aminocarbonyl)-1 ,V:3',1"-terphenyl-4- sulfonate (Intermediate 10, 83 mg, 0.16 mmol) and cyclopropylamine (0.172 mL, 0.62 mmol) in THF (5 mL) was heated at reflux under N₂ for 17 h. Further cyclopropylamine (0.172 mL, 0.62 mmol) was added, and the mixture was heated at reflux under N₂ for 74H. After cooling to rt, concentration in vacuo, dissolution in DMSO / MeOH (1 :1 , 2 mL) and filtration; purification by mass-directed HPLC yielded the title compound (32 mg) as a white solid.

MS [M+1]⁺ 408.13; ¹H NMR δ» (400.13 MHz, Cf₆-DMSO, TMS): 8.12 (br s, 1 H), 8.01 (br s, 1 H), 7.93-7.89 (m, 3H), 7.72 (t, J = 7.2Hz, 4H), 7.45 (d, J = 2.0 Hz, 1 H), 7.40 (t, J = 7.7 Hz, 2H), 7.33 (br s, 1 H), 7.27 (t, J = 7.2Hz, 1 H), 6.47 (br s, 2H), 2.16 (br s, 1 H), 0.56-0.43 (m, 4H).

Example 9 : 6"-Amino-4-{[(1-methylethyl)amino]sulfonyl}-1,1^I:3^l,1"-terphenyl-5¹- carboxamide

A solution of pentafluorophenyl 6'-amino-5'-(aminocarbonyl)-1 ,1':3',1"-terphenyl-4- sulfonate (Intermediate 10, 83 mg, 0.16 mmol) and (i-methylethyl)amine (0.212 ml_, 0.62 mmol) in THF (5 mL) was heated at reflux under N₂ for 17 h. Further (i-methylethyl)amine (0.53 mL, 1.55 mmol) was added, and the mixture was heated at reflux under N₂ for 74 h. After cooling to rt, concentration in vacuo, dissolution in DMSO / MeOH (1 :1 , 2 mL) and filtration; purification by mass-directed HPLC yielded the title compound (25.3 mg) as a white solid.

MS [M+1]⁺ 410.29; ¹H NMR δ* (400.13 MHz, Cf₆-DMSO₁ TMS): 8.12 (br s, 1 H), 7.93 (d, J = 2.0 Hz, 1 H)₁ 7.89 (d, J = 8.3Hz, 2H), 7.71 (q, J = 3.9 Hz₁ 4H), 7.66 (d, J = 7.0 Hz, 1 H)₁

7.44 (d, J = 2.0 Hz₁ 1 H), 7.40 (t, J = 7.8 Hz, 2H), 7.33 (br s, 1 H)₁ 7.27 (t, J = 7.3Hz₁ 1 H),

6.45 (br s, 2H), 3.35-3.25 (m, 1 H), 1.02 (d, J = 6.5 Hz, 6H).

Example 10 : 4^l-Amino-4-chloro-4"-[(dimethylamino)sulfonyl]-1,1^I:3^l,1"-terphenyl-5¹- carboxamide

4-Amino-5-bromo-4'-chloro-3-biphenylcarboxamide (Intermediate 4, 31 mg, 0.10 mmol), Λ/,Λ/-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (32 mg, 0.10 mmol), sodium carbonate (61 mg, 0.58 mmol) and dichloro(1 ,1'-bis- (diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (7 mg, 0.096 mmol) were slurried with 1 ,4-dioxane (1 ml_) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (500 mg silica), rinsing with MeOH, and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / MeOH, and purified by preparative HPLC using a 30-80% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (14.9 mg) as a white solid.

MS [M+1]⁺ 430.28 / 432.27 (approximately 3:1 ratio; ¹H NMR S_n (400.13 MHz, Cf₆-DMSO, TMS): 8.14 (br s, 1 H), 7.95 (d, J = 2.0 Hz, 1 H), 7.83 (d, J = 8.3Hz, 2H), 7.77-7.74 (m, 4H), 7.47-7.44 (m, 3H), 7.35 (br s, 1 H), 6.55 (br s, 2H), 2.68 (s, 6H).

Example 11 4ⁱ-Amino-4"-(aminosuifonyi)-4-f iuoro-1 ,1 ':3',1 "-terphenyl-5¹- carboxamide

4-Amino-5-bromo-4'-fluoro-3-biphenylcarboxamide (Intermediate 13, 53 mg, 0.17 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (73 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis- (diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (13 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with methanol (10 mL), filtered through a silica cartridge (500 mg silica) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1 ml_), filtered, and purified by preparative HPLC using a 20-60% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre- equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (16.6 mg) as a white solid.

MS [M+1]⁺ 386.16; ¹H NMR <fc (400.13 MHz, Cf₆-DMSO, TMS): 8.11 (br s, 1 H), 7.92 (s, 1 H), 7.90 (br s, 2H), 7.75 (dd, J = 8.8, 5.5 Hz, 2H), 7.68 (d, J = 8.3Hz, 2H), 7.43 (br s, 2H), 7.41 (d, J = 2.0 Hz, 1 H), , 7.34 (br s, 1 H), 7.23 (t, J = 8.8 Hz, 2H), 6.43 (br s, 2H).

Example 12 : 4'-Amino-4"-[(dimethylamino)sulfonyl]-4-fluoro-1,1^l:3',1"-terphenyl-5^I- carboxamide

4-Amino-5-bromo-4'-fluoro-3-biphenylcarboxamide (Intermediate 13, 53 mg, 0.17 mmol), Λ/,Λ/-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (80 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,V-bis- (diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (13 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with methanol (10 mL), filtered through a silica cartridge (500 mg silica) and the eluent concentrated in vacuo. The crude solid was dissolved in 1 :1 DMSO / methanol (1 mL), filtered, and purified by preparative HPLC using a 30-80% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (6.0 mg) as a white solid. MS [M+1]⁺414.32; ¹H NMR δn (400.13 MHz₁ Cf₆-DMSO, TMS): 8.12 (br s, 1 H), 7.91 (d, J = 2.0 Hz, 1 H), 7.83 (d, J = 8.3Hz₁ 2H), 7.76-7.73 (m, 4H), 7.44 (d, J = 1.8 Hz₁ 1 H)₁ 7.34 (br s, 1 H), 7.23 (t, J = 8.9 Hz, 2H)₁ 6.50 (br s, 2H)₁ 2.68 (s, 6H).

Example 13 : 2-Amino-4¹-(aminosulfonyl)-5-(4-pyridinyl)-3-biphenylcarboxamide

2-Amino-3-bromo-5-(4-pyridinyl)-benzamide (Intermediate 16, 50 mg, 0.17 mnnol), A- (4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (73 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)- ferrocene)palladium(ll)-dichloromethane adduct (12.3 mg, 0.017 mmol) were slurried with

1 ,4-dioxane (1 ml_) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with methanol (10 mL), filtered through a silica cartridge (500 mg silica) and the eluent concentrated in vacuo.

The crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL), filtered, and purified by preparative HPLC using a 0-35 % MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, combined, passed through an aminopropyl functionalised silica cartridge (pre-equilibrated with methanol, 500 mg sorbent) and concentrated to afford the title compound as a white solid (34.6 mg, 0.09 mmol).

MS [M+1]⁺ 369.21 ; ¹H NMR <5H (400.13 MHz, Gf₆-DMSO, TMS): 8.54 (d, J = 5.0 Hz, 2H), 8.18 (br s, 1 H), 8.10 (s, 1 H), 7.92 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 4.8 Hz₁ 2H)₁ 7.68 (d, J = 8.0 Hz, 2H), 7.59 (s, 1 H), 7.44 (s, 2H)₁ 7.40 (s, 1 H)₁ 6.69 (br s, 2H).

Example 14 : 6"-Amino-4-({[2-(4-methyl-1-piperazinyl)ethyl]amino}sulfonyl)- 1 ,1 ':3',1 "-terphenyl-5'-carboxamide

A solution of pentafluorophenyl 6^l-amino-5^l-(aminocarbonyl)-1 ,1':3',1"-terphenyl-4- sulfonate (Intermediate 10, 83 mg, 0.16 mmol) and [2-(4-methyl-1-piperazinyl)ethyl]amine (356 mg, 0.62 mmol) in THF (5 ml.) was heated at reflux under N₂ for 17 h. After cooling to rt, concentration in vacuo, dissolution in DMSO / MeOH (1 :1 , 1 ml_) and filtration; purification by mass-directed HPLC yielded the title compound (58.4 mg) as a yellow solid.

MS [M+1]⁺ 494.24; ¹H NMR <5^ (400.13 MHz, Cf₆-DMSO, TMS): 8.12 (br s, 1 H), 7.93 (d, J = 2.3Hz, 1 H), 7.89 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.0 Hz, 4H)₁ 7.62 (br s, 1 H), 7.43-7.38 (m, 3H), 7.33 (br s, 1 H), 7.27 (t, J = 7.4Hz, 1 H), 6.46 (br s, 2H), 2.91 (br s, 2H), 2.36-2.32 (br m, 10 H), 2.15 (S, 3H).

Example 15 : 6^l-Amino-4-[(dimethylamino)sulfonyl]-1,1':3^I,1"-terphenyl-5'- carboxamide

4-Amino-5-bromo-3-biphenyl-carboxamide (Intermediate 7, 31 mg, 0.11 mmol), N,N- dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (50 mg, 0.17 mmol), sodium carbonate (68 mg, 0.64 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)- ferrocene)palladium(ll)-dichloromethane adduct (8 mg, 0.01 mmol) were slurried with 1 ,4- dioxane (1 ml.) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with water (5 mL) and shaken with chloroform (10 mL). The phases were separated, and the organic phase concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL), filtered, and purified by preparative HPLC using a 30-80% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, combined and concentrated to afford the title compound as an off white solid (3.5 mg, 0.009 mmol).

MS [M+1]⁺ 396.30; ¹H NMR <5H (400.13 MHz, Cf₆-DMSO, TMS): 8.13 (br s, 1H), 7.94 (s, 1 H), 7.83 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.3Hz, 2H), 7.71 (d, J = 7.8 Hz, 2H), 7.46 (s, 1 H), 7.41 (t, J = 7.7 Hz₁ 2H), 7.34 (br s, 1 H), 7.27 (t, J = 7.3Hz, 1 H), 6.49 (br s, 2H), 2.68 (s, 6H).

Example 16 2-Amino-4'-[(dimethylamino)sulfonyl]-5-(4-pyridinyl)-3- biphenylcarboxamide

2-Amino-3-bromo-5-(4-pyridinyl)benzamide (Intermediate 16, 50 mg, 0.17 mmol), N,N- dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (80 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)- ferrocene)palladium(ll)-dichloromethane adduct (12 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with methanol (10 mL), filtered through a silica cartridge (500 mg silica) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL), filtered, and purified by preparative HPLC using a 10-45 % MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, combined, passed through an aminopropyl functionalised silica cartridge (pre-equilibrated with methanol, 500 mg sorbent), eluting with methanol, and concentrated to afford the title compound as a white solid (27.8 mg, 0.07 mmol). MS [M+1]⁺ 397.23; ¹H NMR δ» (400.13 MHz, Cf₆-DMSO₁ TMS): 8.54 (d, J = 4.8 Hz₁ 2H), 8.18 (br s, 1 H), 8.11 (s, 1 H), 7.84 (d, J = 8.3Hz, 2H), 7.77-7.74 (m, 4H), 7.62 (s, 1 H), 7.41 (br s, 1H), 6.75 (br s, 2H), 2.68 (s, 6H).

Example 17 : 6^l-Amino-4-(4-morpholinylsulfonyl)-1,1':3',1"-terphenyl-5'-carboxamide

A solution of pentafluorophenyl 6'-amino-5'-(aminocarbonyl)-1 ,1':3',1"-terphenyl-4- sulfonate (Intermediate 10, 119 mg, 0.22 mmol), morpholine (0.021 ml_, 0.24 mmol) and triethylamine (0.031 mL, 0.24 mmol) in THF (10 mL) was heated at reflux under N₂ for 16 h. Further morpholine (0.97 mL, 1.10 mmol) was added, and heating at reflux under N₂ was continued for 24H. After cooling to rt, concentration in vacuo, dissolution in DMSO / MeOH (1 :1 , 1 mL) and filtration; purification by mass-directed HPLC yielded the title compound (31.8 mg) as a light-yellow solid.

MS [M+1]⁺ 438.34; ¹H NMR Sn (400.13 MHz, oVDMSO, TMS): 8.13 (br s, 1 H), 7.95 (d, J = 2.0 Hz, 1 H), 7.82 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 7.3Hz, 2H), 7.47 (d, J = 2.0 Hz, 1 H), 7.41 (t, J = 7.8 Hz, 2H), 7.84 (br s, 1 H), 7.27 (t, J = 7.3Hz, 1 H), 6.53 (br s, 2H), 3.67 (br t, J = 4.5 Hz, 4H), 2.95 (br t, J = 4.5 Hz, 4H).

Example 18 : 6'-Amino-4-({[3-(dimethylamino)propyl]amino}sulfonyl)-1,1':3',1"- terphenyl-5'-carboxamide

To a solution of pentafluorophenyl 6'-amino-5'-(aminocarbonyl)-1 ,1':3',1"-terphenyl-4- sulfonate (Intermediate 10, 0.10 g, 0.19 mmol) in anhydrous THF (10 mL) was added 1 ,8- diazabicyclo[5.4.0]undec-7-ene (0.038 mL, 0.21 mmol) and Λ/,Λ/-dimethyl-1 ,3- propanediamine (0.026 mL, 0.21 mmol). The reaction mixture was heated at reflux for 8 h and then concentrated in vacuo. Purification by column chromatography (SiO₂, Ethyl acetate (with 1% added triethylamine) / Methanol gradient, 0 to 20% methanol over 15 minutes, followed by 20% methanol for 2 min), followed by crystallisation from ether yielded the title compound (70 mg, 0.15 mmol) as a white solid.

MS [M+1]⁺ 453.01 ; ¹H NMR δπ (400.13 MHz, Cf₆-DMSO, TMS): 8.25 (br s, 1 H), 8.12 (br s,

1 H), 7.93 (d, J = 2.3Hz₁ I H), 7.87 (d, J = 8.5 Hz, 2H), 7.73-7.68 (m, 5H), 7.43 (t, J = 2.0

Hz, 1 H), 7.39 (d, J = 7.8 Hz, 2H), 7.33 (br s, 1 H), 7.27 (t, J = 7.3Hz₁ 2H), 6.46 (br s, 2H), 2.83 (t, J = 7.0 Hz, 2H), 2.22 (t, J = 7.0 Hz, 2H)₁ 2.09 (s, 6H), 1.54 (quint., J = 7.0 Hz, 2H).

Example 19 : 4'-Amino-4-chloro-4"-(1-pyrrolidinylsulfonyl)-1,1':3^l,1"-terphenyl-5^I- carboxamide

4-Amino-5-bromo-4'-chloro-3-biphenyl-carboxamide (Intermediate 4, 31 mg, 0.1 mmol), 1-

{[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]-sulfonyl}pyrrolidine (35 mg, 0.1 mmol), sodium carbonate (61 mg, 0.58 mmol) and dichloro(1 ,1'-bis- (diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (7 mg, 0.01 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (500 mg silica), rinsing with MeOH, and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / MeOH, and purified by preparative HPLC using a 40-95% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (6.7 mg) as a white solid.

MS [M+1]⁺ 456.26 / 458.21 (approximately 3:1 ratio); ¹H NMR S_n (400.13 MHz, Of₆-DMSO, TMS): 8.14 (br s, 1 H), 7.95 (d, J = 1.8 Hz 1 H₁), 7.88 (d, J = 8.3Hz 2H₁), 7.76 (d, J = 8.8 Hz, 2H), 8.3Hz, 2H), 7.46 (s, 2H), 7.44 (s, 1 H), 7.35 (br s, 1 H), 6.54 (br s, 2H), 3.20 (m, 4H), 1.71 (m, 4H).

Example 20 2-Amino-5-(4-pyridinyl)-4'-(1-pyrrolidinylsulfonyl)-3- biphenylcarboxamide

2-Amino-3-bromo-5-(4-pyridinyl)benzamide (Intermediate 16, 50 mg, 0.17 mmol), 1-{[4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]-sulfonyl}pyrrolidine (87 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)- ferrocene)palladium(ll)-dichloromethane adduct (12 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with methanol (10 mL), filtered through a silica cartridge (500 mg silica) and the eluent concentrated in vacuo. The crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL), filtered, and purified by preparative HPLC using a 10-45 % MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, combined, passed through an aminopropyl functionalised silica cartridge (pre-equilibrated with methanol, 500 mg sorbent), eluting with methanol, and concentrated to afford the title compound as a white solid (23.3 mg, 32 %).

MS [M+1]⁺ 423.31 ; ¹H NMR <5_H (400.13 MHz, Gf₆-DMSO, TMS): 8.54 (d, 2H, J = 6.0 Hz), 8.18 (br. s, 1 H), 8.11 (s, 1 H), 7.89 (d, 2H₁ J = 8.0 Hz), 7.77 (d, J = 6.0 Hz, 2H), 7.73 (d, J = 8.3Hz, 2H), 7.62 (d, J = 1.8 Hz, 1 H), 7.41 (br s, 1 H), 6.75 (br s, 2H), 3.21 (m, 4H), 1.72 (m, 4H).

Example 21 : 4^I-Amino-4-fluoro-4"-(1-pyrrolidinylsulfonyl)-1,1':3^I,1"-terphenyl-5¹ carboxamide

4-Amino-5-bromo-4'-fluoro-3-biphenylcarboxamide (Intermediate 13, 53 mg, 0.17 mmol), 1-{[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]-sulfonyl}pyrrolidine (87 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)- ferrocene)palladium(ll)-dichloromethane adduct (13 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with methanol (10 mL), filtered through a silica cartridge (500 mg silica) and the eluent concentrated in vacuo. The crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL), filtered, and purified by preparative HPLC using a 30-80% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (3.2 mg) as a white solid. MS [M+1]⁺ 440.20; ¹H NMR 4_H (400.13 MHz, cfe-DMSO, TMS): 8.12 (br s, 1 H), 7.91 (d, J = 2.0 Hz, 1 H), 7.88 (d, J = 8.3Hz₁ 2H), 7.77-7.72 (m, 4H), 7.43 (d, J = 2.0 Hz, 1 H), 7.34 (br S₁ 1H)₁ 7.23 (t, J = 8.9 Hz, 2H), 6.49 (br s, 2H), 3.20 (m, 4H), 1.71 (m, 4H).

Example 22 : 6'-Amino-4-(aminosulfonyl)-1,1':3^l,1"-terphenyl-5'-carboxamide

4-Amino-5-bromo-3-biphenyl-carboxamide (Intermediate 7, 31 mg, 0.11 mmol), 4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (45 mg, 0.17 mmol), sodium carbonate (68 mg, 0.64 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)- ferrocene)palladium(ll)-dichloromethane adduct (8 mg, 0.01 mmol) were slurried with 1 ,4- dioxane (1 mL) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with water (5 mL) and shaken with chloroform (10 mL). The phases were separated, and the organic phase was concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL), filtered, and purified by preparative HPLC using a 25-45% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, combined and concentrated to afford the title compound as a white solid (3.0 mg, 0.008 mmol).

MS [M+1]⁺ 368.31 ; ¹H NMR ^ (400.13 MHz, Cf₆-DMSO, TMS): 8.12 (br s, 1 H), 7.93 (s, 2H), 7.91 (s, 1 H), 7.70 (t, J = 7.5 Hz, 4H), 7.48-7.36 (m, 4H), 7.34 (br s, 1 H), 7.27 (t, J = 7.3Hz, 1 H), 6.43 (s, 2H).

Example 23 : 6^>-Amino-4-({[2-(dimethylamino)ethyl]amino}sulfonyl)-1,1':3',1"- terphenyl-5'-carboxamide

To a solution of pentafluorophenyl 6'-amino-5'-(aminocarbonyl)-1 ,1':3',1"-terphenyl-4- sulfonate (Intermediate 10, 0.10 g, 0.19 mmol) in anhydrous THF (10 mL) was added 1 ,8- diazabicycloβAOlundec^-ene (0.038 mL, 0.21 mmol) and Λ/,Λ/-dimethyl-1 ,2- ethanediamine (0.022 mL, 0.21 mmol). The solution was heated at reflux for 8 h, and then concentrated in vacuo. Purification by column chromatography (SiO₂, Ethyl acetate (with

1% added triethylamine) / Methanol gradient, 0 to 20% methanol over 15 minutes, followed by 20% methanol for 2 min), followed by crystallisation from ether yielded the title compound (40 mg, 0.09 mmol) as a white solid.

MS [M+1]⁺ 439.34; ¹H NMR δ» (400.13 MHz, Cf₆-DMSO, TMS): 8.12 (br s, 1 H), 7.94-7.87 (m, 3H), 7.75-7.65 (m, 5H), 7.44-7.48 (m, 3H), 7.33 (br s, 1 H), 7.30-7.22 (m, I H), 6.45 (br, s, 2H), 2.90 (br t, J = 6.5 Hz, 2H), 2.85 (br s, 2H), 2.14 (s, 6H).

Example 24 : 6'-Amino-4-(1-pyrrolidinylsulfonyl)-1,1':3',1"-terphenyl-5^f-carboxamide

4-Amino-5-bromo-3-biphenyl-carboxamide (Intermediate 7, 47 mg, 0.16 mmol), 1-{[4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]sulfonyl}pyrrolidine (82 mg, 0.24 mmol), sodium carbonate (483 uL of a 2M aqueous solution, 0.97 mmol), dichloro(1 ,1'- bis-(diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (12 mg, 0.016 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (0.5 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (5 g silica), eluting with methanol (10 ml_). After concentration in- vacuo, purification by mass-directed HPLC yielded the title compound (63 mg) as a yellow-brown solid.

MS [M+1]⁺ 422.30; ¹H NMR S_H (400.13 MHz, Cf₆-DMSO, TMS): 8.12 (br s, 1 H), 7.94 (d, J = 2.0 Hz, 1 H), 7.88 (d, J = 8.3Hz, 2H), 7.74 (d, J = 8.3Hz, 2H), 7.71 (d, J = 7.5 Hz, 2H), 7.45 (d, J = 2.0 Hz, 1 H), 7.41 (t, J = 7.8 Hz, 2H), 7.34 (br s, 1 H), 7.27 (t, J = 7.3Hz, 1 H), 6.49 (br s, 2H), 3.20 (br t, J = 6.5 Hz, 4H), 1.71 (br t, J = 6.7 Hz, 4H).

Example 25 : 6^l-Amino-4-(methylsulfonyl)-1,1':3',1"-terphenyl-5'-carboxamide

4-Amino-5-bromo-3-biphenyl-carboxamide (Intermediate 7, 50 mg, 0.17 mmol), [4- (methylsulfonyl)phenyl]boronic acid (52 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (13 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with methanol (10 mL), filtered through a silica cartridge (500 mg silica) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL), filtered, and purified by preparative HPLC using a 20-60% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (3.6 mg) as a white solid.

MS [M+1]⁺ 367.31 ; ¹H NMR δ* (400.13 MHz, cfe-DMSO, TMS): 8.13 (br s, 1 H), 8.02 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 2.0 Hz, 1 H), 7.77 (d, J = 8.3Hz, 2H), 7.71 (d, J = 7.5 Hz, 2H), 7.44 (d, J = 1.8 Hz₁ 1 H), 7.41 (t, J = 7.7 Hz, 2H), 7.35 (br s, 1 H), 7.27 (t, J = 7.4Hz, 1 H), 6.48 (br s, 2H), 3.27 (s, 3H).

Example 26 : 4-Amino-5-{1-[(4-cyanophenyl)sulfonyl]-1,2,3,6-tetrahydro-4-pyridinyl}- 4'-fluoro-3-biphenylcarboxamide

A mixture of 4-amino-4'-fluoro-5-(1 ,2,3,6-tetrahydro-4-pyridinyl)-3-biphenylcarboxamide (Intermediate 18, 50 mg, 0.16 mmol) and 4-cyanobenzenesulfonyl chloride (39 mg, 0.19 mmol) in pyridine (3 mL) was stirred at rt for 5 d. After concentration in vacuo and dissolution in DMSO / methanol (0.5 mL, 1 :1) purification by preparative HPLC using a 30- 70% MeCN (aq) gradient yielded the title compound (21.7 mg, 0.05 mmol) as a white solid.

MS [M+1]⁺ 477.32; ¹H NMR <5H (400.13 MHz, Cf₆-DMSO, TMS): 8.17 (d, J = 8.0 Hz, 2H), 8.04 (d, J = 8.0 Hz, 2H), 7.99 (br s, 1 H), 7.75 (s, 1 H), 7.66-7.63 (m, 2H), 7.22 (t, J = 8.8 Hz, 3H), 7.09 (s, 1 H), 6.35 (s, 2H), 5.66 (s, 1 H), 3.76 (br s, 2H), 3.39 (br s, 2H), 2.32 (br s, 2H).

Example 27 4-Amino-4'-fluoro-5-(1,2,3,6-tetrahydro-4-pyridinyl)-3- biphenylcarboxamide

See Intermediate 18.

Example 28 : 4-Amino-5-(4-pyridinyl)-3-biphenylcarboxamide

4-Amino-5-bromo-3-biphenylcarboxamide (Intermediate 7, 32 mg, 0.11 mmol), 4- pyridylboronic acid (21 mg, 0.17 mmol), sodium carbonate (71 mg, 0.67 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (9 mg, 0.01 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled reaction mixture was diluted with water (5 mL) and concentrated in vacuo to remove the 1 ,4- dioxane. 2M aqueous sodium hydroxide solution (1 mL) was added to the resultant aqueous suspension which was then extracted with chloroform (3 x 10 mL). The combined organic fractions were concentrated in vacuo to give a dark mauve tar. The crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL) and purified by preparative HPLC using a 10-45% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, combined and concentrated in vacuo, re- dissolved in methanol (5 mL) and passed through an aminopropyl functionalised silica cartridge (500 mg sorbent, pre-equilibrated with methanol), eluting with methanol. Concentration yielded the title compound as a pale yellow solid (10.1 mg, 0.03 mmol).

MS [M+1]⁺ 290.29; ¹H NMR & (400.13 MHz, cfe-DMSO, TMS): 8.67 (d, J = 4.8 Hz, 2H), 8.13 (br s, 1 H), 7.94 (s, 1 H), 7.71 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 4.8 Hz, 2H) 7.47-7.37 (m, 3H), 7.35 (br s, 1 H), 7.27 (t, J = 7.0 Hz, 1 H), 6.52 (br s, 2H).

Example 29 : 4-Amino-4',5-dibromo-3-biphenylcarboxamide

A mixture of 4-amino-3-biphenylcarboxamide (Intermediate 6, 55 mg, 0.26 mmol) and N- bromosuccinimide (50 mg, 0.28 mmol) in glacial acetic acid was stirred at rt for 3 h. After dilution with methanol, the crude mixture was concentrated in vacuo with pre-adsorbtion onto an inert sorbent (approximately 0.5 g). Purification by column chromatography (SiO₂, 55-70% ethyl acetate in cyclohexane gradient), followed by preparative HPLC using a 40- 95 % MeCN (aq) gradient yielded the title compound as the minor product (the major product being 4-arnino-5-bromo-3-biphenylcarboxamide, Intermediate 7).

MS [M+1]⁺ 368.94, 370.92, 372.90 (Approximately 1 :2:1 ratio); ¹H NMR S_n (400.13 MHz, Cf₆-DMSO, TMS): 8.16 (br s, 1 H), 7.91 (d, J = 9.8 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.43 (br s, 1 H), 6.83 (br s, 2H).

Example 30 : 2-Amino-3-bromo-5-(4-pyridinyl)benzamide

See Intermediate 16.

Example 31 6'-Amino-4-[(methylsulfonyl)amino]-1 ,1 ':3',1 "-terphenyl-5¹- carboxamide

4-Amino-5-bromo-3-biphenyl-carboxamide (Intermediate 7, 48 mg, 0.17 mmol), {4- [(methylsulfonyl)amino]phenyl}boronic acid (53 mg, 0.25 mmol), sodium carbonate (105 mg, 0.99 mmol) and dichloro(1 ,1 ^l-bis-(diphenylphosphino)-ferrocene)palladium(ll)- dichloromethane adduct (12 mg, 0.016 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a 5g silica cartridge, eluting with methanol (10 ml_). After concentration in-vacuo, purification by mass-directed HPLC yielded the title compound (43 mg) as an off-white solid.

MS [M+1]⁺ 382.13; ¹H NMR δ» (400.13 MHz, Cf₆-DMSO, TMS): 9.84 (br s, 1H), 8.08 (br s, 1 H), 7.88 (d, J = 1.8 Hz, 1 H), 7.68 (d, J = 7.3Hz, 2H), 7.45-7.38 (m, 5H), 7.32-7.24 (m, 4H), 6.33 (br s, 2H), 3.05 (s, 3H).

Example 32 : 4-Amino-5-bromo-4'-chloro-3-biphenylcarboxamide

See Intermediate 4.

Example 33 : 5-(1-{[4-(Acetylamino)phenyl]sulfonyl}-1,2,3,6-tetrahydro-4-pyridinyl)- 4-amino-4'-fluoro-3-biphenylcarboxamide

A mixture of 4-amino-4'-fluoro-5-(1 ,2,3,6-tetrahydro-4-pyridinyl)-3-biphenylcarboxamide (Intermediate 18, 50 mg, 0.16 mmol) and 4-(acetylamino)benzenesulfonyl chloride (45 mg, 0.19 mmol) in pyridine (3 mL) was stirred at rt for 5 d. After concentration in vacuo and dissolution in DMSO / methanol (0.5 mL, 1 :1 ) purification by preparative HPLC using a 30-70% MeCN (aq) gradient yielded the title compound (18.4 mg, 0.04 mmol) as a yellow solid.

MS [M+1]⁺ 509.31 ; ¹H NMR <5H (400.13 MHz, Cf₆-DMSO, TMS): 10.4 (s, 1H), 7.98 (br s, 1 H), 7.84 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.74 (br s, 1 H), 7.66-7.63 (m, 2H), 7.21 (t, J = 8.7 Hz₁ 3H)₁ 7.15 (br s, 1 H)₁ 6.33 (s, 2H), 5.66 (s, 1 H)₁ 3.67 (s, 2H)₁ approximately 3.30-3.26 (m, overlapping with water peak, approximately 2H), 2.34 (br s, 2H), 2.08 (S₁ 3H).

Example 34 2-Amino-4'-[(methylsulfonyl)amino]-5-(4-pyridinyl)-3- biphenylcarboxamide

2-Amino-3-bromo-5-(4-pyridinyl)benzamide (Intermediate 16, 50 mg, 0.17 mmol), {4- [(methylsulfonyl)amino]phenyl}boronic acid (56 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)- dichloromethane adduct (12 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 ml.) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with methanol (10 ml_), filtered through a silica cartridge (500 mg silica) and the eluent concentrated in vacuo. The crude solid was dissolved in 1 :1 DMSO / methanol solution (1 ml_), filtered, and purified by preparative HPLC using a 0-35 % MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, combined, passed through an aminopropyl functionalised silica cartridge (pre-equilibrated with methanol, 500 mg sorbent) and concentrated to afford the title compound as a white solid (34.6 mg, 55 %).

MS [M+1]⁺ 383.12; ¹H NMR S_n (400.13 MHz, cfe-DMSO, TMS): 9.88 (br s, 1 H), 8.53 (d, J = 6.0 Hz₁ 2H), 8.14 (br s, 1 H), 8.05 (d, J = 2.0 Hz, 1 H)₁ 7.74 (d, J = 6.0 Hz, 2H), 7.54 (d, J = 2.0 Hz₁ 1 H), 7.43 (d, 2H, J = 8.5 Hz), 7.36 (b. s, 1 H)₁ 7.32 (d, J = 8.5 Hz, 2H), 6.59 (b. s, 2H)₁ 3.04 (S₁ 3H).

Example 35 : 4-Amino-4'-fluoro-5-(4-pyridinyl)-3-biphenylcarboxamide

4-Amino-5-bromo-4¹-fluoro-3-biphenyl-carbox-amide (Intermediate 13, 53 mg, 0.17 mmol), 4-pyridylboronic acid (32 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (13 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with methanol (10 mL), filtered through a silica cartridge (500 mg silica) and the eluent concentrated in vacuo. The crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL), filtered, and purified by preparative HPLC using a 20-60% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre- equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (2.7 mg) as a white solid.

MS [M+1]⁺ 308.36; ¹H NMR <5π (400.13 MHz, Cf₆-DMSO, TMS): 8.66 (d, J = 5.8 Hz, 2H), 8.12 (br s, 1 H), 7.92 (d, J = 1.5 Hz, 1 H), 7.75 (dd, J = 8.5 Hz, 5.5 Hz, 2H), 7.53 (d, J = 5.8 Hz, 2H), 7.43 (d, J = 1.8 Hz, 1 H), 7.35 (br s, 1 H), 7.23 (t, J = 8.8 Hz, 2H), 6.52 (br s, 2H).

Example 36 : 4-Amino-5-{1-[(4-cyanophenyl)sulfonyl]-1,2,3,6-tetrahydro-4-pyridinyl}- 3-biphenylcarboxamide

A mixture of 4-amino-5-(1 ,2,3,6-tetrahydro-4-pyridinyl)-3-biphenylcarboxamide (Intermediate 20, 28 mg, 0.10 mmol) and 4-[(chloromethyl)sulfonyl]benzonitrile (21 mg, 0.11 mmol) in pyridine (2 mL) was stirred at rt under N₂ for 6 h. Further 4- [(chloromethyl)sulfonyl]benzonitrile (4 mg, 0.02 mmol) was added, and the reaction was stirred at rt under N₂ for 18 h. After concentration in vacuo, purification by mass-directed HPLC yielded the title compound (16.7 mg, 0.04 mmol) as a white-yellow solid.

MS [M+1]⁺ 459.20; ¹H NMR S_n (400.13 MHz₁ Cf₆-DMSO, TMS): 8.17 (d, J = 8.3Hz, 2H), 8.04 (d, J = 8.3Hz, 2H), 7.99 (br s, 1 H), 7.78 (d, J = 2.0 Hz, 1 H), 7.61 (d, J = 7.5 Hz, 2H), 7.40 (t, J = 7.7 Hz, 2H), 7.25 (t, J = 7.3Hz, 1 H), 7.21 (s, 1 H), 7.12 (d, J = 2.0 Hz, 1 H), 6.35 (br s, approximately 2H), 5.67 (s, 1 H), 3.77 (br s, 2H), 3.40-3.38 (m, overlapping with water peak, approximately 2H), 2.33 (br s, 2H).

Example 37 : 4^l-Amino-4-fluoro-4"-[(methylsulfonyl)amino]-1,1':3^l,1"-terphenyl-5^>- carboxamide

4-Amino-5-bromo-4'-fluoro-3-biphenylcarboxamide (Intermediate 13, 53 mg, 0.17 mmol), {4-[(methylsulfonyl)amino]phenyl}boronic acid (55 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)- dichloromethane adduct (13 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 °C for 20 mins. The cooled mixture was diluted with methanol (10 mL), filtered through a silica cartridge (500 mg silica) and the eluent concentrated in vacuo. The crude solid was dissolved in 1:1 DMSO / methanol solution (1 mL), filtered, and purified by preparative HPLC using a 20-60% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (33.4 mg) as a white solid.

MS [M+1]⁺ 400.14; ¹H NMR δ» (400.13 MHz, CZ₆-DMSO, TMS): 9.86 (br s, approximately 1 H), 8.07 (br s, 1 H), 7.84 (s, 1 H), 7.72 (dd, J = 8.5, 5.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H),

] 7.35 (d, J = 1.8 Hz, 1 H), 7.33-7.24 (m, 3H), 7.22 (t, J = 8.9 Hz, 2H), 6.33 (br s, 2H), 3.04 (br s, 3H).

Example 38 : 4-Amino-5-{1-[(3,4-difluorophenyl)sulfonyl]-1,2,3,6-tetrahydro-4- pyridinyl}-4'-fluoro-3-biphenylcarboxamide

A mixture of 4-amino-4'-fluoro-5-(1 ,2,3_l6-tetrahydro-4-pyridinyl)-3-biphenylcarboxamide (Intermediate 18, 50.0 mg, 0.16 mmol) and 3,4-difluorobenzenesulfonyl chloride (41 mg, 0.19 mmol) in pyridine (3 ml_) was stirred at rt for 5 d. After concentration in vacuo and dissolution in DMSO / methanol (0.5 ml_, 1 :1) purification by preparative HPLC using a 40- 95% MeCN (aq) gradient yielded the title compound (24.4 mg, 0.04 mmol) as a yellow solid.

MS [M+1]⁺ 488.16; ¹H NMR δn (400.13 MHz, Cf₆-DMSO, TMS): 8.04-7.95 (m, 2H), 7.81- 7.73 (m, 3H), 7.66 (dd, J = 8.8, 5.5 Hz, 2H), 7.21 (t, J = 8.8 Hz, 3H), 7.16 (d, J = 2.0 Hz, 1 H), 6.36 (S, 2H), 5.68 (s, 1 H), 3.74 (br s, 2H), 3.37-3.30 (m, 2H), 2.35 (br s, 2H).

Example 39 : 4-Amino-5-bromo-3-biphenylcarboxamide

See Intermediate 7. Example 40 : 4^l-Amino-4-chloro-4"-[(methylsulfonyl)amino]-1,1ⁱ:3',1"-terphenyl-5^I- carboxamide

4-amino-5-bromo-4'-chloro-3-biphenyl-carboxamide (Intermediate 4, 31 mg, 0.1 mmol), {4-[(methylsulfonyl)amino]phenyl}boronic acid (22 mg, 0.1 mmol), sodium carbonate (61 mg, 0.58 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)ferrocene)palladium(ll)- dichloromethane adduct (7 mg, 0.01 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (500 mg silica), rinsing with MeOH, and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / MeOH, and purified by preparative HPLC using a 30-80% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre- equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (14.6 mg) as a white solid.

MS [M+1]⁺416.11 / 418.10 (approximately 3:1 ratio); ¹H NMR δ* (400.13 MHz, cfe-DMSO, TMS): 8.09 (br s, 1 H), 7.89 (d, J = 2.0 Hz, 1 H), 7.73 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 6.8 Hz, 2H), 7.42 (d, J = 6.5 Hz, 2H), 7.38 (d, J = 2.0 Hz, 1 H), 7.31 (s, 2H), 7.29 (s, 1 H), 6.39 (br s, 2H), 3.03 (s, 3H).

Example 41 4^l-Amino-4"-[(aminosulfonyl)methyl]-4-fluoro-1,1^I:3\1"-terphenyl-5¹- carboxamide

4-Amino-5-bromo-4¹-fluoro-3-biphenyl-carboxamide (Intermediate 13, 53 mg, 0.17 mmol), 1-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide (77 mg, 0.17 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis- (diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (13 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 ml_) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with methanol (10 ml_), filtered through a silica cartridge (500 mg silica) and the eluent concentrated in vacuo. The crude solid was dissolved in 1 :1 DMSO / methanol solution (1 ml_), filtered, and purified by preparative HPLC using a 20-50% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (19.6 mg) as a white solid.

MS [M+1]⁺ 400.14; ¹H NMR <5H (400.13 MHz, d₆-DMSO, TMS): 8.09 (br s, 1 H), 7.87 (d, J = 1.8 Hz, 1 H), 7.73 (dd, J = 8.8, 5.5 Hz, 2H), 7.48 (s, 4H), 7.38 (d, J = 2.0 Hz, 1 H), 7.31 (br s, 1 H), 7.23 (t, J = 8.9 Hz, 2H), 6.81 (br s, 2H), 6.32 (br s, 2H), 4.33 (s, 2H).

Example 42 : 6^>-Amino-1,1^>:3',1"-terphenyl-4,5^>-dicarboxamide

4-Amino-5-bromo-3-biphenyl-carboxamide (Intermediate 7, 50 mg, 0.17 mmol), [4- (aminocarbonyl)phenyl]boronic acid (43 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (13 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge, eluting with methanol, and the eluant concentrated in vacuo before dissolution in DMSO / methanol (1 :1) and purification by preparative HPLC using a 20-60% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (33.5 mg).

MS [M+1]⁺ 332.32; ¹H NMR <5H (400.13 MHz, Cf₆-DMSO₁ TMS): 8.10 (br s, 1 H), 8.04 (br s, 1 H), 8.00 (d, J = 8.3Hz, 2H), 7.91 (d, J = 1.8 Hz, 1 H), 7.70 (d, J = 7.5 Hz, 2H), 7.56 (d, J = 8.3 Hz, 4H), 7.44-7.37 (m, 4H), 7.32 (br s, 1 H), 7.26 (t, J = 7.3Hz, 1 H), 6.39 (s, 2H).

Example 43 6'-Amino-3-[(dimethylamino)sulfonyl]-1 ,1 ':3',1 "-terphenyl-5¹- carboxamide

4-Amino-5-bromo-3-biphenyl-carboxamide (Intermediate 7, 50 mg, 0.17 mmol), {3- [(dimethylamino)suifonyi]phenyl}boronic acid (59 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)- dichloromethane adduct (13 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. After concentration in vacuo and dissolution in DMSO / methanol (1 :1 , 1 mL), the title compound was purified by preparative HPLC using a 30-80% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (1.6 mg).

MS [M+1]⁺ 396.19; ¹H NMR 4_H (400.13 MHz, cfe-Acetone, TMS): 8.00 (br s, 1 H), 7.90 (br s, 1 H)₁ 7.88-7.76 (m, 4H), 7.69 (s, 1 H), 7.67 (s, 2H), 7.52 (d, J = 2.0 Hz, 1 H)₁ 7.41 (t, J = 7.0 Hz, 2H), 7.28 (t, J = 8.0 Hz, 1 H), 6.41 (br s, approximately 1 H), 6.38 (br s, approximately 1 H), 2.75 (S₁ 6H). Example 44 6'-Amino-4-[(aminosulfonyl)methyl]-1 ,1 '13',I "-terphenyl-5¹- carboxamide

4-Amino-5-bromo-3-biphenyl-carboxamide (Intermediate 7, 31 mg, 0.11 mmol), 1-[4- (4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide (48 mg, 0.17 mmol), sodium carbonate (68 mg, 0.64 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)- ferrocene)palladium(ll)-dichloromethane adduct (8 mg, 0.01 mmol) were slurried with 1 ,4- dioxane (1 ml_) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with water (5 ml_) and extracted with chloroform (10 ml_). The phases were separated, and the organic layer was concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1 ml_), filtered, and purified by preparative HPLC using a 10-45% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, combined and concentrated to afford the title compound as a white solid (2.9 mg, 0.008 mmol).

MS [M+1]⁺ 382.29; ¹H NMR Sn (400.13 MHz, Cf₆-DMSO, TMS): 8.10 (br s, 1 H), 7.90 (s, 1 H), 7.69 (d, J = 7.5 Hz, 2H), 7.48 (s, 4H), 7.42-7.38 (m, 3H), 7.31 (br s, 1 H), 7.26 (t, J = 7.3Hz, 1 H), 6.84 (br s, 2H), 6.32 (br s, 2H), 4.33 (s, 2H).

Example 45 : 2-Amino-5-(4-pyrϊdinyl)-3-biphenylcarboxamide

2-Amino-3-bromo-5-(4-pyridinyl)benzamide (Intermediate 16, 50 mg, 0.17 mmol), phenylboronic acid (77 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (12 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 ml.) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 °C for 20 mins. The cooled mixture was diluted with methanol (10 ml_), filtered through a silica cartridge (500 mg silica) and the eluent concentrated in vacuo. The crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL), filtered, and purified by preparative HPLC using a 10-45% MeCN (aq) gradient, to yield the title compound as a white solid (32.9 mg, 0.11 mmol).

MS [M+1]⁺ 290.17; ¹H NMR S_n (400.13 MHz, Cy₆-DMSO, TMS): 8.53 (d, J = 6.3Hz, 2H), 8.15 (br s, 1 H), 8.07 (d, J = 2.0 Hz, 1 H), 7.75 (d, J = 6.3Hz, 2H), 7.57-7.38 (m, 6H), 7.37 (br s, 1 H), 6.56 (br s, 2H).

Example 46 : 4-Amino-4'-chloro-5-(4-pyridinyl)-3-biphenylcarboxamide

4-Amino-5-bromo-4'-chloro-3-biphenyl-carboxamide (Intermediate 4, 31 mg, 0.10 mmol), 4-pyridylboronic acid (13 mg, 0.10 mmol), sodium carbonate (61 mg, 0.58 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (7 mg, 0.01 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (500 mg silica), rinsing with MeOH, and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / MeOH, and purified by preparative HPLC using a 20-60% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (6.9 mg, 0.02 mmol) as a white solid.

MS [M+1]⁺ 324.30 / 326.30 (approximately 3:1 ratio); ¹H NMR 6» (400.13 MHz, Cf₆-DMSO₁ TMS): 8.67 (d, J = 5.8 Hz, 2H), 8.13 (br s, 1H), 7.95 (s, 1 H), 7.76 (d, J = 8.3Hz, 2H), 7.52 (d, J = 5.8 Hz, 2H), 7.46 (s, 2H), 7.44 (s, 1 H), 7.36 (br s, 1 H), 6.57 (br s, 2H). Example 47 : 2-Amino-5-(4-pyridinyl)-3,4'-biphenyldicarboxamide

2-Amino-3-bromo-5-(4-pyridinyl)benzamide (Intermediate 16, 50 mg, 0.17 mmol), [4- (aminocarbonyl)phenyl]boronic acid (43 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (12 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 ml.) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge, eluting with methanol, and the eluent concentrated in vacuo. The resulting crude solid was dissolved in DMSO / methanol (1 :1 , 1 ml_), filtered and purified by preparative HPLC using a 0-35% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, combined, passed through an aminopropyl functionalised silica cartridge (pre-equilibrated with methanol, 1 g sorbent), rinsing with methanol, and concentrated to yield the title compound (5.9 mg, 0.018 mmol).

MS [M+1]⁺ 333.36; ¹H NMR <5H (400.13 MHz₁ Cf₆-DMSO, TMS): 8.54 (d, J = 6.0 Hz, 2H), 8.16 (br s, 1 H), 8.08 (d, J = 2.0 Hz, 1 H), 8.05 (s, 1 H), 8.01 (d, J = 8.0 Hz₁ 2H), 7.76 (d, J = 6.0 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1 H), 7.56 (d, J = 8.3Hz, 2H), 7.41 (s, 1 H), 7.39 (s, 1 H), 6.65 (s, 2H).

Example 48 2-Amino-4'-[(aminosulfonyl)methyl]-5-(4-pyridinyl)-3- biphenylcarboxamide

2-Amino-3-bromo-5-(4-pyridinyl)benzamide (Intermediate 16, 50 mg, 0.17 mmol), 1-[4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methane-sulfonamide (77 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)- ferrocene)palladium(ll)-dichloromethane adduct (12 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 ml_) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with methanol (10 ml_), filtered through a silica cartridge (1 g silica) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in DMSO / methanol (1 :1 , 1 ml_), filtered, and purified by preparative HPLC using a 0-35% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, combined, passed through an aminopropyl functionalised silica cartridge (pre-equilibrated with methanol) and concentrated to afford the title compound (28.5 mg, 0.074 mmol).

MS [M+1]⁺ 383.14; ¹H NMR S_H (400.13 MHz, Cf₆-DMSO, TMS): 8.54 (d, J = 5.5 Hz, 2H), 8.16 (br s, 1 H), 8.07 (s, 1 H), 7.75 (d, J = 5.8 Hz, 2H), 7.55 (s, 1 H), 7.51-7.46 (m, 4H), 7.38 (br s, 1 H), 6.81 (br s, 2H), 6.57 (br s, 2H), 4.34 (s, 2H). Example 49 : 6^l-Amino-4"-fluoro-1,1':3',1"-terphenyl-4,5^l-dicarboxamide

4-Amino-5-bromo-4'-fluoro-3-biphenyl-carboxamide (Intermediate 13, 53 mg, 0.17 mmol), [4-(aminocarbonyl)phenyl]boronic acid (43 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)- dichloromethane adduct (13 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with methanol (10 mL), filtered through a silica cartridge (500 mg silica), rinsing with methanol, and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL), filtered, and purified by preparative HPLC using a 20-60% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (24.4 mg, 0.07 mmol) as a white solid.

MS [M+1]⁺ 350.20, ¹H NMR & (400.13 MHz, Cf₆-DMSO, TMS): 8.09 (br s, 1 H), 8.04 (br s, 1 H), 7.99 (d, J = 8.0 Hz, 2H), 7.88 (br s, 1 H)₁ 7.74 (dd, J = 8.4, 5.6 Hz, 2H), 7.56 (d, J = 8.3Hz, 2H), 7.39 (br s, 2H), 7.32 (br s, 1 H), 7.23 (t, J = 8.8 Hz, 2H), 6.39 (br s, 2H).

Example 50 : β'-Amino-Λ^-^methyloxyJ-a^-methyl-i-piperazinyOphenyl]- 1,1':3',1"-terphenyl-4,5'-dicarboxamide

4-Amino-5-bromo-3-biphenyi-carboxamide (intermediate 7, 50 mg, 0.17 mmoi), [4-({[4- (methyloxy)-3-(4-methyl-1-piperazinyl)phenyl]amino}carbonyl)phenyl]boronic acid (95 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis- (diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (13 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge, eluting with methanol and the eluent concentrated in vacuo. The crude solid was dissolved in DMSO / methanol solution (1 :1 , 1 mL), filtered, and purified by preparative HPLC using a 20-60% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration yielded the title compound (18.9 mg, 0.04 mmol).

MS [M+1]⁺ 536.37, ¹H NMR S_n (400.13 MHz, Cf₆-DMSO, TMS): 10.1 (s, 1 H), 8.12 (s, 1 H), 8.80 (d, J = 8.3Hz₁ 2H), 7.93 (d, J = 1.8 Hz, 1 H), 7.71 (d, J = 7.5 Hz, 2H)₁ 7.64 (d, J = 8.3Hz, 2H), 7.50-7.37 (m, 5H), 7.33 (s, 1 H), 7.27 (t, J = 7.3Hz, 1 H), 6.91 (d, J = 8.8 Hz, 1 H), 6.41 (S₁ 2H), 3.77 (s, 3H), 2.98 (br s, 4H), 2.47 (br s, approximately 4H, overlapping with DMSO peak), 2.22 (s, 3H).

Example 51 : 4-Amino-5-bromo-4'-fluoro-3-biphenylcarboxamide

See Intermediate 13.

Example 52 : 2-Amino-5-(4-pyridinyl)benzamide

See Intermediate 15.

Example 53 : 1 ,1-Dimethylethyl 4-[4-amino-5-(aminocarbonyl)-3-biphenylyl]-3,6- dihydro-1(2H)-pyridinecarboxylate

See Intermediate 19. Example 54 6'-Amino-3-[(methylsulfonyl)amino]-1,1^>:3^>,1"-terphenyl-5^>- carboxamide

4-Amino-5-bromo-3-biphenyl-carboxamide (Intermediate 7, 27 mg, 0.09 mmol), {3- [(methylsulfonyl)amino]phenyl}boronic acid (29 mg, 0.14 mmol), sodium carbonate (58 mg, 0.55 mmol), dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)- dichloromethane adduct (7 mg, 0.009 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a 5g silica cartridge, eluting with methanol (10 mL). After concentration in-vacuo, purification by mass-directed HPLC yielded the title compound (10 mg, 0.03) as a light-brown oil.

MS [M+1]⁺ 382.13; ¹H NMR S_n (400.13 MHz, CDCI₃, TMS): 9.13 (s, 1 H), 7.62 (d, J = 2.0 Hz, 1H), 7.57-7.47 (m, 6H), 7.42 (t, J = 7.7 Hz, 2H), 7.37-7.22 (m, 2H), 6.60-6.20 (br s, approximately 2H), 3.09 (s, 3H).

Example 55 : 6'-Amino-3-(aminosulfonyl)-1,1':3^l,1"-terphenyl-5'-carboxamide

A mixture of 4-amino-5-bromo-3-biphenylcarboxamide (Intermediate 7, 31 mg, 0.11 mmol), 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (45 mg, 0.16 mmol), sodium carbonate (68 mg, 0.64 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)- ferrocene)palladium(ll)-dichloromethane adduct (8 mg, 0.011 mmol) in 1 ,4-dioxane (1 mL) and water (1 mL) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. Water (5 mL) and chloroform (10 ml_) were added, and the phases were separated. The aqueous phase was extracted with chloroform (10 mL), and the combined organic phases were concentrated in vacuo. Purification by preparative HPLC using a 20-60% MeCN (aq) gradient yielded the title compound (4.5 mg, 0.012 mmol) as an off-white solid.

MS [M+1]⁺ 368.30; ¹H NMR δ» (400.13 MHz, CDCI₃, TMS): 8.13 (br s, 1 H), 7.93 (d, J = 10.6 Hz, 2H), 7.83 (d, J = 7.5 Hz, 1H), 7.74-7.67 (m, 4H), 7.45-7.30 (m, 6H), 7.28 (t, J = 7.0 Hz, 1 H), 6.41 (s, 2H).

Example 56 : 6^l-Amino-Λ/⁴-[4-(1H-imidazol-1-ylmethyl)phenyl]-1,1^l:3^l,1"-terphenyl- 4,5'-dicarboxamide

4-Amino-5-bromo-3-biphenyl-carboxamide (Intermediate 7, 50 mg, 0.17 mmol), [4-({[3- (1H-imidazoi-1-yimethyi)phenyi]amino}carbonyi)phenyijboronic acid (83 mg, 0.26 mmoi), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)- ferrocene)palladium(ll)-dichloromethane adduct (13 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge, eluting with methanol and the eluent concentrated in vacuo. The crude solid was dissolved in DMSO / methanol solution (1 :1 , 1 mL), filtered, and purified by preparative HPLC using a 20-60% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, concentrated in vacuo, before dissolution in methanol and passage through an aminopropyl functionalised silica cartridge (1 g sorbent, pre- equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration yielded the title compound (17.5 mg).

MS [M+1]⁺ 488.30; ¹H NMR S_H (400.13 MHz, CDCI₃, TMS): 10.34 (s, 1 H), 8.12 (br s, 1 H), 8.08 (d, J = 8.3Hz, 2H), 7.93 (d, J = 2.0 Hz, 1 H), 7.78-7.64 (m, 5H), 7.65 (d, J = 8.3Hz, 2H), 7.47-7.32 (m, 5H), 7.27 (t, J = 7.4Hz, 1 H), 7.18 (s, 1 H), 6.99 (d, J = 7.5 Hz, 1H), 6.93 (s, 1 H), 6.41 (s, 2H), 5.22 (s, 2H).

Example 57 : 2-Amino-3,5-di-4-pyridinylbenzamide

2-Amino-3-bromo-5-(4-pyridinyl)benzamide (Intermediate 16, 50 mg, 0.17 mmol), 4- pyridylboronic acid (32 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (12 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with methanol (10 mL), filtered through a silica cartridge (500 mg silica) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL), filtered, and purified by preparative HPLC using a 0-35% MeCN

(aq) gradient. Fractions corresponding to the desired product were identified by LCMS, concentrated, re-dissolved in methanol and passed through an aminopropyl functionalised silica cartridge (pre-equilibrated with methanol, 500 mg sorbent) and concentrated to afford the title compound as a white solid (4.8 mg, 0.02 mmol).

MS [M+1]⁺ 291.34; ¹H NMR δ* (400.13 MHz, Cf₆-DMSO, TMS): 8.68 (d, J = 6.0 Hz, 2H), 8.54 (d, J = 6.0 Hz, 2H), 8.18 (br s, 1 H), 8.11 (d, J = 2.0 Hz, 1 H), 7.77 (d, J = 6.3Hz, 2H), 7.62 (d, J = 1.8 Hz, 1 H), 7.53 (d, J = 5.8 Hz, 2H), 7.42 (br s, 1 H), 6.78 (br s, 2H).

Example 58 : 5-{1-[(1-Acetyl-4-piperidinyl)carbonyl]-1,2,3,6-tetrahydro-4-pyridinyl}-4- amino-4'-fluoro-3-biphenylcarboxamide

A mixture of 4-amino-4^I-fluoro-5-(1 ,2,3,6-tetrahydro-4-pyridinyl)-3-biphenylcarboxamide (Intermediate 18, 50 mg, 0.16 mmol) and i-acetyl-4-piperidinecarbonyl chloride (30 mg, 0.19 mmol) in pyridine (3 ml.) was stirred at rt for 5 d. Further 1-acetyl-4- piperidinecarbonyl chloride (152 mg, 0.80 mmol) was added, and the mixture was heated at 6O⁰C for 5 d, before the addition of further 1-acetyl-4-piperidinecarbonyl chloride (304 mg, 1.60 mmol) and heating at 100⁰C for 1 h. After concentration in vacuo, the title compound was purified by preparative HPLC using a 20-60% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, concentrated in vacuo, re-dissolved in methanol and passed through an aminopropyl functionalised silica cartridge (pre-equilibrated with methanol, 1 g sorbent), eluting with methanol. Concentration yielded the title compound (6.7 mg, 0.014 mmol) as a white solid.

MS [M+1]⁺ 465.40; ¹H NMR <5H (400.13 MHz, Cy₆-DMSO, TMS): 8.01 (br s, 1 H), 7.77 (s, 1 H), 7.69 (t, J = 6.8 Hz, 2H), 7.31 (s, 1 H), 7.22 (t, J = 8.5 Hz, 3H), 6.42 (s, 2H), 5.76 (s, 1 H), 4.38 (br d, J = 12.3Hz, 1 H), 4.23 (br s, 1 H), 4.08 (br s, 1 H), 3.87-3.69 (m, 3H), 3.18- 3.05 (m, 1 H), 3.02-2.87 (m, 1 H), 2.69-2.56 (m, 1 H), 2.41 (br s, 1 H), 2.35-2.26 (m, 1 H), 2.00 (s, 3H), 1.68 (br s, 2H), 1.61-1.47 (m, 1 H), 1.44-1.31 (m, 1 H).

Example 59 : 6'-Amino-Λ/⁴,Λ/⁴-dimethyl-1,1^l:3^l,1"-terphenyl-4,5'-dicarboxamide

4-Amino-5-bromo-3-biphenyl-carboxamide (Intermediate 7, 50 mg, 0.17 mmol), {4- [(dimethylamino)carbonyl]phenyl}boronic acid (50 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,r-bis-(diphenylphosphino)-ferrocene)palladium(ll)- dichloromethane adduct (13 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge, eluting with methanol and the eluent concentrated in vacuo. The crude solid was dissolved in DMSO / methanol solution (1 :1 , 1 mL), filtered, and purified by preparative HPLC using a 20-60% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration yielded the title compound (22.4 mg, 0.06 mmol).

MS [M+1]⁺ 360.34; ¹H NMR 4_H (400.13 MHz, Cf₆-DMSO, TMS): 8.10 (br s, 1 H), 7.91 d, J = 2.0 Hz, 1 H), 7.70 (d, J = 7.3HZ, 2H), 7.54 (d, J = 8.3Hz, 2H), 7.51 (d, J = 8.3Hz, 2H), 7.43-7.37 (m, 3H), 7.31 (br s, 1 H), 7.26 (t, J = 7.4Hz, 1 H), 6.39 (s, 2H), 3.00 (s, 6H).

Example 60 : 4-Amino-5-(1-{[4-(dimethylamino)phenyl]carbonyl}-1,2,3,6-tetrahydro- 4-pyridinyl)-4'-fluoro-3-biphenylcarboxamide

A mixture of 4-amino-4^l-fluoro-5-(1 ,2,3,6-tetrahydro-4-pyridinyl)-3-biphenylcarboxamide (Intermediate 18, 50 mg, 0.16 mmol) and 4-(dimethylamino)benzoyl chloride (35 mg, 0.19 mmol) in pyridine (3 mL) was stirred at rt for 5 d. After concentration in vacuo, the title compound was purified by preparative HPLC using a 35-80% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, concentrated in vacuo, re-dissolved in methanol and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre-equilibrated with methanol), eluting with methanol. Concentration yielded the title compound (26.6 mg, 0.014 mmol) as a yellow solid.

MS [M+1]⁺ 459.39; ¹H NMR ^ (400.13 MHz, Cf₆-DMSO, TMS): 8.01 (br s, 1 H), 7.77 (s, 1 H), 7.71 (d, J = 5.5 Hz, 1 H), 7.69 (d, J = 5.5 Hz₁ 1 H), 7.36 (t, J = 8.9 Hz, 3H), 7.21 (t, J = 8.8 Hz, 3H), 6.73 (d, J = 8.8 Hz, 2H), 6.44 (s, 2H), 5.76 (br s, 1 H), 4.17 (br s, 2H), 3.73 (br s, 2H), 2.95 (s, 6H), 2.42 (br s, 2H). Example 61 : 4-Amino-5-[2,6-bis(methyloxy)-3-pyridinyl]-3-biphenylcarboxamide

4-Amino-5-bromo-3-biphenyl-carboxamide (Intermediate 7, 50 mg, 0.17 mmol), 2,6- bis(methyloxy)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (68 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)- ferrocene)palladium(ll)-dichloromethane adduct (13 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge, eluting with methanol and the eluent concentrated in vacuo. The crude solid was dissolved in DMSO / methanol solution (1 :1 , 1 mL), filtered, and purified by preparative HPLC using a 30-80% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, concentrated, re-dissolved in methanol and passed through an aminopropyl functionalised silica cartridge (pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration yielded the title compound (25.5 mg, 0.07 mmol).

MS [M+1]⁺ 350.31 ; ¹H NMR ft (400.13 MHz, Cf₆-DMSO, TMS): 8.05 (br s, 1 H), 7.87 (d, J = 1.8 Hz, 1 H), 7.65 (d, J = 7.5 Hz, 2H), 7.56 (d, J = 7.8 Hz, 2H), 7.39 (t, J = 7.7 Hz, 2H), 7.31 (d, J = 2.0 Hz, 1 H), 7.24 (t, J = 7.3Hz, approximately 1 H), 6.49 (d, J = 8.0 Hz, 1 H), 6.21 (s, 1 H), 6.17 (s, approximately 1 H), 3.92 (s, 3H), 3.86 (s, 3H).

Example 62 : 1,1-Dimethylethyl 4-[4-amino-5-(aminocarbonyl)-4'-fluoro-3- biphenylyl]-3,6-dihydro-1(2W)-pyridinecarboxylate

See Intermediate 17. Example 63 6'-Amino-4"-fluoro-/V\/V*-dimethyM ,1 "tf¹,! "-terphenyl-4,5¹- dicarboxamide

4-Amino-5-bromo-4¹-fluoro-3-biphenyl-carboxamide (Intermediate 13, 53 mg, 0.17 mmol), {4-[(dimethylamino)carbonyl]phenyl}boronic acid (50 mg, 0.26 mmol), sodium carbonate (109 mg, 1.03 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)- dichloromethane adduct (13 mg, 0.017 mmol) were slurried with 1 ,4-dioxane (1 mL) and water (1 mL). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was diluted with methanol (10 mL), filtered through a silica cartridge (500 mg silica) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL), filtered, and purified by preparative HPLC using a 30-80% MeCN (aq) gradient. Fractions corresponding to the desired product were identified by LCMS, and passed through an aminopropyl functionalised silica cartridge (1 g sorbent, pre-equilibrated with methanol, 2 column volumes), eluting with methanol. Concentration in vacuo yielded the title compound (14.5 mg, 0.04 mmol) as a white solid.

MS [M+1]⁺ 378.24, ¹H NMR δ* (400.13 MHz, Gf₆-DMSO₁ TMS): 8.10 (br s, 1 H), 7.88 (d, J = 1.8 Hz, 1 H), 7.74 (dd, J = 8.8, 5.5 Hz, 2H), 7.53 (d, J = 8.3Hz, 2H), 7.50 (d, J = 8.3Hz, 2H), 7.40 (d, J = 2.0 Hz, 1H), 7.32 (br s, 1 H), 7.23 (t, J = 8.9 Hz, 2H), 6.40 (br s, 2H), 3.00 (s, 6H).

Example 64 6^l-Amino^-[(Λ/,Λ/-dimethylglycyl)amino]-1,1^l:3^I _>1"-terphenyl-5¹- carboxamide

4-Amino-5-bromo-3-biphenyl-carboxamide (Intermediate 7, 31 mg, 0.11 mmol), Λ^.Λ/²- dimethyl-Λ/¹-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]glycinamide (28 mg, 0.16 mmol), sodium carbonate (68 mg, 0.64 mmol) and dichloro(1 ,1'-bis- (diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (8 mg, 0.011 mmol) were slurried with 1 ,4-dioxane (1 ml_) and water (1 ml_). The mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. Water (5 ml.) and chloroform (10 mL) were added, and the phases were separated. The aqueous phase was extracted with chloroform (10 mL), and the combined organic phases were concentrated in vacuo. Purification by preparative HPLC using a 25-45% MeCN (aq) gradient yielded the title compound (3.0 mg) as a white solid.

MS [M+1]⁺ 389.37; ¹H NMR ^ (400.13 MHz, Cy₆-DMSO, TMS): 9.85 (s, 1 H), 8.07 (br s, 1 H)₁ 7.87 (d, J = 1.5 Hz, 1 H), 7.89 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 7.5 Hz, 2H), 7.45-7.35 (m, 5H), 7.34-7.21 (m, 2H), 6.32 (s, 2H)₁ 3.09 (s, 2H), 2.29 (s, 6H).

Example 65 : 4-amino-3-biphenylcarboxamide

See Intermediate 6.

Example 66 : 4'-Amino-4"-[(dimethylamino)sulfonyl]-4-(methylsulfonyl)-1,1^>:3',1"- terphenyl-5'-carboxamide

A mixture of 4-amino-5-bromo-4'-(methylsulfonyl)-3-biphenylcarboxamide (Intermediate 23, 71 mg, 0.19 mmol), Λ/,Λ/-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzenesulfonamide (89 mg, 0.29 mmol), aqueous sodium carbonate (2M, 0.57 mL, 1.15 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)- dichloromethane adduct (16 mg, 0.02 mmol) in 1 ,4-dioxane (2 ml_) and water (1.43 ml_) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (2 g silica), eluting with methanol (3 column volumes) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1.5 ml_), filtered, and purification by preparative HPLC using a 25-55% MeCN (aq) gradient yielded the title compound (20.3 mg, 0.04 mmol) as a white solid.

MS [M+1]⁺ 474.24; ¹H NMR 4_H (400.13 MHz, Cf₆-DMSO, TMS): 8.18 (br s, 1 H), 8.06 (d, J = 1.5 Hz, 1 H), 8.01 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H)₁ 7.58 (d, J = 1.5 Hz, 1 H), 7.41 (br s, 1 H), 6.69 (s, 2H), 3.23 (s, 3H), 2.68 (s, 6H).

Example 67 : 4-Amino-5-(4-pyridinyl)-3,4'-biphenyldicarboxamide

A mixture of 4-amino-5-bromo-3,4'-biphenyldicarboxamide (Intermediate 26, 110 mg, 0.33 mmol), 4-pyridinylboronic acid (61 mg, 0.50 mmol), aqueous sodium carbonate (2M, 0.99 ml_, 1.98 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)- dichloromethane adduct (27 mg, 0.04 mmol) in 1 ,4-dioxane (2 ml.) and water (1.01 ml.) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (2 g silica), eluting with methanol (3 column volumes) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in

1 :1 DMSO / methanol solution (1 ml_), filtered, and purification by mass-directed HPLC yielded the title compound (40 mg, 0.12 mmol) as a red solid.

MS [M+1]⁺333.10; ¹H NMR δ* (400.13 MHz, cfe-DMSO, TMS): 8.67 (d, J = 6.0 Hz, 2H), 8.02 (d, J = 2.3 Hz, 1 H), 7.98 (s, 1 H), 7.91 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 8.5 Hz, 2H), 7.55-7.52 (m, 3H), 7.38 (br s, 1 H), 7.33 (s, 1 H), 6.62 (s, 2H). Example 68 : 4^l-Amino-4-(methyloxy)-4"-(1-pyrrolidinylsulfonyl)-1,1':3^l,1"-terphenyl- δ'-carboxamide

A mixture of 4-amino-5-bromo-4'-(methyloxy)-3-biphenylcarboxamide (Intermediate 28, 72 mg, 0.22 mmol), 1-{[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]sulfonyl}pyrrolidine (1 13 mg, 0.34 mmol), aqueous sodium carbonate (2M, 0.67 ml_, 1.34 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)- dichloromethane adduct (18 mg, 0.03 mmol) in 1 ,4-dioxane (2 mL) and water (1.33 mL) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (2 g silica), eluting with methanol (3 column volumes) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (2 mL), filtered, and purification by preparative HPLC using a 35-70% MeCN (aq) gradient yielded the title compound (36.1 mg, 0.08 mmol) as an off- white solid.

MS [M+1]⁺ 452.3; ¹H NMR δ* (400.13 MHz, Cf₆-DMSO, TMS): 8.11 (br s, 1 H)₁ 7.90-7.86 (m, 3H), 7.73 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 2.0 Hz, 1 H), 7.32 (br s, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.40 (s, 2H), 3.77 (s, 3H), 3.24-3.15 (m, 4H), 1.75- 1.64 (m, 4H).

Example 69 2-Amino-4'-[(dimethylamino)sulfonyl]-5-(3-pyridinyl)-3- biphenylcarboxamide

A mixture of 2-amino-3-bromo-5-(3-pyridinyl)benzamide (Intermediate 30, 65 mg, 0.22 mmol), Λ/,Λ/-dimethyl-4-(4,4_l5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (104 mg, 0.33 mmol), aqueous sodium carbonate (2M, 0.67 mL, 1.34 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (18 mg, 0.03 mmol) in 1 ,4-dioxane (2 mL) and water (1.33 mL) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (2 g silica), eluting with methanol (3 column volumes) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (2 mL), filtered, and purification by preparative HPLC using a 10-45% MeCN (aq) gradient yielded the title compound (14.3 mg, 0.04 mmol) as a light-yellow solid.

MS [M+1]⁺ 397.3; ¹H NMR S_H (400.13 MHz, c/₆-DMSO, TMS): 9.04 (d, J = 1.8 Hz, 1 H), 8.55 (d, J = 4.8 Hz, 1 H), 8.31 (br d, J = 8.3 Hz, 1 H), 8.14 (br s, 1 H), 8.05 (d, J = 2.3 Hz, 1 H), 7.84 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1 H), 7.60-7.56 (m, 1 H), 7.41 (s, 1 H), 6.67 (br s, 2H), 2.68 (s, 6H).

Example 70 : 4-Amino-4¹-(methylsulfonyl)-5-(4-pyridinyl)-3-biphenylcarboxamide

A mixture of 4-amino-5-bromo-4'-(methylsulfonyl)-3-biphenylcarboxamide (Intermediate 23, 65 mg, 0.18 mmol), 4-pyridinylboronic acid (33 mg, 0.26 mmol), aqueous sodium carbonate (2M, 0.53 mL, 1.06 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)- ferrocene)palladium(ll)-dichloromethane adduct (14 mg, 0.02 mmol) in 1 ,4-dioxane (2 mL) and water (1.47 mL) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (2 g silica), eluting with methanol (3 column volumes) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL), filtered, and purification by preparative HPLC using a 0-35% MeCN (aq) gradient yielded the title compound (12.3 mg, 0.03 mmol) as a bright-yellow solid. MS [M+1]⁺ 368.26; ¹H NMR S_H (400.13 MHz, cfe-DMSO, TMS): 8.68 (d, J = 5.5 Hz, 2H), 8.18 (br s, 1 H)₁ 8.06 (d, J = 2.3 Hz, 1 H), 8.01 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 5.8 Hz, 2H), 7.42 (br s, 1 H), 6.72 (s, 2H), 3.23 (s, 3H).

Example 71 : 4^l-Amino-4-(methyloxy)-4"-(methylsulfonyl)-1,1':3^l,1"-terphenyl-5¹- carboxamide

A mixture of 4-amino-5-bromo-4'-(methyloxy)-3-biphenylcarboxamide (Intermediate 28, 63 mg, 0.20 mmol), [4-(methylsulfonyl)phenyl]boronic acid (59 mg, 0.30 mmol), aqueous sodium carbonate (2M₁ 0.59 nriL, 1.18 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)- ferrocene)palladium(ll)-dichloromethane adduct (16 mg, 0.02 mmol) in 1 ,4-dioxane (2 ml.) and water (1.41 ml.) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (2 g silica), eluting with methanol (3 column volumes) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (2 ml_), filtered, and purification by preparative HPLC using a 30-55% MeCN (aq) gradient yielded the title compound (16.8 mg, 0.04 mmol) as a white solid.

MS [M+1]⁺ 397.3; ¹H NMR δ» (400.13 MHz, Cf₆-DMSO, TMS): 8.11 (br s, 1 H), 8.02 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 2.0 Hz, 1 H), 7.76 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H)₁ 7.38 (d, J = 2.0 Hz, 1 H), 7.33 (br s, 1 H), 6.97 (d, J = 8.8 Hz₁ 2H), 6.39 (s, 2H)₁ 3.77 (s, 3H)₁ 3.27 (s, 3H).

Example 72 : 4^I-Amino-4"-(aminosulfonyl)-4-(methyloxy)-1,1':3',1"-terphenyl-5¹- carboxamide

A mixture of 4-amino-5-bromo-4'-(methyloxy)-3-biphenylcarboxamide (Intermediate 28, 75 mg, 0.23 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (99 mg, 0.35 mmol), aqueous sodium carbonate (2M, 0.70 ml_, 1.40 mmol) and dichloro(1 ,1'- bis-(diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (19 mg, 0.03 mmol) in 1 ,4-dioxane (2 mL) and water (1.30 ml_) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (2 g silica), eluting with methanol (3 column volumes) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1.5 mL), filtered, and purification by preparative HPLC using a 30-55% MeCN (aq) gradient yielded the title compound (28.7 mg, 0.07 mmol) as a light-brown solid.

MS [M+1]⁺ 398.3; ¹H NMR S_n (400.13 MHz, Cf₆-DMSO, TMS): 8.21 (br s, 1 H), 8.03 (d, J = 8.5 Hz, 2H), 7.97 (s, 1 H), 7.79 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.54 (s, 2H), 7.48 (d, J = 2.0 Hz, 1 H), 7.43 (br s, 1 H), 7.08 (d, J = 8.8 Hz, 2H), 6.46 (s, 2H), 3.89 (s, 3H).

Example 73 : 4^l-Amino-4"-(aminosulfonyl)-4-(methylsulfonyl)-1,1^l:3^l,1"-terphenyl-5'- carboxamide

A mixture of 4-amino-5-bromo-4'-(methylsulfonyl)-3-biphenylcarboxamide (Intermediate 23, 62 mg, 0.17 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzenesulfonamide (71 mg, 0.25 mmol), aqueous sodium carbonate (2M, 0.50 mL, 1.00 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)- dichloromethane adduct (14 mg, 0.02 mmol) in 1 ,4-dioxane (2 mL) and water (1.50 mL) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (2 g silica), eluting with methanol (3 column volumes) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1.5 ml_), filtered, and purification by preparative HPLC using a 15-50% MeCN (aq) gradient yielded the title compound (7.9 mg, 0.02 mmol) as a white solid.

MS [M+1]⁺ 446.09; ¹H NMR δ» (400.13 MHz, Cf₆-DMSO₁ TMS): 8.18 (br s, 1 H), 8.06-8.03 (m, 1 H), 8.01 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 3.5 Hz, 2H), 7.91 (d, J = 3.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 2.3 Hz, 1 H), 7.44 (s, 2H), 7.41 (br s, 1 H), 6.64 (s, 2H), 3.23 (s, 3H).

Example 74 : 4^>-Amino-4"-[(dimethylamino)sulfonyl]-4-(methyloxy)-1,1':3^I,1"- terphenyl-5'-carboxamide

A mixture of 4-amino-5-bromo-4'-(methyloxy)-3-biphenylcarboxamide (Intermediate 28, 74 mg, 0.23 mmol), Λ/,Λ/-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzenesulfonamide (107 mg, 0.34 mmol), aqueous sodium carbonate (2M, 0.69 ml_, 1.38 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)- dichloromethane adduct (19 mg, 0.03 mmol) in 1 ,4-dioxane (2 mL) and water (1.31 mL) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (2 g silica), eluting with methanol (3 column volumes) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (2 mL), filtered, and purification by preparative HPLC using a 35-70% MeCN (aq) gradient yielded the title compound (19.6 mg, 0.05 mmol) as an off- white solid.

MS [M+1]⁺ 426.3; ¹H NMR S_n (400.13 MHz, Cf₆-DMSO, TMS): 8.11 (br s, 1 H), 7.87 (d, J = 1.8 Hz, 1 H), 7.83 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 2.0 Hz₁ 1 H), 7.32 (br s, 1 H), 6.97 (d, J = 8.8 Hz, 2H), 6.41 (s, 2H), 3.77 (s, 3H), 2.68 (S₁ 6H).

Example 75 : 4'-Amino-4-(methylsulfonyl)-4"-(1-pyrrolidinylsulfonyl)-1,1':3^l,1"- terphenyl-5'-carboxamide

A mixture of 4-amino-5-bromo-4'-(methylsulfonyl)-3-biphenylcarboxamide (Intermediate 23, 63 mg, 0.17 mmol), 1-{[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]sulfonyl}pyrrolidine (86 mg, 0.26 mmol), aqueous sodium carbonate (2M, 0.51 ml_, 1.02 mmol) and dichloro(1 ,V-bis-(diphenylphosphino)-ferrocene)palladium(ll)- dichloromethane adduct (14 mg, 0.02 mmol) in 1 ,4-dioxane (2 mL) and water (1.49 ml.) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (2 g silica), eluting with methanol (3 column volumes) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1.5 mL), filtered, and purification by preparative HPLC using a 20-60% MeCN (aq) gradient yielded the title compound (5.1 mg, 0.01 mmol) as a brown solid.

MS [M+1]⁺ 500.23; ¹H NMR δπ (400.13 MHz₁ Qf₆-DMSO, TMS): 8.19 (br s, 1 H)₁ 8.06 (d, J = 1.5 Hz₁ 1 H), 8.01 (d, J = 8.5 Hz₁ 2H)₁ 7.92 (d, J = 8.8 Hz₁ 2H), 7.89 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 1.8 Hz, 1 H), 7.41 (br s, 1 H)₁ 6.69 (s, 2H), 3.23 (s, 3H), 3.22-3.18 (m, 4H), 1.75-1.69 (m, 4H).

Example 76 : 4-Amino-4'-(methyloxy)-5-(4-pyridinyl)-3-biphenylcarboxamide

A mixture of 4-amino-5-bromo-4'-(methyloxy)-3-biphenylcarboxamide (Intermediate 28, 64 mg, 0.20 mmol), 4-pyridinylboronic acid (37 mg, 0.30 mmol), aqueous sodium carbonate (2M, 0.60 mL, 1.20 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)- ferrocene)palladium(ll)-dichloromethane adduct (16 mg, 0.02 mmol) in 1 ,4-dioxane (2 mL) and water (1.40 mL) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (2 g silica), eluting with methanol (3 column volumes) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL), filtered, and purification by preparative HPLC using a 15-40% MeCN (aq) gradient yielded the title compound (14.1 mg, 0.04 mmol) as a yellow-orange solid.

MS [M+1]⁺ 320.30; ¹H NMR δ* (400.13 MHz, cfe-DMSO, TMS): 8.67 (d, J = 5.3 Hz, 2H), 8.11 (br s, 1 H), 7.88 (d, J = 2.3 Hz, 1 H), 7.64 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 6.0 Hz, 2H), 7.40 (d, J = 2.0 Hz, 1 H), 7.34 (br s, 1 H), 6.97 (d, J = 8.8 Hz, 2H), 6.45 (s, 2H), 3.77 (s, 3H).

Example 77 : 2-Amino-5-(3-pyridinyl)-4'-(1-pyrrolidinylsulfonyl)-3- biphenylcarboxamide

A mixture of 2-amino-3-bromo-5-(3-pyridinyl)benzamide (Intermediate 30, 63 mg, 0.22 mmol), 1-{[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]sulfonyl}pyrrolidine (109 mg, 0.32 mmol), aqueous sodium carbonate (2M, 0.65 mL, 1.29 mmol) and dichloro(1 ,1'- bis-(diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (18 mg, 0.02 mmol) in 1 ,4-dioxane (2 mL) and water (1.35 mL) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (2 g silica), eluting with methanol (3 column volumes) and the eluent concentrated in vacuo.

The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (2 mL), filtered, and purification by preparative HPLC using a 25-50% MeCN (aq) gradient yielded the title compound (37.8 mg, 0.09 mmol) as a yellow solid.

MS [M+1]⁺ 423.30; ¹H NMR δ* (400.13 MHz, Cf₆-DMSO, TMS): 9.13 (d, J = 1.5 Hz, 1 H), 8.62 (d, J = 4.5 Hz₁ 1 H), 8.52 (br d, J = 8.0 Hz, 1 H), 8.15 (br s, 1 H), 8.09 (d, J = 2.0 Hz, 1 H), 7.90 (d, J = 8.3 Hz, 2H)₁ 7.74 (d, J = 8.3 Hz, 2H), 7.76-7.71 (m, 1 H), 7.63 (d, J = 2.3 Hz, 1 H), 7.44 (S₁ 1 H), 6.73 (br s, 2H), 3.21 (br t, J = 6.7 Hz, 4H), 1.72 (br t, J = 6.8 Hz₁ 4H).

Example 78 : 4'-amino-4"-[(dimethylamino)sulfonyl]-1₎1':3',1"-terphenyl-4,5¹- dicarboxamide

A mixture of 4-amino-5-bromo-3,4'-biphenyldicarboxamide (Intermediate 26, 111 mg, 0.33 mmol), Λ/,Λ/-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (140 mg, 0.45 mmol), aqueous sodium carbonate (2M, 0.99 mL, 1.98 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (27 mg, 0.04 mmol) in 1 ,4-dioxane (2 mL) and water (1.01 mL) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (2 g silica), eluting with methanol (3 column volumes) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / MeOH and purified by preparative HPLC to yield the title compound (2.4 mg).

MS [M+1]⁺ 438.93; ¹H NMR δπ (400.13 MHz, Cf₆-DMSO₁ TMS): 8.17 (br s, 1 H)₁ 8.02 (d, J = 2.0 Hz, 1 H), 7.98 (br s, 1 H), 7.92 (d, J = 8.5 Hz₁ 2H), 7.83 (apparent t, J = 8.5 Hz, 4H), 7.76 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 2.0 Hz, 1 H), 7.37 (br s, 1 H), 7.32 (s, 1 H), 6.59 (s, 2H)₁ 2.68 (s, 6H).

Example 79 : 4'-amino-4"-(aminosulfonyl)-1,1':3',1"-terphenyl-4,5'-dicarboxamide

A mixture of 4-amino-5-bromo-3,4'-biphenyldicarboxamide (Intermediate 26, 111 mg, 0.33 mmol), 4-(4,4,5,5-tetramethyl-1 ,3₎2-dioxaborolan-2-yl)benzenesulfonamide (141 mg, 0.50 mmol), aqueous sodium carbonate (2M, 1.00 ml_, 2.00 mmol) and dichloro(1 ,1'-bis- (diphenylphosphino)-ferrocene)palladium(ll)-dichloromethane adduct (27 mg, 0.04 mmol) in 1 ,4-dioxane (2 ml.) and water (1.00 ml_) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (2 g silica), eluting with methanol (3 column volumes) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / MeOH and purified by preparative HPLC to yield the title compound (9.4 mg).

MS [M+1]⁺411.02; ¹H NMR S_H (400.13 MHz, Cy₆-DMSO, TMS): 8.15 (br s, 1 H), 8.00 (d, J = 2.5 Hz, 1 H), 7.98 (br s, 1 H), 7.92 (d, J = 3.5 Hz, 2H), 7.90 (d, J = 3.5 Hz, 2H), 7.81 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 2.0 Hz, 1 H), 7.44 (br s, 2H), 7.36 (br s, 1 H), 7.32 (br s, 1 H), 6.54 (s, 2H).

Example 80: 4'-amino-4"-(methylsulfonyl)-1,1^I:3',1"-terphenyl-4,5'-dicarboxamide

A mixture of 4-amino-5-bromo-3,4'-biphenyldicarboxamide (Intermediate 26, 109 mg, 0.33 mmol), [4-(methylsulfonyl)phenyl]boronic acid (98 mg, 0.49 mmol), aqueous sodium carbonate (2M, 0.98 ml_, 1.96 mmol) and dichloro(1 ,1'-bis-(diphenylphosphino)- ferrocene)palladium(ll)-dichloromethane adduct (27 mg, 0.04 mmol) in 1 ,4-dioxane (2 mL) and water (1.02 mL) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. The cooled mixture was filtered through a silica cartridge (2 g silica), eluting with methanol (3 column volumes) and the eluent concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / MeOH and purified by preparative HPLC to yield the title compound (1.9 mg). MS [M+1]⁺ 410.05; ¹H NMR «5H (400.13 MHz, cfe-DMSO, TMS): 8.17 (br s, 1 H), 8.03 (apparent d, J = 8.0 Hz, 3H), 7.98 (br s, 1 H), 7.92 (d, J = 8.5 Hz₁ 2H), 7.81 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 2.0 Hz₁ 1 H), 7.38 (br s, 1 H), 7.32 (br s, 1 H), 6.58 (s, 2H), 3.27 (s, 3H).

intermediates and Examples wherein Z is OH INTERMEDIATES

Intermediate 1 : 4-Hydroxy-3-biphenylcarbonitrile

A mixture of 5-bromo-2-hydroxybenzonitrile (7.27 g, 36.7 mmol), phenylboronic acid (6.72 g, 55.0 mmol), sodium carbonate (23.3 g, 220 mmol) and dichloro(1 ,1'-bis- (diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (1.50 g, 1.84 mmol) in 1 ,4-dioxane (200 m!_) and water (200 m!_) was heated at 8O⁰C for 20 h. After cooling to rt, the mixture was partially concentrated in vacuo to remove the 1 ,4-dioxane. The remaining aqueous solution was decanted away from residual solid, and diluted with water (300 ml_), followed by the cautious addition of aqueous hydrochloric acid (2M, 300 mL) and chloroform (200 ml_). After filtration to remove a residual dark-brown solid, the aqueous and organic phases were separated, and the aqueous phase extracted with chloroform (200 mL). The combined organic phases were concentrated in vacuo, and combined with the dark-brown solid residue from the filtration. The material was dissolved in methanol (200 mL) and concentrated in vacuo with pre-adsorbtion onto an inert sorbent (approximately 20 g). Purification by column chromatography (SiO₂, a gradient of 20 to 40% solvent B in A over 45 min; where solvent A = cyclohexane and solvent B = 10% glacial acetic acid in ethyl acetate) yielded the title compound (3.61 g, 18.5 mmol) as a beige solid.

MS [M-1]^" 194.19; ¹H NMR δ» (400.13 MHz, Cl₆-DMSO, TMS): 11.2 (br s, 1 H), 7.92 (d, J = 2.3 Hz₁ 1 H), 7.82 (dd, J = 8.7, 2.4 Hz₁ 1 H), 7.64 (d, J = 7.5 Hz, 2H), 7.44 (t, J = 7.5 Hz₁ 2H), 7.33 (t, J = 7.3 Hz, 1 H)₁ 7.10 (d, J = 8.8 Hz, 1 H). Intermediate 2 : 4-Hydroxy-3-biphenylcarboxamide

To a suspension of 4-hydroxy-3-biphenylcarbonitrile (Intermediate 1 , 3.61 g, 18.5 mmol) in water (550 mL) and ethanol (100 mL) was cautiously added sodium hydroxide (20 g, 0.50 mol) and 30 % w/w hydrogen peroxide solution (100 mL). After stirring at rt for 3 d, further 30 % w/w hydrogen peroxide solution (50 mL) was added, and the mixture stirred for 1 d. 30 % w/w Hydrogen peroxide solution (50 mL) and ethanol (100 mL) were added and stirring continued for 1 d, before the addition of further 30 % w/w hydrogen peroxide solution (50 mL) and stirring for 1 d. After filtration, aqueous hydrochloric acid (5M, 300 mL) was added cautiously and the resulting precipitate was isolated by filtration and washed with water (500 mL) to yield the title compound (2.90 g, 13.6 mmol) as a white solid.

MS [M+1 J⁺ 214.29; ¹H NMR «5H (400.13 MHz, Of₆-DMSO, TMS): 13.12 (br s, I H), 8.59 (br s, 1 H), 8.19 (d, J = 2.0 Hz, 1 H), 7.97 (br s, 1 H), 7.75 (dd, J = 8.5, 2.0 Hz, 1 H), 7.68 (d, J = 7.8 Hz, 2H), 7.45 (t, J = 7.7 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1 H), 6.97 (d, J = 8.5 Hz, 1 H).

Intermediate 3 : 5-Bromo-4-hydroxy-3-biphenylcarboxamide

A solution of 4-hydroxy-3-biphenylcarboxamide (Intermediate 2, 2.90 g, 13.6 mmol) and Λ/-bromosuccinimde (2.42 g, 13.6 mmol) in glacial acetic acid (60 mL) was stirred at rt for 2.5 d before concentration in vacuo. Re-dissolution in methanol (200 mL) was followed by concentration in vacuo with pre-adsorbtion onto an inert sorbent (approximately 20 g). Purification by column chromatography (SiO₂, a gradient of 15 to 25% solvent B in A over 45 min; where solvent A = cyclohexane and solvent B = 10% glacial acetic acid in ethyl acetate) yielded the title compound (3.35 g, 11.5 mmol) as a white solid, after concentration in vacuo of product containing fractions, suspension in cyclohexane (100 ml.) and filtration.

MS [M+1]⁺ 292.18, 294.23 (approximately 1 :1 ratio); ¹H NMR S_H (400.13 MHz, Of₆-DMSO, TMS): 12.0 (s, 1H)₁ 8.83 (br s, 1 H), 8.23 (br d, J = 2.0 Hz, 2H), 8.06 (d, J = 1.5 Hz₁ 1H), 7.72 (d, J = 7.5 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H)₁ 7.35 (t, J = 7.4 Hz, 1 H).

Intermediate 4 : 5-Bromo-4-(methyloxy)-3-biphenylcarboxamide

Methyl iodide (0.24 ml_, 3.86 mmol) was added to a mixture of 5-bromo-4-hydroxy-3- biphenylcarboxamide (Intermediate 3, 1.00 g, 3.42 mmol) and potassium carbonate (1.42 g, 10.3 mmol) in acetone (50 ml_) at rt. After stirring at rt for 16 h, further methyl iodide

(0.24 mL, 3.86 mmoi) was added) and stirring at rt continued for 1 d. After concentration in vacuo, ethyl acetate (50 mL) was added and the resulting mixture was filtered, rinsing the residue with ethyl acetate (100 mL). The filtrate was concentrated in vacuo and combined with the residue, and aqueous hydrochloric acid (1 M, 50 mL) was added. The mixture was sonicated, and the title compound (890 mg, 2.89 mmol) isolated by filtration as an off-white solid.

MS [M+1]⁺ 306.06, 308.04 (approximately 1 :1 ratio); ¹H NMR S_n (400.13 MHz, ck-DMSO, TMS): 8.00 (s, 1 H), 7.88 (br s, 1 H), 7.76 (s, 1 H), 7.70 (s, 1 H), 7.68 (br s, 2H), 7.47 (t, J = 7.3 Hz, 2H), 7.40 (br d, J = 6.5 Hz₁ 1 H), 3.84 (s, 3H).

Intermediate 5 : 5-Bromo-4'-chloro-4-hydroxy-3-biphenylcarboxamide

A mixture of 5-bromo-2-hydroxybenzamide (5.15 g, 23.8 mmol), (4-chlorophenyl)boronic acid (5.58 g, 35.7 mmol), sodium carbonate (15.2 g, 143 mmol) and dichloro(1 ,1'-bis- (diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (1.95 g, 2.39 mmol) in 1 ,4-dioxane (250 ml_) and water (250 ml.) was heated at 8O⁰C under N₂ for 3.5 h. After partial concentration in vacuo to remove the 1 ,4-dioxane, water (500 mL) was added, followed by the cautious addition of aqueous hydrochloric acid (2M₁ 130 mL). Chloroform (250 mL) was added, the phases were separated, and the aqueous phase was extracted with chloroform (2 x 250 mL). The combined organic phases were concentrated in vacuo with pre-adsorbtion onto an inert sorbent (approximately 15 g). Purification by column chromatography (SiO₂, 20 to 50% ethyl acetate in cyclohexane gradient over 30 min, followed by 100% ethyl acetate for 5 min) yielded 4'-chloro-4-hydroxy-3- biphenylcarboxamide (2.85 g, 11.5 mmol) as a light-red solid, which was used without purification.

4'-Chloro-4-hydroxy-3-biphenylcarboxamide (1.91 g, 7.71 mmol) and Λ/-bromosuccinimide (1.37 g, 7.70 mmol) in glacial acetic acid (50 mL) were stirred at rt for approximately 18 h, after which time further Λ/-bromosuccinimide (206 mg, 1.16 mmol) was added and stirring at rt continued for 1 h. After concentration in vacuo, water (200 mL) was added and the mixture ultraso.nicated. The title compound (2.49 g, 7.62 mmol, approximately 80% pure by ¹H NMR)) was isolated by filtration as a purple solid.

MS [M+1]⁺ 326.13, 328.12 (approximately 1 :1 ratio); ¹H NMR S_n (400.13 MHz, d₆-DMSO, TMS): (Approximately 80% pure) 14.27 (s, 1 H), 8.83 (br s, 1 H)₁ 8.26 (br s, 1 H), 8.24 (d, J = 2.0 Hz, 1 H), 8.09 (d, J = 2.0 Hz, 1 H), 7.76 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H).

Intermediate 6 : 5-Bromo-4'-chloro-4-(methyloxy)-3-biphenylcarboxamide

A mixture of 5-bromo-4'-chloro-4-hydroxy-3-biphenylcarboxamide (Intermediate 5, 3.33 g, 10.2 mmol), potassium carbonate (4.23 g, 30.6 mmol) and methyl iodide (1.27 mL, 20.4 mmol) in acetone (210 mL) was stirred at rt under N₂ for 17 h. Methyl iodide (0.64 mL, 10.2 mmol) was added, and after stirring at rt for 5 h, a further portion of methyl iodide (6.35 ml_, 102 mmol) was added and the mixture stirred at rt for 18 h. After concentration in vacuo, water (200 ml.) and chloroform (200 ml_) were added and the phases were separated. The aqueous phase was extracted with chloroform (2 x 200 ml_), and the combined organic phases were concentrated in vacuo with pre-adsorbtion onto an inert sorbent (approximately 15 g). Purification by column chromatography (SiO₂, 20 to 60% ethyl acetate in cyclohexane gradient over 40 min, followed by 100% ethyl acetate for 5 min) yielded the title compound (1.41 g, 4.14 mmol) as a white solid.

MS [M+1]⁺ 340.04, 342.02 (approximately 1 :1 ratio); ¹H NMR S_n (400.13 MHz₁ Cf₆-DMSO, TMS): 8.02 (d, J = 2.3 Hz, 1 H), 7.89 (br s, 1 H), 7.77 (d, J = 2.3 Hz, 1 H), 7.74 (d, J = 8.8 Hz, 2H), 7.68 (br s, 1 H), 7.52 (d, J = 8.5 Hz, 2H), 3.84 (s, 3H).

Intermediate 7 : 4"-(Aminosulfonyl)-4-chloro-4^I-(methyloxy)-1,1^I:3^I,1"-terphenyl-5'- carboxamide

A mixture of 5-bromo-4'-chloro-4-(methyloxy)-3-biphenylcarboxamide (Intermediate 6, 706 mg, 1.69 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (719 mg, 2.54 mmol), aqueous sodium carbonate (2M, 5 ml_, 10 mmol) and dichloro(1 ,1'- bis(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (138 mg, 0.17 mmol) in 1 ,4-dioxane (10 ml_) and water (5 ml_) was heated at 8O⁰C under N₂ for 1 h. The mixture was concentrated in vacuo, water (30 ml_) and chloroform (30 mL) were added, the mixture was filtered, the phases were separated, and the aqueous phase was extracted with chloroform (2 x 30 mL) and ethyl acetate (3 x 20 mL). A solid residue from the filtration was combined with the organic phases and the mixture concentrated in vacuo with pre-adsorbtion onto an inert sorbent (approximately 10 g). Purification by column chromatography (SiO₂, 60 to 90% ethyl acetate in cyclohexane gradient over 45 min, followed by 100% ethyl acetate for 5 min) yielded the title compound (400 mg, 0.96 mmol) as a white solid. MS [M+1]⁺ 417.10; ¹H NMR S_H (400.13 MHz, Cf₆-DMSO, TMS): 7.92 (d, J = 8.5 Hz, 2H), 7.89 (br s, 1 H), 7.85-7.82 (m, 3H), 7.79 (d, J = 8.5 Hz, 2H)₁ 7.74 (d, J = 2.5 Hz, 1 H), 7.65 (br s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.44 (s, 2H), 3.49 (s, 3H).

Intermediate 8 : 4-Chloro-4"-[(dimethylamino)sulfonyl]-4^>-(methyloxy)-1 ,1^t:3^>,1"- terphenyl-5'-carboxamide

A mixture of 5-bromo-4'-chloro-4-(methyloxy)-3-biphenylcarboxamide (Intermediate 6, 694 mg, 2.04 mmol), {4-[(dimethylamino)sulfonyl]phenyl}boronic acid (625 mg, 2.01 mmol), aqueous sodium carbonate (2M, 6.12 mL, 12.2 mmol) and dichloro(1 ,1'- bis(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (167 mg, 0.20 mmol) in 1 ,4-dioxane (10 mL) and water (3.9 mL) was heated at 8O⁰C under N₂ for 2 h. The mixture was concentrated in vacuo, water (30 mL) and chloroform (30 mL) were added, the mixture was filtered, the phases were separated, and the aqueous phase was extracted with chloroform (2 x 30 mL) and ethyl acetate (3 x 30 mL). The combined organic layers were concentrated in vacuo with pre-adsorbtion onto an inert sorbent (approximately 15 g). Purification by column chromatography (SiO₂, 60 to 90% ethyl acetate in cyclohexane gradient over 45 min, followed by 100% ethyl acetate for 5 min) yielded the title compound (590 mg, 1.33 mmol) as a white solid.

MS [M+1]⁺ 445.04; ¹H NMR Sn (400.13 MHz, (Z₆-DMSO, TMS): 7.92 (s, 1 H), 7.90 (s, 2H), 7.87-7.83 (m, 3H), 7.80 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 2.5 Hz, 1 H), 7.66 (br d, J = 2.0 Hz, 1 H), 7.53 (d, J = 8.5 Hz, 2H), 3.48 (s, 3H), 2.67 (s, 6H).

Intermediate 9 : 2-[(Phenylmethyl)oxy]-5-(4-pyridinyl)benzonitrile

To a stirred mixture of 5-bromo-2-hydroxybenzonitrile (9.67 g, 48.8 mmol) and potassium carbonate (20.2 g, 146 mmol) in acetone (100 ml.) was added benzyl bromide (6.39 ml_, 53.7 mmol). After stirring at rt for 16 h the suspension was filtered, washing with acetone

(200 ml_), and the filtrate concentrated in vacuo. Aqueous sodium hydroxide (2M) was added, and the mixture was ultrasonicated and extracted into dichloromethane (200 ml_).

The phases were separated, and the aqueous phase extracted with dichloromethane (200 ml_). The combined organic phases were concentrated in vacuo to yield 5-bromo-2- [(phenylmethyl)oxy]benzonitrile (14.0 g, 48.4 mmol) as an oil which solidified to a white solid upon standing and was used without further purification.

5-Bromo-2-[(phenylmethyl)oxy]benzonitrile (5.86 g, 20.3 mmol), 4-pyridylboronic acid (5.00 g, 40.7 mmol), sodium carbonate (12.9 g, 122 mmol) and dichloro(1 ,1'- bis(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (1.66 g, 2.03 mmol) were each split into two equal portions by mass, and each portion was slurried with 1 ,4-dioxane (10 ml.) and water (10 mL). Each mixture was heated with stirring in a microwave reactor at 150 ⁰C for 20 min. The mixtures were combined and filtered through a silica cartridge (50 g silica), eluting with methanol (300 mL). The eluant was concentrated in vacuo and ethyl acetate (300 mL) and aqueous hydrochloric acid (2M, 100 mL) were added. The phases were separated, and the organic phase was extracted with aqueous hydrochloric acid (2M, 3 x 100 mL). The combined aqueous phases were taken to pH 12 by the cautious addition of sodium carbonate and extracted with dichloromethane (5 x 200 mL). The combined organic phases were concentrated in vacuo, re-dissolved in methanol (200 mL) and concentrated in vacuo with pre-adsorbtion onto an inert sorbent. Purification by column chromatography (SiO₂, 80-100% ethyl acetate in cyclohexane gradient over 40 min) yielded the title compound (0.99 g, 3.44 mmol) as a white solid.

MS [M+1]⁺ 287.09; ¹H NMR S_H (400.13 MHz, cfe-DMSO, TMS): 8.63 (d, J = 4.5 Hz, 2H)₁ 8.29 (s, 1 H), 8.15 (dd, J = 8.8, 2.0 Hz, 1 H), 7.77 (d, J = 4.8 Hz, 2H), 7.53-7.41 (m, 5H), 7.37 (t, J = 7.0 Hz, 1 H), 5.39 (s, 2H). Intermediate 10 : 2-Hydroxy-5-(4-pyridinyl)benzonitrile hydrochloride

A solution of 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzonitrile hydrochloride (the hydrochloride salt of Intermediate 9, 3.12 g, 9.67 mmol) in ethanol (300 mL) and DMF (50 mL) was added to an evacuated flask containing 10% wt. palladium on carbon (300 mg). The suspension was vigorously stirred under an atmosphere of hydrogen for 40 h. After filtration, concentration in vacuo yielded the title compound (1.30 g, 5.59 mmol) as a beige solid.

MS [M+1]⁺ 197.13; ¹H NMR S_n (400.13 MHz, cfe-DMSO, TMS): 12.08 (br s, 1 H), 8.88 (d, J = 6.0 Hz, 2H), 8.43 (s, 1 H), 8.29 (d, J = 5.8 Hz, 2H), 8.20 (dd, J = 8.8, 2.3 Hz, 1 H), 7.25 (d, J = 8.8 Hz, 1 H).

Intermediate 11 : 2-Hydroxy-5-(4-pyridinyl)benzamide

To a suspension of 2-hydroxy-5-(4-pyridinyl)benzonitrile hydrochloride (Intermediate 10, 2.00 g, 8.60 mmol) in ethanol (100 mL) and aqueous sodium hydroxide solution (100 mL) was added 30 % w/w hydrogen peroxide solution (100 mL) over 30 min. After stirring at rt for 16 h, additional 30 % w/w hydrogen peroxide solution (50 mL) was added, and the mixture stirred for 60 h. Sodium hydroxide (approximately 5 g) and 30 % w/w hydrogen peroxide solution (50 mL) were added and the mixture stirred for 24 h, before the addition of ethanol (50 mL) and 30 % w/w hydrogen peroxide solution (50 mL). After stirring for a further 24 h, the mixture was carefully acidified to approximately pH 1 with aqueous hydrochloric acid (2M, 200 ml_), and then to pH 7 by the addition of potassium carbonate. The mixture was extracted into ethyl acetate (2 x 200 ml_) and the combined organic phases concentrated in vacuo to yield the title compound (approximately 1.85 g, 8.64 mmol) as a bright yellow solid.

MS [M+1]⁺ 215.33; ¹H NMR «5H (400.13 MHz, Of₆-DMSO, TMS): 13.34 (br s, 1 H), 8.70 (br s, 1 H), 8.61 (d, J = 5.5 Hz, 2H), 8.38 (d, J = 2.3 Hz, 1H), 8.05 (br s, 1 H), 7.92 (dd, J = 8.8, 2.3 Hz, 1 H), 7.75 (d, J = 6.0 Hz, 2H), 7.02 (d, J = 8.5 Hz₁ 1 H).

Intermediate 12 : 3-Bromo-2-hydroxy-5-(4-pyridinyl)benzamide

A solution of 2-hydroxy-5-(4-pyridinyl)benzamide (Intermediate 11 , 1.85 g, 8.64 mmol) and Λ/-bromosuccinimde (1.69 g, 9.49 mmol) in glacial acetic acid (200 ml.) was ultrasonicated for 30 min before concentration in vacuo. Water (150 ml.) was added to the resulting crude solid, and the mixture uitrasonicated before filtration and rinsing with water. The title compound (1.23 g, 4.20 mmol) was isolated as an orange solid.

MS [M+1]⁺ 293.19, 295.22 (approximately 1 :1 ratio); ¹H NMR δ» (400.13 MHz, cfe-DMSO, TMS): 8.92 (s, 1 H), 8.71 (d, J = 4.5 Hz, 2H), 8.46 (d, J = 1.8 Hz, 1 H), 8.36 (s, 1 H), 8.33 (d, J = 1.8 Hz, 1 H), 7.95 (d, J = 5.8 Hz, 2H).

EXAMPLES Example 1 A-KDimethylaminoJsulfonyll-β'-hydroxy-i.rrS'.r'-terphenyl-S¹- carboxamide

A mixture of 5-bromo-4-(methyloxy)-3-biphenylcarboxamide (Intermediate 4, 25 mg, 0.08 mmol), Λ/,Λ/-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (38 mg, 0.12 mmol), sodium carbonate (52 mg, 0.49 mmol) and dichloro(1 ,1'- bis(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (6 mg, 0.003 mmol) in 1 ,4-dioxane (1 ml.) and water (1 mL) was heated with stirring in a microwave reactor at 150⁰C for 20 mins. MeOH (5 mL) was added and the mixture was filtered through a silica cartridge (500 mg silica), eluting with MeOH (10 mL), and the eluent concentrated in vacuo. Pyridine (2 mL) and lithium iodide (55 mg) were added to the resulting solid, and the mixture was heated with stirring in a microwave reactor at 175°C for 2 h. After concentration in vacuo, water (5 mL) was added to the resulting crude solid, and the mixture sonicated. Concentrated hydrochloric acid (37%, 0.5 mL) was added, and the crude solid was isolated by filtration. After dissolution in 1 :1 DMSO / methanol solution (1 mL), purification by preparative HPLC using a 40-95 % MeCN (aq) gradient yielded the title compound (17.8 mg, 0.04 mmol) as an off-white solid.

MS [M+1]⁺ 397.33; ¹H NMR Sn (400.13 MHz, Cf₆-DMSO, TMS): 8.82 (br s, 1 H)₁ 8.29 (d, J = 2.3 Hz, 1 H), 8.17 (br s, 1 H), 7.95 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 2.0 Hz, 1 H)₁ 7.79 (t, J = 7.3 Hz, 5H), 7.47 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.4 Hz₁ 1 H), 2.67 (s, 6H).

Example 2 : e'-Hydroxy^-ύ^'mefnyisuifonyOaminoj-i.i'iS'.r'-terphenyi-S'- carboxamide

A mixture of 5-bromo-4-(methyloxy)-3-biphenylcarboxamide (Intermediate 4, 25 mg, 0.08 mmol), {4-[(methylsulfonyl)amino]phenyl}boronic acid (26 mg, 0.12 mmol), sodium carbonate (52 mg, 0.49 mmol) and dichloro(1 ,1'- bis(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (6 mg, 0.003 mmol) in 1 ,4-dioxane (1 mL) and water (1 mL) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. MeOH (5 mL) was added and the mixture was filtered through a silica cartridge (500 mg silica), eluting with MeOH (10 mL), and the eluent concentrated in vacuo. Pyridine (2 mL) and lithium iodide (55 mg) were added to the resulting solid, and the mixture was heated with stirring in a microwave reactor at 175 ⁰C for 2 h. After concentration in vacuo, water (5 mL) was added to the resulting crude solid, and the mixture sonicated. Concentrated hydrochloric acid (37%, 0.5 mL) was added, and the crude solid was isolated by filtration. After dissolution in 1 :1 DMSO / methanol solution (1 mL), purification by preparative HPLC using a 30-80 % MeCN (aq) gradient yielded the title compound (15.6 mg, 0.04 mmol) as a brown solid.

MS [M+1]⁺ 383.30; ¹H NMR ^ (400.13 MHz, cfe-DMSO, TMS): 13.97 (s, 1H), 9.83 (s, 1H), 8.76 (br s, 1 H), 8.20 (d, J = 2.0 Hz, 1 H), 8.09 (br s, 1 H), 7.77 (s, 1 H), 7.75 (d, J = 1.3 Hz₁ 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1 H), 7.28 (d, J = 8.8 Hz, 2H), 3.03 (s, 3H).

Example 3 ^'-(AminosulfonylM-chloro-^-hydroxy-i ,1 ^*:3',1 "-terphenyl-5¹- carboxamide

A mixture of 4"-(aminosulfonyl)-4-chloro-4^l-(methyloxy)-1 ,1':3^l,1"-terphenyl-5¹- carboxamide (Intermediate 7, 64 mg, 0.15 mmol) and lithium iodide (103 mg, 0.77 mmol) in pyridine (2 mL) was heated with stirring in a microwave reactor at 150 ⁰C for 105 min. The mixture was concentrated in vacuo, water (20 mL) and aqueous hydrochloric acid (2M, 10 drops) were added. After concentration in vacuo to approximately half the original volume, MeOH (5 mL) was added and the resulting white precipitate isolated by filtration to yield the title compound (58 mg, 0.14 mmol) as a white solid.

MS [M+1]⁺ 403.19; ¹H NMR <5H (400.13 MHz, c/₆-DMSO, TMS): 8.81 (s, 1 H), 8.27 (d, J = 2.0 Hz, 1 H), 8.18 (s, 1 H), 7.89-7.81 (m, 7H), 7.53 (d, J = 8.5 Hz, 2H), 7.40 (s, 2H).

Example 4 : 4-Chloro-4"-[(dimethylamino)sulfonyl]-4^l-hydroxy-1,1':3^l,1"-terphenyl- 5"-carboxamide

A mixture of 4-chloro-4"-[(dimethylamino)sulfonyl]-4'-(methyloxy)-1 ,1':3',1"-terphenyl-5¹- carboxamide (Intermediate 8, 102 mg, 0.23 mmol) and lithium iodide (153 mg, 1.14 mmol) in pyridine (3 mL) was heated with stirring in a microwave reactor at 150 ⁰C for 2 h. The mixture was concentrated in vacuo, re-dissolved in water (10 mL) and acidified to pH 6 with 2M aqueous hydrochloric acid. Isolation by filtration of the resulting precipitate yielded the title compound (93 mg, 0.22 mmol) as a light-beige solid.

MS [M+1]⁺ 430.93, 432.91 (approximately 3:1 ratio); ¹H NMR <5H (400.13 MHz, d₆-DMSO, TMS): 14.22 (s, 1 H), 8.83 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 2.0 Hz, 1 H), 7.84 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 2.67 (s, 6H).

Example 5 : 4-Hydroxy-5-(4-pyridinyl)-3-biphenylcarboxamide

A mixture of 5-bromo-4-(methyloxy)-3-biphenylcarboxamide (Intermediate 4, 25 mg, 0.08 mmol), 4-pyridinylboronic acid (15 mg, 0.12 mmol), sodium carbonate (52 mg, 0.49 mmol) and dichloro(1 ,1'-bis(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (6 mg, 0.003 mmol) in 1 ,4-dioxane (1 mL) and water (1 mL) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. MeOH (5 mL) was added and the mixture was filtered through a silica cartridge (500 mg silica), eluting with MeOH (10 mL), and the eluent concentrated in vacuo. Pyridine (2 mL) and lithium iodide (55 mg) were added to the resulting solid, and the mixture was heated with stirring in a microwave reactor at 175 ⁰C for 2 h. After concentration in vacuo, water (5 mL) was added to the resulting crude solid, and the mixture sonicated. Concentrated hydrochloric acid (37%, 0.5 ml.) was added, and the resulting solid was isolated by filtration. After dissolution in 1 :1 DMSO / methanol solution (1 ml_), purification by preparative HPLC using a 20-60 % MeCN (aq) gradient yielded the title compound (11.1 mg, 0.04 mmol) as a black solid.

MS [M+1]⁺ 291.34; ¹H NMR & (400.13 MHz, cfe-DMSO, TMS): 14.20 (s, 1 H), 8.82 (s, 1 H), 8.65 (br s, 2H), 8.30 (d, J = 2.3 Hz, 1 H), 8.18 (br s, 1 H), 7.89 (d, J = 2.0 Hz, 1 H), 7.79 (d, J = 7.3 Hz, 2H), 7.74 (d, J = 3.5 Hz, 2H), 7.47 (t, J = 7.8 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1 H).

Example 6 : 4'-[(Dimethylamino)sulfonyl]-2-hydroxy-5-(4-pyridinyl)-3- biphenylcarboxamide

A mixture of 3-bromo-2-hydroxy-5-(4-pyridinyl)benzamide (Intermediate 12, 50 mg, 0.17 mmol), Λ/,Λ/-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (79 mg, 0.26 mmol), sodium carbonate (108 mg, 1.02 mmol) and dichloro(1 ,1'- bis(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (12 mg, 0.02 mmol) in 1 ,4-dioxane (2 mL) and water (2 mL) was heated with stirring in a microwave reactor at 150 ⁰C for 50 mins. The mixture was filtered through a silica cartridge (500 mg silica), eluting with MeOH (10 mL), and the eluant concentrated in vacuo. The resulting crude solid was dissolved in 1 :1 DMSO / methanol solution (1 mL) and purified by preparative HPLC using a 20-60 % MeCN (aq) gradient to yield the title compound (3.4 mg, 0.01 mmol) as a white solid.

MS [M+1]⁺ 398.3; ¹H NMR ^ (400.13 MHz, Of₆-DMSO, TMS): 14.59 (s, 1 H), 8.93 (s, 1 H), 8.79 (br d, J = 4.3 Hz, 2H), 8.56 (d, J = 2.0 Hz, 1 H), 8.33 (s, 1 H), 8.18-8.15 (m, 3H), 7.97 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H), 2.67 (s, 6H).

Example 7 : 6'-Hydroxy-4-(1-pyrrolidinylsulfonyl)-1,1^l:3',1"-terphenyl-5'-carboxamide

A mixture of 5-bromo-4-(methyloxy)-3-biphenylcarboxamide (Intermediate 4, 25 mg, 0.08 mmol), 6'-hydroxy-4-(1-pyrrolidinylsulfonyl)-1 ,1':3^l,1"-terphenyl-5'-carboxamide (41 mg, 0.12 mmol), sodium carbonate (52 mg, 0.49 mmol) and dichloro(1 ,1'- bis(diphenylphosphino)ferrocene)palladium(ll)-dichloromethane adduct (6 mg, 0.003 mmol) in 1 ,4-dioxane (1 ml_) and water (1 ml_) was heated with stirring in a microwave reactor at 150 ⁰C for 20 mins. MeOH (5 ml_) was added and the mixture was filtered through a silica cartridge (500 mg silica), eluting with MeOH (10 ml_), and the eluent concentrated in vacuo. Pyridine (2 ml.) and lithium iodide (55 mg) were added to the resulting solid, and the mixture was heated with stirring in a microwave reactor at 175 ⁰C for 2 h. After concentration in vacuo, water (5 ml_) was added to the resulting crude solid, and the mixture sonicated. Concentrated hydrochloric acid (37%, 0.5 ml.) was added, and the resulting solid was isolated by filtration. After dissolution in 1 :1 DMSO / methanol solution (1 ml_), purification by preparative HPLC using a 40-95 % MeCN (aq) gradient yielded the title compound (5.0 mg, 0.012 mmol).

MS [M+1]⁺ 423.32; ¹H NMR S_n (400.13 MHz, Cf₆-DMSO, TMS): 14.18 (s, 1 H), 8.82 (br s, 1 H), 8.28 (d, J = 2.0 Hz, 1 H), 8.16 (br s, 1 H), 7.93 (d, J = 8.3 Hz, 2H), 7.88-7.83 (m, 3H)₁ 7.78 (d, J = 7.3 Hz, 2H)₁ 7.47 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.3 Hz₁ 1 H), 3.22-3.17 (m, 4H)₁ 1.73-1.67 (m, 4H).

BIOLOGICAL DATA IKK2 Time-Resolved Fluorescence Resonance Energy Transfer Assay

Recombinant human IKK2 (residues 1-737) was expressed in baculovirus as a C-terminal GST-tagged fusion protein, and its activity was assessed using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Briefly, IKK2 (typically 2-5 nM final) diluted in assay buffer (50 mM HEPES, 10 mM MgCI₂, 1 mM CHAPS pH 7.4 with 1 mM DTT and 0.01 % w/v BSA) was added to wells containing various concentrations of compound or DMSO vehicle (less than 5 % final). The reaction was initiated by the addition of GST-kBα substrate (25 nM final)/ATP (1 μM final), in a total volume of 6 μl. The reaction was incubated for 30 minutes at room temperature, then terminated by the addition of stop reagent (3 μl) containing 50 mM EDTA and detection reagents in buffer (100 mM HEPES pH 7.4, 150 mM NaCI and 0.1% w/v BSA). Detection reagents comprise antiphosphoserine-lκBα-32/36 monoclonal antibody 12C2 (Cell Signalling Technology, Beverly Massachusetts, USA) labelled with W-1024 europium chelate (Wallac OY, Turku, Finland) and an allophycocyanin-labelled anti-GST antibody (Prozyme, San Leandro, California, USA). The reaction mixture (9 μl total volume) was further incubated for at least 60 minutes at room temperature. The degree of phosphorylation of GST-lκBα was measured using a suitable time-resolved fluorimeter such as Packard Discovery (Perkin- Elmer Life Sciences, Pangboume, Berkshire, UK), Wallac Viewlux (Perkin-Elmer Life Sciences, Pangbourne, Berkshire, UK) or Rubystar (BMG, Aylesbury, Buckinghamshire, UK) as a ratio of specific 665 nm energy transfer signal to reference europium 620 nm signal.

All the above Examples had an activity of pK5.0 or above in the above identified assay.

Claims

CLAIMSWe claim:

1. A compound of Formula (I):

(I) wherein:

Z is NH₂ or OH;

R¹ represents phenyl (optionally substituted by halogen, -SO₂C_1-3 alkyl, Ci_-6 alkoxy,

_!>3_|-,4

CONR R ) or pyridinyl; R³ and R⁴ are independently Ci_-3 alkyl or H;

R represents:

(a) halogen

(b) H

(c) pyridinyl

wherein p is 0 or 1 ,

X represents a bond (i.e. is absent), C_1-3 alkylene, -NH-,

R⁵ represents C_1-6 alkyl, NR⁶R⁷; R⁶ and R⁷ indepently represent H₁ Ci_-6 alkyl (optionally substituted by Ci_-6 alkoxy), C_3-7 CyClOa I kyl, C^ alkylene NR⁸R⁹; or R⁵ and R⁶ together with the nitrogen to which they are joined form a 5 or 6 membered heterocyclic ring (optionally containing a further heteroatam selected from N or O and optionally being substituted by C_1-3 alkyl);

R⁸ and R⁹ are independently H, Ci_-3 alkyl, C_1-3 alkoxy, -COC _I-3 alkyl, or R⁸ and R⁹ together with the nitrogen atom to which they are joined form a 5 or 6 membered heterocyclic ring (optionally containing a further heteroatom selected from N or O and optionally substituted by C_1-3 alkyl);

q is 0 or 1 ;

One of R¹¹ and R¹² is NHCOCi_-6 alkyl, CN, halogen; the other is H or halogen,

1

N(CH₃)₂, (g) CONH₂;

alkyl

R¹² is

-C_1-6 alkoxy;

with the proviso that when Z is OH, R² is not H or halogen;

or a salt, solvate, or physiologically functional derivative thereof.

2. A compound according to claim 1 where Z is NH₂.

3. A compound according to claims 1 or 2 wherein R¹ is phenyl (substituted in the para position by SO₂CH₃, OCH₃, CONH₃, Cl, F), phenyl or pyridyl.

4. A compound according to claim 1 - 3 wherein R² is:

(wherein X and R⁵ are as defined for formula (I) above), Br, pyridinyl,

(wherein R¹⁰ is as defined for formula (I) above).

5. A compound according to claims 1 - 4 wherein R² is:

(wherein R⁵ and X are as defined above in formula (I)).

6. A compound according to claim 5 wherein X is a bond.

7. A compound according to claims 5 - 6 wherein R⁵ is methyl or NR⁶R⁷ wherein R⁶ and R⁷ are independently H, cyclopropyl, C-ι-₃ alkyl, (CH₂)_2- 3N(CHa)₂, (CH₂J_2-3NHCOCH₃, (CHa)_2-3NH₂, (CH₂)₂N(CH₃)₂,

/ \

{CH₂)₂.₃-N b i^CH^ ₂-3— N N-CH,

or R⁵ and R⁶ together with the nitrogen to which they are joined form a pyrrolidyl, or morpholino ring,

8. A compound according to claim 1 wherein the compound is as formula 2:

(2) wherein:

R^a represents phenyl (optionally substituted by halogen, SO₂C_1-3 alkyl, OC_1-3 alkyl) or pyridinyl;

R^b represents

R^c represents C_1-6alkyl, NR^dR^e;

R^d and R^e independently represent H, C_1-6 alkyl, C_3-7 cycloalkyl, C^ alkylene NR^fR⁹; or R^d and R^e together with the nitrogen to which they are joined form a 5 or 6 membered heterocyclic ring (optionally containing a further heteroatam selected from N or O and optionally being substituted by C_1-3alkyl);

R^f and R⁹ are independently H, Ci_-3 alkyl, C_1-3 alkoxy, -COC_1-3 alkyl, or R^f and R⁹ together with the nitrogen atom to which they are joined form a 5 or 6 membered heterocyclic ring (optionally containing a further heteroatom selected from N or O and optionally substituted by C_1-3 alkyl);

9. A compound according to claim 8 wherein R^a represents phenyl (optionally substituted by fluoro, chloro, SO₂CH₃ or OCH₃) or pyridinyl.

10. A compound according to claim 9 wherein R^a represents phenyl (substituted in the para position by fluoro, chloro, SO₂CH₃ or OCH₃) phenyl or pyridinyl.

11. A compound according to claims 8 - 10 wherein R^c is CH₃, or NR^dR^e wherein R^d and R^eare independently H₁ cyclopropyl, C_1-3 alkyl, (CH₂)_2-3NH₂, (CH₂)₂.₃N(CH₃)₂, (CH₂J_2- ₃NHCOCH₃

-(CH₂)^ N P -(CH₂ 2)'2,-3, N '\ N "-CH

or R^d and R^e together with the Nitrogen to which they are joined form a pyrrolidyl or morpholino ring or a salt, solvate or physiologically functional derivative thereof

12. A compound as claimed in claim 1or 2, selected from the group consisting of:

4'-Amino-4"-(aminosulfonyl)-4-chloro-1 ,1':3',1"-terphenyl-5^l-carboxamide;

6'-Amino-4-{[(2-aminoethyl)amino]sulfonyl}-1 ,1':3^l,1"-terphenyl-5'-carboxamide;

4-({[2-(Acetylamino)ethyl]amino}sulfonyl)-6^I-amino-1 ,1':3',1"-terphenyl-5'-carboxamide;

6^l-Amino-4-({[2-(4-morpholinyl)ethyl]amino}sulfonyl)-1 ,1^l:3',1"-terphenyl-5'-carboxamide; 6'-Amino-4-({[2-(1 -pyrrolidinyl)ethyl]amino}sulfonyl)-1 , 1 ':3\ 1 "-terphenyl-δ'-carboxamide; β'-Amino^-røS-CmethyloxyJpropylJaminoJsulfonyO-i .riS'.r'-terphenyl-δ'-carboxamide;

6'-Amino-4-({[3-(4-morpholinyl)propyl]amino}sulfonyl)-1 ,1':3',1"-terphenyl-5^l-carboxamide;

6'-Amino-4-[(cyclopropylamino)sulfonyl]-1 J^3\1Meφhenyl-5'-carboxamide;

6'-Amino-4-{[(1 -methylethyl)amino]sulfonyl}-1 , 1 ':3\ 1 "-terphenyl-5'-carboxamide; 4^l-Amino-4-chloro-4"-[(dimethylamino)sulfonyl]-1 ,1':3',1"-terphenyl-5'-carboxamide;

4^l-Amino-4"-(aminosulfonyl)-4-fluoro-1 ,1':3',1"-terphenyl-5^l-carboxamide;

4'-Amino-4"-[(dimethylamino)sulfonyl]-4-fluoro-1 , 1 ':3', 1 "-terphenyl-5'-carboxamide;

2-Amino-4'-(aminosulfonyl)-5-(4-pyridinyl)-3-biphenylcarboxamide;

6'-Amino-4-({[2-(4-methyl-1 -piperazinyl)ethyl]amino}sulfonyl)-1 ,1':3',1 "-terphenyl-5¹- carboxamide;

6^I-Amino-4-[(dimethylamino)sulfonyl]-1 ,1^l:3',1"-terphenyl-5'-carboxamide;

2-Amino-4'-[(dimethylamino)sulfonyl]-5-(4-pyridinyl)-3-biphenylcarboxamide;

6^l-Amino-4-(4-morpholinylsulfonyl)-1 ,1':3',1^ll-terphenyl-5'-carboxamide;

6'-Amino-4-({[3-(dimethylamino)propyl]amino}sulfonyl)-1 ,1':3^l,1"-terphenyl-5'- carboxamide;

4^l-Amino-4-chloro-4"-(1-pyrrolidinylsulfonyl)-1 ,1':3',rⁱ-terphenyl-5'-carboxamide;

2-Amino-5-(4-pyridinyl)-4'-(1-pyrrolidinylsulfonyl)-3-biphenylcarboxamide;

4'-Amino-4-fluoro-4"-(1-pyrrolidinylsulfonyl)-1 ,1':3',1"-terphenyl-5'-carboxamide;

6^l-Amino-4-(aminosulfonyl)-1 ,1':3',1"-terphenyl-5'-carboxamide; 6'-Amino-4-({[2-(dimethylamino)ethyl]amino}sulfonyl)-1 ,1':3^I,1"-terphenyl-5'-carboxamide ;

6'-Amino-4-(1-pyrrolidinylsulfonyl)-1 ,1':3',1"-terphenyl-5'-carboxamide;

6^l-Amino-4-(methylsulfonyl)-1 ,1 ':3',1"-terphenyl-5'-carboxamide;

4-Amino-5-{1-[(4-cyanophenyl)sulfonyl]-1 ,2,3,6-tetrahydro-4-pyridinyl}-4'-fluoro-3- biphenylcarboxamide; 4-Amino-4'-fluoro-5-(1 ,2,3,6-tetrahydro-4-pyridinyl)-3-biphenylcarboxamide;

4-Amino-5-(4-pyridinyl)-3-biphenylcarboxamide; 4-Amino-4',5-dibromo-3-biphenylcarboxamide;

2-Amino-3-bromo-5-(4-pyridinyl)benzamide;

6^l-Amino-4-[(methylsulfonyl)amino]-1 ,1':3',1"-terphenyl-5^l-carboxamide;

4-Amino-5-bromo-4'-chloro-3-biphenylcarboxamide; 5-(1-{[4-(Acetylamino)phenyl]sulfonyl}-1 ,2,3,6-tetrahydro-4-pyridinyl)-4-amino-4^I-fluoro-3- biphenylcarboxamide;

2-Amino-4'-[(methylsulfonyl)amino]-5-(4-pyridinyl)-3-biphenylcarboxamide;

4-Amino-4'-fluoro-5-(4-pyridinyl)-3-biphenylcarboxamide;

4^I-Amino-4-fluoro-4"-[(methylsulfonyl)amino]-1 ,1 ^l:3',1^I'-terphenyl-5'-carboxamide;

4-Amino-5-bromo-3-biphenylcarboxamide; 4^l-Amino-4-chloro-4'^l-[(methylsulfonyl)amino]-1 ,1':3',1'^l-terphenyl-5'-carboxamide;

4^l-Amino-4"-[(aminosulfonyl)methyl]-4-fluoro-1 ,1':3',1^ll-terphenyl-5'-carboxamide;

6^l-Amino-1 ,1':3^l,1"-terphenyl-4,5^l-dicarboxamide;

6'-Amino-3-[(dimethylamino)sulfonyl]-1 ,1':3',1"-terphenyl-5'-carboxamide;

6'-Amino-4-[(aminosulfonyl)methyl]-1 ,1':3^l,1"-terphenyl-5'-carboxamide; 2-Amino-5-(4-pyridinyl)-3-biphenylcarboxamide;

4-Amino-4'-chloro-5-(4-pyridinyl)-3-biphenylcarboxamide;

2-Amino-5-(4-pyridinyl)-3,4'-biphenyldicarboxamide;

2-Amino-4'-[(aminosulfonyl)methyl]-5-(4-pyridinyl)-3-biphenylcarboxamide;

6'-Amino-4"-fluoro-1 ,1':3',1"-terphenyl-4,5^l-dicarboxamide; 6^l-Amino-Λ/⁴-[4-(rnethyloxy)-3-(4-methyl-1-piperazinyl)phenyl]-1 ,1':3',1"-terphenyl-4,5'- dicarboxamide;

4-Amino-5-bromo-4'-fluoro-3-biphenylcarboxamide;

2-Amino-5-(4-pyridinyl)benzamide;

1 ,1 -Dimethylethyl 4-[4-amino-5-(aminocarbonyl)-3-biphenylyl]-3,6-dihydro-1 (2H)- pyridinecarboxylate;

6'-Amino-3-[(methylsulfonyl)amino]-1 ,1':3',1"-terphenyl-5^l-carboxamide;

6^l-Amino-3-(aminosulfonyl)-1 ,1^I:3',1"-terphenyl-5'-carboxamide;

6'-Amino-Λ/⁴-[4-(1 H-imidazol-1 -ylmethyl)phenyl]-1 , 1 ':3\ 1 "-terphenyl-4,5'-dicarboxamide;

2-Amino-3,5-di-4-pyridinylbenzamide; 5-{1-[(1-Acetyl-4-piperidinyl)carbonyl]-1 ,2,3,6-tetrahydro-4-pyridinyl}-4-amino-4^l-fluoro-3- biphenylcarboxamide; 6^l-Amino-Λ/⁴,Λ/⁴-dimethyl-1 ,1^l:3',1"-terphenyl-4,5^l-dicarboxamide;

4-Amino-5-(1-{[4-(dimethylamino)phenyl]carbonyl}-1 ,2,3,6-tetrahydro-4-pyridinyl)-4^l-fluoro-

3-biphenylcarboxamide;

4-Amino-5-[2,6-bis(methyloxy)-3-pyridinyl]-3-biphenylcarboxamide; 1 ,1 -Dimethylethyl 4-[4-amino-5-(aminocarbonyl)-4^l-fluoro-3-biphenylyl]-3,6-dihydro-1 (2H)- pyridinecarboxylate;

6'-Amino-4"-fluoro-Λ/⁴,Λ/⁴-dimethyl-1 ,1 ':3',1 "-terphenyl-4,5'-dicarboxamide;

6^I-Amino-4-[(Λ/,Λ/-dimethylglycyl)amino]-1 ,1^l:3',1"-terphenyl-5'-carboxamide;

4-amino-3-biphenylcarboxamide; 4'-Amino-4"-[(dimethylamino)sulfonyl]-4-(methylsulfonyl)-1 ,1':3',1"-terphenyl-5'- carboxamide;

4-Amino-5-(4-pyridinyl)-3,4'-biphenyldicarboxamide;

4'-Amino-4-(methyloxy)-4"-(1-pyrrolidinylsulfonyl)-1 ,1^l:3^l,1"-terphenyl-5'-carboxamide;

2-Amino-4'-[(dimethylamino)sulfonyl]-5-(3-pyridinyl)-3-biphenylcarboxamide; 4-Amino-4'-(methylsulfonyl)-5-(4-pyridinyl)-3-biphenylcarboxamide;

4'-Amino-4-(methyloxy)-4"-(methylsulfonyl)-1 ,1':3',1"-terphenyl-5'-carboxamide;

4^l-Amino-4"-(aminosulfonyl)-4-(methyloxy)-1 ,1':3^l,1"-terphenyl-5'-carboxamide;

4'-Amino-4"-(aminosulfonyl)-4-(methylsulfonyl)-1 ,1':3',1"-terphenyl-5^l-carboxannide;

4'-Amino-4^ll-[(dimethylamino)sulfonyl]-4-(rnethyloxy)-1 ,1^I:3^I,1^ll-terphenyl-5'-carboxamide; 4'-Amino-4-(methy!sulfo.ny!)-4'^l-(1-pyrro!idinylsu!fony!)-1 ,1':3^l,1''-terpheny!-5'-carboxamide;

4-Amino-4'-(methyloxy)-5-(4-pyridinyl)-3-biphenylcarboxamide;

2-Amino-5-(3-pyridinyl)-4'-(1-pyrrolidinylsulfonyl)-3-biphenylcarboxamide;

4'-amino-4"-[(dimethylamino)sulfonyl]-1 ,1':3',1"-terphenyl-4,5'-dicarboxamide;

4^I-amino-4"-(aminosulfonyl)-1 ,1^l:3',1"-terphenyl-4,5'-dicarboxamide; 4^l-amino-4"-(methylsulfonyl)-1 ,1^l:3^I,1 "-terphenyl-4,5^l-dicarboxamide;

4-[(Dimethylamino)sulfonyl]-6'-hydroxy-1 ,r:3',1"-terphenyl-5^I-carboxamide;

6'-Hydroxy-4-[(methylsulfonyl)amino]-1 ,1^l:3',1"-terphenyl-5^I-carboxamide;

4"-(Aminosulfonyl)-4-chloro-4'-hydroxy-1 ,1^l:3',1"-terphenyl-5'-carboxamide;

4-Chloro-4"-[(dimethylamino)sulfonyl]-4'-hydroxy-1 ,1':3^l,1"-terphenyl-5'-carboxamide; 4-Hydroxy-5-(4-pyridinyl)-3-biphenylcarboxamide;

4'-[(Dimethylamino)sulfonyl]-2-hydroxy-5-(4-pyridinyl)-3-biphenylcarboxamide;

6'-Hydroxy-4-(1 -pyrrolidinylsulfonyl)-1 , 1 ':3', 1 "-terphenyl-5'-carboxamide;

or a salt, solvate, or physiologically functional derivative thereof.

13. A pharmaceutical composition, comprising a compound as claimed in any one of claims 1 - 12, or a salt, solvate, or a physiologically functional derivative thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.

14. A compound as claimed in any of claims 1 - 12, or a salt, solvate, or a physiologically functional derivative thereof for use in therapy.

15. A method of treating a disorder in a mammal, said disorder being mediated by at least one of inappropriate IKK2 activity, comprising: administering to said mammal a compound as claimed in any one of claims 1 - 12, or a salt, solvate, or a physiologically functional derivative thereof.

16. A method according to claim 15 wherein the disorder mediated by inappropriate IKK2 activity is inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease); osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin damage; autoimmune diseases including systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation associated with infection and certain viral infections, including acquired immune deficiency syndrome (AIDS), adult respiratory distress syndrome, and Ataxia Telangiestasia, comprising administering to said mammal of a compound of formula (I), or a salt, solvate or pharmaceutically functional derivative thereof.

17. Use of a compound as claimed in any of claims 1 - 12, or a salt, solvate, or a physiologically functional derivative thereof in the preparation of a medicament for use in the treatment of a disorder mediated by inappropriate IKK2 activity.

18. Use according to claim 17 wherein disorder mediated by inappropriate IKK2 activity is inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease); osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin damage; autoimmune diseases including systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restonosis, diabetes, glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation associated with infection and certain viral infections, including acquired immune deficiency syndrome (AIDS), adult respiratory distress syndrome, and Ataxia

Telangiestasia, comprising administering a therapeutically effective amount to a mammal of a compound of formula (I)₁ or a salt, solvate or pharmaceutically functional derivative thereof.

19. Use according to claim 18 or a method according to claim 14 wherein the IKK2 disorder is an inflammatory or tissue repair disorder.

20. Use or a method according to claim 19 wherein the IKK2 disorder is rheumatoid arthritis, inflammatory bowel disease, asthma and COPD.

21. Use according to claim 17 or a method according to claim 15 wherein the IKK2 disorder is selected from the group consisting of autoimmune diseases; tissue or organ rejection, Alzheimer's disease, stroke atherosclerosis, restenosis, diabetes, glomerulonephritis, osteoarthritis, osteoporosis, and Ataxia Telangiestasia.

22. Use or a method according to claim 21 wherein said disease is an autoimmune disease.

23. Use or a method according to claim 22 wherein the autoimmune disease is systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, or alkylosing spondylitis, diabetes.

24. Use according to claim 17 or a method according to claim 15 wherein the disease is cancer and or cachexia.

25. Use or a method according to claim 23 wherein the cancer is Hodgkins disease.