CA2686485A1 - Purinones and 1h-imidazopyridinones as pkc-theta inhibitors - Google Patents

Abstract

A chemical genus of purinones and 1H-imidazopyridinones, which are useful as PKC.THETA. inhibitors, and their methods of use are disclosed. The genus is represented by the formula (I). A representative example is: (II).

Description

INHIBITORS
Field of the Invention [0001] The present invention relates to a chemical genus of purinones and 1H-imidazopyridinones which are useful as PKCBinhibitors.

Backaound of the Invention [0002] Members of the protein kinase C (PKC) family of serine/threonine kinases play critical roles in the regulation of cellular differentiation and proliferation of diverse cell types. Ten mammalian members of PKC family have been identified and designated a, 13, y, 4 s, 4' q, 0, ,u, and Z. The predicted structure of PKCBdisplays the highest homology with members of the Ca2+ independent novel PKC subfamily, including PKCS, s, and q. PKCO is most highly related to PKCS.

[0003] PKCO is expressed predominantly in lymphoid tissue and skeletal muscle.
It has been shown that PKCBis essential for T-cell receptor (TCR)-mediated T-cell activation but inessential during TCR-dependent thymocyte development. PKCB, but not other PKC isoforms, translocates to the site of cell contact between antigen-specific T-cells and antigen presenting cells (APC), where it localizes with the TCR in the central core of the T-cell activation. PKC 0, but not the a, 4 or ;
isoenzymes, selectively activated a FasL promoter-reporter gene and upregulated the mRNA
or cell surface expression of endogenous FasL. On the other hand, PKCfland spromoted T-cell survival by protecting the cells from Fas-induced apoptosis, and this protective effect was mediated by promoting p90Rsk-dependent phosphorylation of BAD.
Thus, PKCO appears to play a dual regulatory role in T-cell apoptosis.

[0004] The selective expression of PKCB in T-cells and its essential role in mature T-cell activation establish that PKC@ inhibitors are useful for the treatment or prevention of disorders or diseases mediated by T lymphocytes, for example, autoimmune disease such as rheumatoid arthritis and lupus erythematosus, and inflammatory disease such as asthma and inflammatory bowel diseases.

[0005] PKC 0 is identified as a drug target for immunosuppression in transplantation and autoimmune diseases (Isakov et al. (2002) Annual Review of Immunology, 20, 761-794). PCT Publication W02004/043386 identifies PKCOas a target for treatment of transplant rejection and multiple sclerosis. PKCOalso plays a role in inflammatory bowel disease (The Journal of Pharmacology and Experimental Therapeutics (2005), 313 (3), 962-982), asthma (WO 2005062918), and lupus (Current Drug Targets: Inflammation & Allergy (2005), 4 (3), 295-298).

[0006] In addition, PKC 0 is highly expressed in gastrointestinal stromal tumors (Blay, P. et al. (2004) Clinical Cancer Research, 10, 12, Pt.1), it has been suggested that PKC 0 is a molecular target for treatment of gastrointestinal cancer (Wiedmann, M. et al. (2005) Current Cancer Drug Targets 5(3), 171). Thus, small molecule PKCO
inhibitors can be useful for treatment of gastrointestinal cancer.

[0007] Experiments conduced in PKC@knock-out mice led to the conclusion that PKCB inactivation prevented fat-induced defects in insulin signalling and glucose transport in skeletal muscle (Kim J. et al, 2004, The J. of Clinical Investigation 114 (6), 823). This data suggests that PKCO is a potential therapeutic target for the treatment of type 2 diabetes, and hence small molecule PKCBinhibitors can be useful for treating such disease.

[0008] Therefore, PKCOinhibitors are useful in treatment of T-cell mediated diseases including autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, and multiple sclerosis and inflammatory diseases such as asthma and inflammatory bowel disease. In addition, PKCBinhibitors are useful in treatment of transplant rejection, gastrointestinal cancer, and diabetes.

Summary of the Invention [0009] In one aspect the invention relates to compounds of the formula I:
H
N

>Z--O
N

Rz wherein:

Q is chosen from N and CH;

R' is chosen from nitrogen-attached heterocyclyl, substituted nitrogen-attached heterocyclyl and Rz1 R23 1 i HN- C N
R22 n R24 wherein n is an integer from 2 to 6;
RZl is chosen separately in each occurrence from -H, C1-C4 alkyl and -OH;
RZZ is chosen separately in each occurrence from -H, Cl-C4 alkyl and a bond to R24;

R23 is chosen from -H, C1-C4 alkyl and a bond to R24;
R24 is chosen from -H, C1-C4 alkyl or together with either of R22 or R23 forms a 5-7 membered nitrogen heterocycle optionally substituted with C1-C4 alkyl, and R2 is chosen from aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, hetroarylalkyl, and substituted heteroarylalkyl.

[0010] In another aspect the invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula I, or salt thereof.

[0011] In another aspect the invention relates to a method for treating T-cell mediated diseases including autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, and multiple sclerosis, inflammatory diseases such as asthma and inflammatory bowel disease, transplant rejection, gastrointestinal cancer, and diabetes. The method comprises administering a therapeutically effective amount of a compound of formula I, or salt thereof.

Detailed Description of the Imventioti [0012] In its broadest sense, the invention relates to compounds of the formula I, or salt thereof:

(I) H
Q N
R l"\ N N >==o wherein:

Q is chosen from N and CH;

Rl is chosen from nitrogen-attached heterocyclyl, substituted nitrogen-attached heterocyclyl and 1 i HN- C N
R22 n R2a wherein n is an integer from 2 to 6;

R2' is chosen separately in each occurrence from -H, Cl-C4 alkyl and -OH;
R22 is chosen separately in each occurrence from -H, Cl-C4 alkyl and a bond to Rz4;

R23 is chosen from -H, Cl-C4 alkyl and a bond to R24;
R24 is chosen from -H, C1-C4 alkyl or together with either of Rzz or Rz3 forms a 5-7 membered nitrogen heterocycle optionally substituted with C1-C4 alkyl; and R2 is chosen from aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, hetroarylalkyl, and substituted heteroarylalkyl.

I I 21 /Rzs HN- C- N
Rzz Rza [0013] In the description of R1, when Rl is n , the terminology "RZl is chosen separately in each occurrence from -H, C1-C4 alkyl and -OH,"
and "R`z is chosen separately in each occurrence from -H, C1-C4 alkyl" is intended to 1 I 21 R21 R21 fR2s HN-C-C-C N

mean that when n is 3, for example, then R1 may be R12 R22 R24 where each occurrence of R21 and each occurrence of R22 is chosen among the recited possibilities, such as:

..wt~
H 1 ` I OH I H /R2s HN-C-C-C N

[0014] H CH3 H R24 , for example.

Furthermore, in the definition of Rl, when it is said that R22 may be a bond to Rz4, .i,vv I
~ /Rz3 HN-C-C-C-N

when n is 3, for example, then R' may be Similarly, in the definition of Rl;
when it is said that R23 may be a bond to R24, then IFaNO

maybe [0015] The following structures are exemplary of compounds in which R24 together with either of RZZ or R23 forms a 5-7 membered nitrogen heterocycle:

I I 21 i 21 R ~ 23 R21 N`fv' R21 0 _ N

N~

(n is 3); R22 n Rzz n ((''H2)0.5 (C'H2)0-5 ~ / Nl [0016] In one embodiment, R' is chosen from -N~ccH2>1_5 (cH~1-5 and ~~
~tc"2>a3 wherein R9 is chosen from amino(Cl-C6)alkyl, (C1-C6)alkylamino(Cl-C6)alkyl and di [(Cl-C6)alkyl]amino(Cl-C6)alkyl.

~nrtir> r HN- C N
22 R2a [0017] In another embodiment, Rl is R n [0018] In another embodiment, R22 is chosen separately in each occurrence from -H
and Cl-C4 alkyl; and R24 together with R23 forms a 5-7 membered nitrogen heterocycle optionally substituted with Cl-C4 alkyl.

[0019] In another embodiment, R22 is chosen separately in each occurrence from -H
and Cl-C4 alkyl; R23 is chosen from -H, Cl-C4 alkyl; and Rz4 is -H or Cl-C4 alkyl.
[0020] In another embodiment, RZZ is chosen separately in each occurrence from H, Cl-C4 alkyl and a bond to Rz4; R23 is chosen from H, Cl-C4 alkyl; and R24 together with one occurrence of R22 forms a 5-7 membered nitrogen heterocycle optionally substituted with Cl-C4 alkyl.

L ~
[0021] In another embodiment, Rz is chosen from, R1Z
~ f i ~-L ~ ~-L S
(cH2)1-3 , and wherein Rlo, R", and R12 are independently chosen from -H, halogen, -OCH3, -OCF3, -CF3, Cl-C4 alkyl, and phenyl; and L is a Co-Clo alkyl.
[0022] In another embodiment, - 1-\ R11 R10 ~
R11 _ (CHz) -a /~
~j-(CH2)0-4~ V
RZ is chosen from R1Z

~ R'15 -~~ R11 O_q (CHz)Qa - ~-(CH2)p_4-C-(CH)2 (GHz)aa L_/ 1 \ R1z H~1_3 and R16 wherein Rlo, Rll, and R12 are independently chosen from -H, halogen, -OCH3, -OCF3, -CF3, and Cl-C4 alkyl; and R15 and R16 are independently chosen from -H and Cl-C4 alkyl.

[0023] In a narrower embodiment, the invention relates to compounds of the formula I, or salt thereof:

(I) H
Q N
~ I >==o R l ;
Rz wherein:

Q is chosen from N and CH;

(CH2)0.5 (C \2)0-5 ~iR
~-N\ ~ NH ~-N\
R' is chosen from (CH2)1_5 (CH211_5 tCH2>0-3 , and .nnr HN~

wherein (CH2)o_s N-R5 ~-L1-N
R4 is chosen from L-/ ~(cH2)o-3 N
~N r _ 1 ~
~-L1-N~ L ~ r , and -M-NR~Rg;
wherein R5, R6, and R9are independently chosen from -H, Cl-C4 alkyl, -OH, -OCH3, halogen, and aminoalkyl;
R7 and R8 are independently chosen from -H, Cl-C4 alkyl, and amino alkyl;
Ll is a Co-Clo alkyl optionally substituted with -OH, with a proviso that -OH cannot be bonded to a carbon atom that is also bonded to N;

M is Cz-Clo alkyl optionally substituted with -OH, with a proviso that -OH cannot be bonded to a carbon atom that is also bonded to N; and Rlo Rii ` \ , L ~ S
R2 is chosen from, R12 2 (CH2)1-3 and wherein Rlo, Rll, and R12 are independently chosen from -H, halogen, -OCH3, -OCF3, -CF3, Cl-C4 alkyl, and phenyl.
L is a Co-Clo alkyl.
[0024] In another embodiment, ? ~(C`2)0.3 /~iR6 7-{CF+z)o-4-L /N-R$ ~-(CHz)p-a-Nl~ ) R4 is chosen from S v , (CH2)O-3 , ` N ~IIN\
(CH2)p-4-N ~-(CH2)o4 ~(CH2)2-4-N
and ~-(CH2)1-4` i {CH2)Qa-N
R$

wherein R5, R6, and R9are independently chosen from -H, Cl-C4 alkyl, -OH, -OCH3, halogen, and aminoalkyl;
R7 and R8 are independently chosen from -H, Cl-C4 alkyl, and amino alkyl; and R13 and R14 are independently chosen from -H, -OH, and C1-C4 alkyl, with a proviso that -OH cannot be bonded to a carbon atom that is also bonded to N.

[0025] In another embodiment, R5, R6, R7, and Rg are independently chosen from -H and C1-C4 alkyl;

R91s -RI7 -NR7Rg;
wherein Rl7 is a Cl-C4 alkyl.
[0026] In another embodiment, R1s rR7 rr (cHz)1-z CHz CH-CH2-N~ CH2 ~NH
R4 is chosen from R8 and wherein R7 and Rg are independently chosen from -H and -CH3; and R18 is chosen from -H and -OH.

[0027] In another embodiment, R1o _1--\ R11 ~-4CH~o-4 RZ is chosen from R12 R1o (CH2)0-4 -(CeH2)0.4 j ((''H2)1-3 R1o (CH2)0-4 S -(~H2)0-4`111`_t CH2)o-4--and R16 wherein R 10, Rll, and Rl2 are independently chosen from -H, halogen, -OCH3, -OCF3, -CF3, and Cl-C4 alkyl; and Rl5 and R16 are independently chosen from -H and Cg-C4 alkyl.

[0028] In yet another embodiment, the invention relates to compounds of the formula I, or salt thereof:

(I) H
N

>==o R~' \N N

wherein:

Q is chosen from N and CH;

(CHZ)ae (C Hz)0-a R9 ~-N X NH N\
Rl is chosen from (CHz),-$ (CH2)1_$ , (cH2)0-3 and .rvu I
HN`

wherein (C`2)0.3 R6 ~-(CH2)O-4 N-R$ ~-(CKz)o-a`N\ J
R4 is chosen from C~ (CH2)0-3 N
N
~-(CHz)oa-N~ ~} ~-(CHz)o-a (CH~Z_a-N~
/ ~R$ , and -(CH2)1-4` i -(CHz)Qa'N
wherein R5, R6, and R9 are independently chosen from -H, Cl-C4 alkyl, -OH, -OCH3, halogen, and aminoalkyl;
R7 and R 8 are independently chosen from -H, Cl-C4 alkyl, and aminoalkyl; and R13 and R14 are independently chosen from -H, -OH, and Cl-C4 alkyl, with a proviso that -OH cannot be bonded to a carbon atom that is also bonded to N;

R1o _ ~ R11 R10 ~-(CHz)aa ~
~_ R11 ~ / /
-(CHz)o-4 ~~
R2 is chosen from, '1R1Z, ~-{CHZ}aq--- ~ ~
~ -(CHz)ay ~S
(CH2)1-3 and R1o R15 1~ R11 (CH2)0-4- `-(CHz)o-4~I

wherein Rlo, Rll, and R12 are independently chosen from -H, halogen, -OCH3, -OCF3, -CF3, and Cl-C4 alkyl; and R15 and R16 are independently chosen from -H and Cl-C4 alkyl.
[0029] In another embodiment, R5, R6, R7 , and Rg are independently chosen from -H and C1-C4 alkyl;
R9 is -RI7 -NR7RB;
wherein R 17 is a Ci-C4 alkyl.
[0030] In another embodiment, R1 s ~R7 (CH2)1-2 CHZ CH-CHz-N, CHz ~NH
R4 is chosen from RB and wherein R7 and Rg are independently chosen from -H and -CH3; and R18 is chosen from -H and -OH.

[0031] In another embodiment, Q is N. In yet another embodiment, Q is CH.

[0032] In one embodiment, the invention is directed to a method of treatment of a T-cell mediated disease comprising administering a therapeutically effective amount of a compound of formula I, or salt thereof. The T-cell mediated disease may be, for example, an autoimmune disease or an inflammatory disease. The autoimmune disease, may be, for example, rheumatoid arthritis or lupus erythematosus. The inflammatory disease may be, for example, asthma or inflammatory bowel disease.
[0033] In another embodiment, the invention is directed to a method of treatment of cancer, such as gastrointestinal cancer, comprising administering a therapeutically effective amount of a compound of formula I, or salt thereof.

[0034] In yet another embodiment, the invention is directed to a method of treatment of diabetes comprising administering a therapeutically effective amount of a compound of formula I, or salt thereof.

Definitions [0035] Throughout this specification the terms and sub stituents retain their definitions.

[0036] Alkyl and alkane are intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl and the like. Preferred alkyl groups are those of CZO or below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl and the like.

[0037] (Cl to Cr,) Hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof containing only hydrogen and one to n carbons. Examples include vinyl, allyl, cyclopropyl, propargyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. Saturated (Cl to Cr,)hydrocarbon is identical m meaning to (Cl to Cõ)alkyl or (Cl to Cn)alkane as used herein. Whenever reference is made to Co-a alkyl, (Co to Cr,)alkyl, or (Co to Cr,)alkane when number of carbon atoms is 0, a direct bond is implied.

[0038] Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons.

[0039] Fluoroalkyl refers to alkyl residues in which one or more hydrogens have been replaced by fluorine. It includes perfluoroalkyl, in which all the hydrogens have been replaced by fluorine. Examples include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl and pentafluoroethyl.

[0040] Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like. The term oxaalkyl is intended as it is understood in the art [see Nammg and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 196, but without the restriction of 127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups. Similarly, thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons has been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.

[0041] Acyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue maybe replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to four carbons.

[0042] Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from 0, N, or S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from 0, N, or S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from 0, N, or S. As commonly understood, when referring to aryl as a substituent, it is intended that the point of attachment is a ring carbon of the aryl group (or ring carbon or heteroatom of the heteroaryl). For the purpose of the present invention, aryl and heteroaryl refer to systems in which at least one ring, but not necessarily all rings, are fully aromatic. Thus aromatic 6-to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, benzocycloheptane and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, isoindoline, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, tetrahydrocarboline, pyrimidine, pyrazine, tetrazole and pyrazole.

[0043] Arylalkyl means an alkyl residue attached to an aryl ring. As commonly understood, when referring to arylalkyl as a sub stituent, it is intended that the point of attachment is the alkyl group. Examples of arylalkyl are benzyl, phenethyl, phenylpropyl and naphthylethyl. Heteroarylalkyl means an alkyl residue attached to a heteroaryl rmg. Examples include, e.g., pyridinylmethyl, pyrirnidinylethyl and the like.

[0044] Heterocycle means a cycloalkyl or aryl residue in which from one to three carbons is replaced by a heteroatom selected from the group consisting of N, 0 and S.
The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Heterocycles also include spiroheterocycles. It is to be noted that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic. Examples of heterocyclyl residues additionally include piperazmyl, 4-piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, oxadiazolyl, triazolyl and tetrahydr o qu ino 1 inyl.

[0045] Whenever reference is made to nitrogen attached heterocycle or nitrogen heterocycle, such heterocycle contains at least one nitrogen, but may also contain additional nitrogen atom(s) and/or other heteroatoms such as 0 and/or S.

[0046] Aminoalkyl means an amino group bound to a core structure via an alkyl group, e.g., aminomethyl, aminoethyl, aminopenthyl, etc. The alkyl group, as defmed above, could be straight or branched and, therefore, an aminoalkyl includes, e.g., -CH2CH2CH(CH3)CH2NH2, -CHZC(CH3)ZCHZNHZ, etc. Alkylaminoalkyl means a secondary amine bound to a core structure via an alkyl group, e.g., -CH2CH2NHCH3, -CH2CH2CH2NHCH2CH3, etc. Dialkylaminoalkyl means a tertiary amine bound to a core structure via an alkyl group, e.g., -CH2N(CH3)2, -CH2CH2CH2N(CH3)CH2CH3, etc.

[0047] Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with loweralkyl, halogen, haloalkyl, hydroxy, hydroxymethyl, loweralkoxy, perfluoroloweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), sulfonamido, aminosulfonyl, alkylaminosulfonyl, cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, ureido, alkylureido, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.

[0048] The term "halogen" means fluorine, chlorine, bromine or ioduie.

[0049] As used herein, reference to "treatment" or "treating" a patient are intended to include prophylaxis. The terms include amelioration, prevention and relief from the symptoms and/or effects associated with these disorders. The terms "preventing" or "prevention" refer to administering a medicament beforehand to forestall or obtund an attack. Persons of ordinary skill in the medical art (to which the present method claims are directed) recognize that the term "prevent" is not an absolute term. In the medical art it is understood to refer to the prophylactic administration of a drug to diminish the likelihood or seriousness of a condition, and this is the sense intended.

Abbreviations [0050] The following abbreviations and terms have the indicated meanings throughout:

Ac = acetyl anh. = anhydrous BNB = 4-bromomethyl-3-nitrobenzoic acid Boc = t-butyloxy carbonyl Bu = butyl CBZ = carbobenzoxy = benzyloxycarbonyl CDI = carbonyl diimidazole DBU = diazabicyclo[5.4.0]undec-7-ene DCM = dichloromethane = methylene chloride = CH2C12 DEAD = diethyl azodicarboxylate DIC = diisopropylcarbodiimide DIEA = N,N-diisopropylethyl amine DMAP = 4-N,N-dimethylaminopyridine DMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide DVB = 1,4-divinylbenzene EEDQ = 2-ethoxy- 1-ethoxycarbonyl- 1,2-dihydroquino line Et = ethyl FCC = flash column chromography Fmoc = 9-fluorenylmethoxycarbonyl GC = gas chromatography HATU = O-(7-Azabenzotriazol-l-yl)-1,1,3,3-tetramethyluronium hexafluoropho sphate HOAc = acetic acid HOBt = hydroxybenzotriazole Me = methyl mesyl = methanesulfonyl MTBE = methyl t-butyl ether NMO = N-methylmorpholine oxide PEG = polyethylene glycol Ph or K = phenyl PhOH = phenol PfP = pentafluorophenol PPTS = pyridinium p-toluenesulfonate PyBroP = bromo-tris-pyrrolidino-phosphonium hexafluorophosphate rt = room temperature sat'd = saturated TBDMS = t-butyldimethylsilyl TFA = trifluoroacetic acid THF = tetrahydrofuran TIPSO = triisopropylsilanyloxy TMOF = trimethyl orthoformate TMS = trimethylsilyl to syl = p-toluenesulfonyl Trt = triphenylmethyl [0051] Although this invention is susceptible to embodiment in many different forms, preferred embodiments of the invention are shown. It should be understood, however, that the present disclosure is to be considered as an exemplification of the principles of this invention and is not intended to limit the invention to the embodiments illustrated.

[0052] It may be found upon examination that certain members of the claimed genus are not patentable to the inventors in this application. In this event, subsequent exclusions of species from the compass of applicants' claims are to be considered artifacts of patent prosecution and not reflective of the inventors' concept or description of their invention; the invention encompasses all of the members of the genus (I) that are not already in the possession of the public.

[0053] In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
General synthesis of purmones [0054] One method for preparing purinone analogs of the invention is shown in Scheme 1. Displacement of the two chlorides in 2,4-dichloro-5-nitropyrimidine usually occurs in a regioselective manner. Thus, the more reactive chloride in the 4-position is first displaced by an amine R'NH2 to yield compound 2. Addition of a second amine R"NH2 displaces the chloride in the 2-position. Reduction of the nitro group m 3 to an amine using reagents well known in the art (e.g. Raney Ni/ H2, Fe/EtOH/aqAcOH, Na2S2O4/NH4OH/H2O/Dioxane), followed by cyclization using, for example, carbonyl-diimidazole gives purinone 5.

Scheme 1. Synthesis of purinone analogs.
R' ` R"
CI i 'NCI NH2 R~.NN ~ CI NH2 RõN` N NR
N ~ ~ ~
C2N C2N . N 02N . N

reduction O~N I NYN R cyclization R'.N.~N,.N=R~~
HN H2N 1~1 =N

[0055] The purinone analogs of the invention may be prepared on solid support (Scheme 2). For example, an acid cleavable linker can be attached to the Argogel-NHZ resin. The resm with the linker is first reductive aminated with a R'NH2.
The pyrimidine 2a, which is similarly prepared from the first step in Scheme 1, is then attached to the resin bound amine by a nucleophilic displacement reaction.
Reduction of the nitro group, followed by ring closure with 4-nitrophenyl chloroformate, yields the purinone. The product can then be released from the solid support by treatment with acid such as trifloroacetic acid.

Scheme 2. Solid phase synthesis of purinone analogs.

R"
HN
N NOZ
O
i~ 0 OMe reductive CN
~N 3 ~ + R~~ ~L-NH
H I/ 0 2 amination R' 2a H
L

R~~ HN,R" 1. 0 ~
HN reduction C1O
N NOZ N~NHZ
~~ J~ I 2. base L-N N ~J-L-N N
R' R ` R \
NH cleavage N~NH
N I
. ~ ~
%rif-L-NN HN N
R' Rl General synthesis of 1H-imidazopyridinones [0056] 1H-imidazopyridinone analogs of the invention can be prepared by the method shown in Scheme 3. Sequential displacement of the chlorides of 2,6-dichloro-3-nitropyridine 6 yields compound S. Reduction of nitro group by reagents well known in the art, followed by cyclization using, for example, triphosgene affords the 1H-imidazopyridinones 10.

Scheme 3. Synthesis of 1H-imidazopyridinone analogs.

R' CI N CI RNHZY R".HN I N~ CI R`NH~ HN I N` N.Rõ
02N A / 02N ~ pZN

reduction R'~ N N~ NRõ 4clization HN N N.Rõ
~ ~
C~N J

[0057] Following are exemplary procedures for preparation of some of the compounds of the invention.

Synthesis of 9-(2 6-dichlorobenzy1)-2-(3-aminopropylamino --purin-8 9H -one (Compound 120) [0058] One possible process for 9-(2,6-dichlorobenzyl)-2-(3-aminopropylamino)-purin-8(9H)-one (Compound 120) is demonstrated in Scheme 4 below and detailed in the following description.

Scheme 4.
cl NHZ N N HzNNHBoc NNHBoc ?:c1 a O NDIE zN DMSO, RT CI N
z 75 min. 02N) õ78 dC, 1h 11 12 ~ CI
~ cl 1 ~
Raney Ni, MeOH ~H H CD I, THF H
1 atm H N N N~rNHBoc CI N:! N` N~~NHBoc -~ 1 RT, 30 min. p~ N
1:2h CI H2N N H

HCI 1 EtOH H
~I
CI N NYN~,NH2 4=(N II N
H~

9-(2,6-dichlorobenzyl)-2-(3 aminopropyl amino)-7l-F purin-8(9l-)-one N-(2, 6-dichlorobenzyl)-2-chloro-5-nitropyrimidin-4-amine (11) [0059] A 500 mL round-bottom flask under argon atmosphere was charged with 2,4-dichloro-5-nitropyrimidine [5.0 g, 25.8 mmol] and dissolved in THF [30 mL, anh.].
The resulting solution was cooled to -78 C. A THF [25 mL, anh.] solution of 2,6-Dichlorobenzylamine [4.54 g, 25.8 mmol] and NN-Diisopropylethylamine [9.9 mL, 56.7 mmol] was added dropwise over 20 minutes. The resulting off-white suspension was stirred at -78 C for 50 minutes and the cooling bath was then removed.
The mixture warmed slowly over 30 minutes before removal of the volatiles in vacuo. The crude yellow-orange solid was dissolved in minimal MeOH and DCM and applied to a slurry of silica gel. Elution with a gradient of MeOH (0 - 2 %) in DCM gave a first fraction [4.116 g] comprising the title compound 11 and its regiosiomer (N-(2,6-dichlorobenzyl)-4-chloro-5-nitropyrimidin-2-amine) in a ratio of 3:7 by HPLC, followed by a second fraction [4.38 g] containing pure 11 only.

[0060] Data for N-(2,6-dichlorobenzyl)-2-chloro-5-nitropyrimidin-4-amine (11):

'H NMR (300 MHz, CDC13): 6 9.08 (s, 1H), 8.67 (br s, 1H), 7.38 (d, 2H), 7.26 (t, 1H), 5.13 (d, 2H); MS (ESI) m/z 333.0/335.0 [M+H]+; 224.3 nm, 257.3 nm, 285-340 nm tail.

[0061] Data for N-(2,6-dichlorobenzyl)-4-chloro-5-nitropyrimidin-2-amine (regioisomer): k. = 219.6 nm, 319.0 nm.

tert-Butyl-3- (4-(2, 6-d ichlorobenzylamino)-5-nitropyrimid in-2-ylamino)propylcarbamate (12) [0062] A 100 mL round-bottom flask under argon atmosphere was charged with 12 [700 mg, 2.08 mmol] and DMSO [8 mL, anh.] at RT. A DMSO [5 mL, anh.] solution of N-(3-Aminopropyl)carbamic acid tert-butyl ester [362 mg, 2.08 mmol] and NN-Diisopropylethylamine [543 L, 3.12 mmol] was added dropwise over 3 minutes.
The mixture stirred for 1 h and the volatiles were then removed in vacuo. The residue was taken up in Ethyl acetate [30 mL] and washed with sat. aq. NaC1 [5 X 20 mL] to give crude 12 [quantitative yield] which was used in the subsequent reduction step without further manipulation.

tert-Butyl-3- (4-(2, 6-d ichlorobenzylamino)-5-aminopyrimidin-2-ylamino)propylcarbamate (13) [0063] A 250 mL round-bottom flask equipped with a two-way stopcock was charged with 12 [980 mg, 2.08 mmol] and MeOH [25 mL] at RT. A suspension of Raney 2800 Nickel in water [ca. 2-3 mL] was added. Under vigorous stirring, the flask was evacuated and subsequently filled with H2 [1 atm, balloon]. Affter 2.5 h, the HZ was removed and the suspension filtered over fluted paper with MeOH washes. The aqueous methanolic filtrate was concentrated by rotoevaporation to a residue and dried diligently in vacuo to give crude 13 [1.38 g, 100 % + yield] as a tan foam/oil, used in the subsequent acylation/cyclization step without further manipulation.

tert-Butyl-3- (9-(2, 6-d ichlorobenzyl)-8-oxo-8, 9-d ihydro- 7H-purin-2-ylamino)propylcarbamate (14) [0064] A 250 mL round-bottom flask under argon was charged with 13 [730 mg corrected, 1.66 mmol corrected] and THF [18 mL, anh] at RT: Solid 1,1'-Carbonyldiimidazole [806 mg, 4.97 mmol] was added to the tan solution. After min., the resulting orange suspension was concentrated in vacuo to a crude orange oil/solid from which 14 [302 mg] was isolated by flash chromatography using a gradient of MeOH [0 - 7 %] in DCM.

9-(2,6-dichlorobenzyl)-2-(3-aminopropylamino)-7H-purin-8(9H)-one (120) [0065] A 250 mL round-bottom flask was charged with 14 [207 mg, 443 mol] and HC1 / Ethanol [14.5 % wt./wt. solution, 10 mL]. The white suspension stirred at RT
overnight and was then concentrated by rotoevaporation to near-dryness. The contents were then repeatedly co-evaporated with Methanol to give an off-white solid from which pure 120 was isolated by flash chromatography as the free-base [113 mg, 69 %
yield] using a gradient of Methanol [2-20 %] in DCM with 0.5 - 3 % aqueous NH3.
Treatment of the free-base [75 mg] with HC1 / Ethanol [14.5 % wt./wt.
solution, 5 mL] for 1 hour, followed by concentration in vacuo gave pure 120 as the HC1 salt [82 mg].

[0066] Data for 9-(2, 6-dichlorobenzyl)-2-(3-aminopropylamino)-7H purin-8(9H)-one (120): 'H NMR (300 MHz, CD3OD): 6 7.85 (s, 1H), 7.59-7.52 (m, 2 H), 7.45 (dd, H), 5.45 (s, 2H), 3.52 (t, 2H), 3.04 (Br t, 2H), 1.92 (quint., 2H); MS (ESI) m1z 367.0/369.0 [M+H]+

Synthesis of (S)-3-(2,6-dichlorobenzyl)-5-(p3rrolidin-3-ylmethylamino)-1H-imidazo[4,5-b]p31idin-2(3H)-one (Compound 147) [0067] One possible process for (R)-3-(2,6-dichlorobenzyl)-5-(pyrrolidin-3-ylmethylamino)-1H-imidazo[4,5-b]pyridin-2(3H)-one (147) is demonstrated in Scheme 5 below and detailed in the following description.

Scheme 5.
cl CI 1 ~
CI
o/N-CI N CI CI NHZ C~ HN HZN,.:CN Boc NBoc ~~, K2C03/MeCN CI CI HN Nti N:~
~N OC 02N
K2C03/MeCN reflex ~N ~ ~

CI
1) H2/Ni ~ H
Cl N N N"==CN Boc TFA
H
2) triphosgene 0~ ~` C~~N I N~ N~,,,=CN H
N N i H H

N-(2, 6-Dichlorobenzyl)-6-chloro-3-nitropyridin-2-amine (16) [0068] To a mixture of 2, 6-dichloro-3-nitropyridine (1.0 g, 5.18 mmol) and potassium carbonate (848 mg, 6.14 mmol) in 15 mL MeCN was added 2,6-dichlorobenzylamine (0.63 mL, 5.18 mmol) at 0 C. The reaction mixture was stirred for one hour at 0 C and then for 10 hours at room temperature. The organic solvent was evaporated and the residue was purified by silica gel chromatography (EtOAc :
Hex = 1: 10) giving 16 [511 mg].

[0069] Data for N-(2, 6-Dichlorobenzyl)-6-chloro-3-nitropyridin-2-amine (16):
MS
(ESI) m/z 331 / 333 [M+H]+.

(S)-tert-Butyl 3-((6- (2, 6-d ichlorobenzylamino) -5-nitropyrid in -2-ylamino) methyl)pyrrolid ine-l-carboxylate (17) [0070] A mixture of 16 (100 mg, 0.34 mmol), (S)-tert-Butyl-3-(aminomethyl)pyrrolidine-1-carboxylate (0.4 g, 2.0 mmol), potassium carbonate (56.4 mg, 0.41 mmol) in 10 mL MeCN was stirred at reflux for 2 hours. The solvent was removed by vacuum and the residue was purified by silica gel chromatography (MeOH = DCM = 1-. 10) giving 17 [46 mg, 27 % yield].

[0071] Data for (S)-tert-butyl3-((6-(2,6-dichlorobenzylamino)-5-nitropyridin-2-ylamino)methyl)pyrrolidine-l-carboxylate (17): MS (ESI) m/z 495 / 497 [M+H]+.
(S) -tert-Butyl 3- ((3- (2, 6-d ichlorobenzyl) -2-oxo-2, 3-d ihydro-1H-imidazo[4,5-b]pyridin-5-ylamino)methyl)pyrrolidine-l-carboxylate (18) [0072] Under an argon atmosphere, a suspension of Raney 2800 Nickel in water [3 mL] was carefully rinsed with THF (anh., 8 X sip-and-spit) to remove the bulk of the H20. THF [5 mL, anh.] was added to this washed Raney Nickel, followed by intermediate 6 (15 mg, 0.03 mmol). The flask was filled with H2 [1 atm, balloon] and the suspension was stirred vigorously for 4 hours. A THF [2 mL, anh.] solution of tripho sgene [3.8 mg] was then added to the crude aniline-containing reaction mixture.
After I h, the solvent was removed in vacuo and the crude residue was applied to a preparative TLC plate (MeOH :DCM =1:10) from which pure 18 was isolated [8.9 mg, 60 % yield over 2 steps].

[0073] Data for (S)-tert-butyl3-((3-(2,6-dichlorobenzyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-ylamino)methyl)pyrrolidine-l-carboxylate (18): MS
(ESI) m/z 491 / 493 [M+H]+.

(R)-3- (2, 6-Dichlorobenzyl)-5- (pyrrolidin-3-ylmethylamino)-1 H- imidazo[4, 5-b]pyridin-2(3H)-one (147) [0074] Intermediate 18 [8.9 mg, 18 mol] was treated with TFA-DCM [1::1, 3 mL]
for 2 hours at RT. The solvent was removed in vacuo and the residue applied to a preparative RP-HPLC column from which pure 147 [6.3 mg, 69 % yield] was isolated as the TFA salt.

[0075] Data for (R)-3-(2,6-dichlorobenzyl)-S-(pyrrolidin-3-ylmethylamino)-IH-imidazo[4,S-b]pyridin-2(3H)-one (147): 'H NMR (300 MHz, CD3OD): S 7.62 (d, 2H), 7.50 (dd, 1H), 7.28 (d, 1H), 6.35 (d, 1H), 5.53 (s, 2H), 3.35 - 3.55 (m, 9H), 3.15 (m, 1H), 2.75 (m, IH), 2.33 (m, IH), 1.90 (m, 1H); MS (ESI) m/z 392.0/394.0 [M+H]+.

Solid phase synthesis of purinone analog_s [0076] One possible process for solid phase synthesis of purinone analogs of the invention is demonstrated in Scheme 6 below and detailed in the following description.

Scheme 6.

~.Rz N~ NOz O ~
~H~,O I~ OMe Na(OAc)3BH L NH C1~N

/ O+ R DCE, 25 C R~
EtN(i-Pr)2, DMF, 25 C

4, J
L
19 1. O NOZ
Z z A
HN' NaZS204,NH4oH, HN'R c1 0 ~ NOz ~ NHZ DIEA, DCM, 25 C
~ dioxane/H2O, 25 C lj I
JO 2. KOH, ~L-N N a-L-N N H20/DMSO
R~ Rl R?N-~( R?N~O
~ TFA/ CH2C12 NH
N' I N
~LNN HNN
R1 R' Step 1: reductive amination with a primary amine [0077] To a 100 mL shaking vessel containing a suspension of 3.8 g(-0.8 mmoUg, 3.0 mmol, 1.0 eq.) of resin-bound o-methoxybenzaldehyde 19 in 30 mL of 1,2-dichloroethane (DCE) was added 24 mmol (0.40 M, 8.0 eq.) of an amine (see Table 1 for the 43 amines used in the library). The resin suspension was shaken for 15 sec and 5.1 g (24 mmol, 0.40 M, 8.0 eq.) of sodium triacetoxyborohydride was added followed by 30 mL of 1,2-dichloroethane. The suspension was shaken for 16 h at C. The shaking vessel was then drained, and the resin was washed with CH3OH
(1X), CH2C12 (2X), CH3OH (1X), CH2C12 (2X), CH3OH (1X), CH3OH (1X30 min) and CH2C12 (2X). The resulting resin-bound secondary amine 20 gave a positive result with the bromophenol blue staining test. The resin was dried in vacuo.

Step 2: N-arylation with 4-amino-2-chloro-5-nitrop3rimidine [0078] To 5.3 g(-0.7 mmollg, 3.7 mmol, 1.0 eq.) of resin-bound secondary amine in 25 mL of DMF and 2.18 mL of N,N-diisopropylethylamine (12.5 mmol, 0.25 M, 3.4 eq.) in a 100 mL shaking vessel was added a solution of 12.5 mmol (0.25 M, 3.4 eq.) of an 4-amino-2-chloro-5-nitropyrimidine in 25 mL of DMF. The mixture was shaken at 25 C for 16 h. The shaking vessel was drained and the resin was washed with DMF (2X), CH2C12 (1X), DMF (1X), CHZC12 (2X), CH3OH (2X) and CH2C12 (2X). The resulting resin-bound nitropyrimidine 21 gave a negative result with the bromophenol blue staining test. The resin was dried in vacuo.

Step 3: reduction of the nitro group [0079] To a solution of 5.22 g(30.0 mmol, 0.5 M, 45 eq.) of sodium hydrosulfite in 40 mL of H20 was added 20 mL of 1,4-dioxane followed by 1.86 mL of a saturated aqueous solution of ammonia. This solution was added to a medium shaking vessel containing 1.;1 g(-0.6 mmol/g, 0.66 mmol, 1.0 eq.) of the resin-bound 5-nitropyrimidine 21. The resin suspension was shaken for 2 h at 25 C. The shaking vessel was drained and the resin was washed with H20:1,4-dioxane 2:1 (v/v) (1X).
The shaking vessel was recharged with 60 mL of a freshly prepared 0.5 M
solution of sodium hydrosulfite in 40 mL of H20 and 20 mL of 1,4-dioxane and 0.93 mL of a saturated aqueous solution of ammonia that was prepared as described above.
The resin suspension was shaken for 16 h at 25 C. The shaking vessel was drained and the resin was washed with H20:1,4-dioxane 2:1 (v/v) (2X), anhydrous CH3OH
(2X), anhydrous DMF (2X), CH2C12 (2X) and anhydrous THF (2X). The resulting resin-bound 5-aminopyrimidine 22 gave a positive result with the bromophenol blue staining test. The resin was dried in vacuo.

Step 4: formation of purinone ring [0080] To a suspension of 1.54 g(-0.6 mmoUg, 0.93 mmol, 1.0 eq.) of the resin-bound 5-aminopyrimidine 22 in 30 mL of CHZC12 and 5.23 mL (30 mmol, 0.5 M, 32.2 eq.) of N,N-diisopropylethylamine in a medium shaking vessel was added a solution of 6.0 g (30 mmol, 0.5 M, 32.2 eq.) of p-nitrophenylchloroformate in 30 mL of CHZC12. The resulting resin suspension was shaken for 18 h at 25 oC. The shaking vessel was then drained and the resin was washed with CH2C12 (2X), CH3OH (2X), CHZC12 (2X), CH3OH (2X) and CHZC12 (2X). The resulting resin gave a negative result with the bromophenol blue staining test and was used without drying. To this resin was added 60 mL of a solution of 1.68 g (30 mmol, 0.5 M, 32.2 eq.) of KOH in 15 mL of H20 and 45 mL of DMSO. The resulting resin suspension was shaken for 18 h. The shaking vessel was then drained and the resin washed with HZO:DMSO
1:3 (v/v), CH3OH (2X), DMF (2X), CH3OH (2X) and CHZC12 (2X). The resulting resin-bound purinone 23 was dried in vacuo.

Step 5:: cleavage from resin [0081] To the resin-bound purinone 23 (0.5 g) was added 10 mL of a 1::1 mixture of CHZC12/TFA (v/v). To mixture was stirred for 1 h at 25 C. The resin was removed by filtration and filtrate was evaporated to afford 24, which was purified by either flash chromatography or semi-preparative HPLC.

PKC-theta IMAP Assay [0082] The activity of the compounds described in the present invention may be determined by the following procedure. This procedure describes a kinase assay that measures the phosphorylation of a fluorescently-labeled peptide by full-length human recombinant active PKCO via fluorescent polarization using commercially available IMAP reagents.

[0083] The PKCO used was made from full-length, human eDNA (accession number LO 1087) with an encoded His-6 sequence at the C-terminus. PKCO was expressed using the baculovirus expression system. The protein was purified with Ni-NTA affinity chromatography yielding a protein with 91%purity.

[0084] The substrate for this assay is a fluorescently-labeled peptide having the sequence LHQRRGSIKQAKVHHVK (FITC)-NH2. The stock solution of the peptide is 2 mM in water.

[0085] The IMAP reagents come from the IMAP Assay Bulk Kit, product #R8063 or #R8125 (Molecular Devices, Sunnyvale, CA). The kit materials include a 5X
IMAP Binding Buffer and the IMAP Binding Reagent. The Binding Solution is prepared as a 1:400 dilution of IMAP Binding Reagent into the 1X IMAP Binding Buffer.

[0086] The substrate/ATP buffer for this assay consists of 20 mM HEPES, pH 7.4 with 5 mM MgC12, and 0.01% Tween-20. Additionally, the buffer contains 100 nM
substrate, 20 .M ATP, and 2 mM DTT which are added fresh just prior to use.
The kinase buffer containing the PKCO consists of 20 mM HEPES, pH 7.4 with 0.01%
Tween-20. This buffer also contains.2 ng/ L PKCO and 2 mM DTT which are added fresh just prior to use.

[0087] The plates used are Corning 3710 (Corning Incorporated, Corning, NY).
These are non-treated black polystyrene, 384-well with flat-bottoms. The serial dilutions are performed Nunc V-bottom 96-well plates (Cat#442587, Nune A/S, Roskilde, Denmark).

[0088] The assay procedure starts the preparation of stock solutions of compounds at 10 mM in 100% DMSO. The stock solutions and the control compound are serially diluted 1:3.16 a total of 11 times into DMSO (37 L of compound into 80 L of DMSO). After the serial dilution has been completed, a further dilution is performed by taking 4 L compound and adding to 196 L substrate/ATP Buffer. Then, 10 L
aliquots of the compounds are transferred to the Costar 3710 plate. The kinase reaction is initiated by the addition of 10 L PKCO. This reaction is allowed to incubate for 1 hour at ambient temperature. The reaction is then quenched by the addition of 60 L of Binding Solution. The plate is incubated for an additiona130 minutes at ambient temperature. The assay is measured using an AcquestTm Ultra-HTS Assay Detection System (Molecular Devices) in fluorescence polarization mode using 485 nm excitation and 530 nm emission.

[0089] Table 1 illustrates several examples of the compounds of the invention.
These compounds were synthesized using one of the suitable procedures described above.
The molecular weight of the compounds was confirmed by mass spectroscopy (m/z).
The compounds of Table 1 were tested using the above-described PKCO IMAP
assay.
[0090] All compounds in Table 1 below exhibited PKCO IMAP assay IC50 values equal or less than 10 M. Entries in the 100 series exhibited IC50 values less than 100 nM; entries in the 200 series exhibited IC50 values less than 1 pM; and entries in the 300 series exhibited IC50 values equal or less than 10 M.

Table 1 H
N
N
>==o N N
HNN N
~
f N
o~>>\
HN HN
~CH / 1 ci \_j //'__C CH""d\
F %_j F CI
F

F H
N
HN rI F N ~CH - I ~O HN N

N
F
HN
N
' N /'--CH
_ J
N HN\\
~f N CI
H

H F
N HN

>==o F F
N
N F
HN N
HN
N
JjY~ N
HN N

Br N
H

H
N
H
N CH
N H
I I >==() N
N
H N ~N N
N
CI

HN CI N NH
' 1 \

F
CI C

H H
N N N N
HNN N HN~N N >==o CI
HN HN F NC? F

CI
F

F F
HN HN
\ICH F F F
F F
HNff HN F
N
N
N
N\ N
O

H H

H
N
N

N
HN N O

HN N N
HN
O
-\- F HN
F CI
F

H
N

N HNYN

N
N NH
I ` N
N

NH
CI CI
CI
CI O

N HN N
N ~
`I \ N ~
Hi N
Nw\(\\\
H N N NH
/\ "~~\
/ CH F
\, f ~r ci F
F ci HzN

HN N

II H
N
NH
N N
N H NNN
O F
F
HN
cl F

H
HNY ` 'N\ N>==

N N N O
NH HN
N~ CI
o ~CH
Ci H N
Ci ~

CI

N~ N
N H

~ 1 >==o N
\~ N
HN N
J ~ CI ~

~CH F NH
HN_ / 1 ~ N
\_f F 0 F F

H
N
N )~N
HN
a //'--CH
HN~
H
N ~N~/ NH2 F
o~ X~ F
N
H F

HN N
N HN N
Y
~
NH NI
N- ~ NH

N
O
F
CI
Br ' ~
F

H HNYN
~~\
/\\ N CN NH
H~ ~

O
F
~CH / 1 HN\_j CI F

H
HN N

II \ CH H
N \41!N
NH \
NII
O I
F F
NH
F ~ 1 ~ N
CI

H2N HzN

HNYN HN /N
~
N N
NH NH
N~

O
O
F
F
F

F F
CI

H HN N
N N

N NH
H N N /

O
HN , F F
1 p / 1 F F

HNYN
N
NH

F
H
F O NI ~F ~N H

H
N ~O y HN~\ //N
aN~ N
H N N
NH
Ci N~
HN/\CH' o ~ ' 1 F o /
CI
F F

H
f I N
N H
N
N
N
H N N
N
HN N
CI
HN~\CH

1 ~
CI Br H F
N N O HN
~CH F F
HN N
F
HN
HNH F N N
1 ' F N ' O
N
F H

H
N
N >==o HN N

`A~ NH
HN~CH' F H
N N N
F ~ I N
~
N ~
F H

NH

H
N
CI

NH N
HN N
N-~1\\ CI

CH
N N H N //'--// ~NH CI
0~

HZ N

HN
N

NH
HN N N
CI
N
//-`CH CI O
H N\_j CI

CI

HN
~N
N H
NH N N
N >==o -~\o HN N N
F

H N Br F ~~

F

HN F
ci F
HN F N~
\Y~ 'N
' N N N N
N 0 ~ ~ >==o N ~ N
H H

H
N
0 ci I I ~

HN~N N

c l NH
N ~ N H
HN o ~ N

HN

ci c -N
HN
H
N~N N CI N~ \~N
N >==o o~ N
\ H H

HN
yN
N
NH
F
O
C(--~ H F
N~N` ~ ~NH2 !
~ v \f o==< N, F

H F

N
HN` fli H N
N
N NH
O
N
N

HN CI F
F

N

H
N
NH

~N N
N
N/ ~
~
F N
CI NH
NH

/ O

\ Ci 0 b--\ NH
H H
N
N NH2 :]C

N I yN ~ N N N H H

~NH
C
HN N N
C",OCH
NH
C i I N ::c ~ N O~ H N NH2 H

NH
F
CH~
F

N H F N NH

N N N
zz~- NH
---~
O O
H

OH

HN
Y N
N
NH
N -~ cF, C N
H
N N`
O YI -./ ~/

H N

\N

NH HN y N
\\~I
N N

_ N
CI N
Xr NH

CI
O

N

HN N
H ~
N ` N N /

0==< NH
N
H

NH O CI

d(cl Ns N N N
N~, N N
>==O
/ ~
N ~ N
H H

HN
II N
N
NH
ci ~
I
H \
N N N
{.~ 1 HzN ~~ >~ O

N

N

HN
II N
N
NH
N ' NH
C CH
-~ p NNNH
Ci 0 ~ I

H

HNyN
~
N
NH
/ N
O \~\\
N O

N~ N It HN ~ 1 II >==~ F
N
H
F F

HN N

CI N
NH

H F

N \% N F
H

HyN
HN
~N
\
N
NH
cx:? ~NH CH/
~ /
N NH

J Y CI ====<< O I I
H

OH

HN

II N
N
NH
N NH
0 ~ 1+
~ N\` NH
F a ( H ~N

NH

N N HN

N
NH
CI yNH N

O

CI ~ ~
F ~`

N
N

H
N N N H N N IN

a===< CB
( ~ N

H
OH
H

I ~
HN\ /N
)~N `I i HN ~~
N
N NH

N~
CH
O
H
~--~

H \

N

HN N~

II HNN
N I
NH N f NH
N
N
F CI

I
fN

HN`\I 'N
Tf I

ci N
NH
1 / N-~

H

:I[ ~ NHz F

H f N ~

HN
YN

N
NH
,NN, I N

O
N N~NHZ

0-1 ~ CI
f IN
N

N

HN` 'N
\I/ F
N
NH
NH
N-~ N I CI H

/
HIV

HzN

HN N
II
N
NH
~O
CI N ~C)H NH

N N NH
I U H

HZN

HN
II N
N
NH
N ci N N
0-< JI I
N
H

YN

II N
N
NH
NH

N

CI
CI

H
N
N

N N >==
I I \N O HN N

HN" N N

F CI
H N HN
F
F

HN
Y N
N
NH
~
N
H` NH2 N N N ~ v O O y ::G,,,N
I N
H
S

N HN N
I >==.
N
~
~ N
HN N N NH
N

CI ci F
N
N
H NII

N N N NH
p~ I \~
N
~
H O
N CI

N

HNN
~~

NH
NH
N

O
N NH
F ~ o~N I ~
N N
H

HNI` iN

N ~ CI
NH F
N
N H
N
H

HN N
HN N y Yi NH NH
N
N
Q

F CI

H
~-s N
+l H N \N N
H
N N N NHy i N
N
H

N
N ~ I N HNyN

N
HN \N N NH
N~,( CI \\~
HN ~
F

N
~

NH
//~N
N~/ 1 F F
N
~NH
N N` N,/, iNHz F
0~ \/ \/
/ O
/ N \
N
H

CI CI
)~
HN N

N N
N HN
N
N

N/ N

N rNH
H

HN
N
Y

N
NH
51:ss,N
CI

[0091] Selectivity for inhibition of PKC@by the compounds of the invention was tested and results are shown in Table 2. The data in Table 2 shows obtained values for PKCf1 isoform selectivity by showing Ki Pan Vera (PV) potencies for PKC@, PKC delta and PKC alpha. For Ki Pan Vera (PV) of PKCB, entries identified with "A" had values below 100 nM; entries identified with `B" had values below 1 M.
For Ki Pan Vera (PV) of PKC delta and PKC alpha, entries identified with "1"
had values above 15 nM; entries identified with "2" had values above 100 nM;
entries identified with "3" had values above 1 M; entries identified with "4" had values above 10 M.

[0092] Table 2 also shows selectivity of the compounds of the invention by showing their IC50 values for kinase SGK. Entries identified with "1" had values above nM; entries identified with "2" had values above 100 nM; entries identified with "3"
had values above 1 .M; entries identified with "4" had values above 10 .M.
In Table 2, "nd" stands for "not determined."

Table 2.

Ki PV- Ki PV- IC50-Ki PV delta alpha SGK1 Compound (nM) (nM) (nM) (nM) 101 A 1 3 nd 107 A 1 3 nd 109 A 1 3 nd 112 A 2 3 I nactive 115 A 2 3 nd 117 A 2 4 I nactive 118 A 2 4 I nactive 120 A 2 4 I nactive 119 A 2 4 I nactive 122 A 2 3 I nactive 129 A 2 4 I nactive 135 A 2 4 nd 136 A 2 4 I nactive 137 A 2 4 Inac:tive 139 B 3 4 I nactive 141 B 2 4 I nactive 145 B 3 4 I nactive 148 A 2 4 nd 149 A 2 4 I nactive 203 B 2 4 I nactive 205 B 2 4 I nactive 206 B 2 4 I nactive 207 B 2 4 nd 208 B 2 4 I nactive 214 B 3 4 nd 215 B 3 4 nd 216 B 3 4 nd 218 B 3 4 nd 224 B 3 3 nd 231 B 3 4 nd 241 B 2 4 I nactive [0093] The compounds of the invention were also tested in vivo. Table 3 below demonstrates results of anti-CD3 induced interleukin-2 (IL-2) production in mice, which was performed following protocols disclosed in Goldberg et al. (2003), J. Med.
Chem. 46, 1337-1349.

Table 3.

Compound Subcutaneous dose % inhibition of m /k IL-2 production Vehicle (no drug) 0 0 FK506 (positive control, 1 87 global immunosu ression) [0094] IL-2 is a T cell-derived lymphokine that modulates immunological effects on many cells of the immune system, including cytotoxic T cells, natural killer cells, activated B cells and lymphokine-activated cells. It is a potent T cell mitogen that is required for the T cell proliferation, promoting their progression from Gl to S phase of the cell cycle. It is a growth factor for all subpopulations of T
lymphocytes, as well as stimulating the growth of NK cells. It also acts as a growth factor to B
cells and stimulates antibody synthesis.

[0095] Due to its effects on both T and B cells, IL-2 is a major central regulator of immune responses. It plays a role in anti-inflammatory reactions, tumor surveillance, and hematopoiesis. It also affects the production of other cytokines, inducing IL-1, TNF-a and TNF-(3 secretion, as well as stimulating the synthesis of IFN-y in peripheral leukocytes. IL-2, although useful in the immune response, also causes a variety of problems. IL-2 damages the blood-brain barrier and the endothelium of brain vessels. These effects may be the underlying causes of neuropsychiatric side effects observed under IL-2 therapy, e.g. fatigue, disorientation and depression. It also alters the electrophysio logical behavior of neurons.

[0096] T cells that are unable to produce IL-2 become inactive (anergic). This renders them potentially inert to any antigenic stimulation they might receive in the future. As a result, agents which inhibit IL-2 production may be used for immunosupression or to treat or prevent inflammation and immune disorders.
This approach has been clinically validated with immunosuppressive drugs such as cyclosporin, FK506, and RS61443.

[0097] The data presented in Tables 1-3 demonstrates utility of the compounds of the invention in inhibition of PKCBand their utility for treatment of T-cell mediated diseases including autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, and multiple sclerosis, inflammatory diseases such as asthma and inflammatory bowel disease, transplant rejection, gastrointestinal cancer, and diabetes.

[0098] Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisometric forms which may be defined in terms of absolute stereochemistry as (R)- or (S)-. The present invention is meant to include all such possible diastereomers as well as their racemic and optically pure forms. Optically active (R)- and (S)-isomers may be prepared using homo-chiral synthons or homo-chiral reagents, or optically resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both (E)- and (Z)-geometric isomers. Likewise, all tautomeric forms are intended to be included.

[0099] The present invention includes compounds of formula (I) in the form of salts.
Suitable salts include those formed with both organic and inorganic acids.
Such salts will normally be pharmaceutically acceptable, although non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

[00100] While it may be possible for the compounds of formula (I) or their salts and solvates to be administered as the raw chemical, it is preferable to present them as a pharmaceutical composition. According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
[00101] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
The most suitable route may depend upon the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[00102] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[00103] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
[00104] Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use.
Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[00105] Formulations for rectal administration may be presented as a suppository with the usual carriers, such as cocoa butter or polyethylene glycol.

[00106] Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.

[00107] Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient.

[00108] The pharmaceutical compositions will usually include a "pharmaceutically acceptable inert carrier" and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques. "Pharmaceutically acceptable carrier"
also encompasses controlled release means. Compositions of the present mvention may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like.

[00109] The compounds of formula (I) are preferably administered orally or by injection (intravenous or subcutaneous). The precise amount of compound administered to a patient will be the responsibility of the attendant physician.
However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity.
Also, the route of administration may vary depending on the condition and its severity.
[00110] The contents of each of the references cited herein, including the contents of the references cited within the primary references, are herein incorporated by reference in their entirety.

Claims (33)

1. A compound, or salt thereof, represented by Formula I, wherein:
Q is chosen from N and CH;

R1 is chosen from nitrogen-attached heterocyclyl, substituted nitrogen-attached heterocyclyl and wherein n is an integer from 2 to 6;
R21 is chosen separately in each occurrence from -H, C1-C4 alkyl and -OH;
R22 is chosen separately in each occurrence from -H, C1-C4 alkyl and a bond to R24;
R23 is chosen from -H, C1-C4 alkyl and a bond to R24;
R24 is chosen from -H, C1-C4 alkyl or together with either of R22 or R23 forms a 5-7 membered nitrogen heterocycle optionally substituted with C1-C4 alkyl, and R2 is chosen from aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, hetroarylalkyl, and substituted heteroarylalkyl.

2. A compound, or salt thereof, according to claim 1, wherein:

R1 is chosen from , and wherein R9 is chosen from amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl and di[(C1-C6)alkyl]amino(C1-C6)alkyl.

3. A compound, or salt thereof, according to claim 1, wherein:
R1 is

4. A compound, or salt thereof, according to claim 3, wherein:
R22 is chosen separately in each occurrence from -H and C1-C4 alkyl;
and R24 together with R23 forms a 5-7 membered nitrogen heterocycle optionally substituted with C1-C4 alkyl.

5. A compound, or salt thereof, according to claim 3, wherein:

R22 is chosen separately in each occurrence from -H and C1-C4 alkyl;
R23 is chosen from -H, C1-C4 alkyl; and R24 is H or C1-C4 alkyl.

6. A compound, or salt thereof, according to claim 3, wherein:
R22 is chosen separately in each occurrence from H, C1-C4 alkyl and a bond to R24;

R23 is chosen from H, C1-C4 alkyl;
R24 together with one occurrence of R22 forms a 5-7 membered nitrogen heterocycle optionally substituted with C1-C4 alkyl.

7. A compound, or salt thereof, according to claim 1, wherein:

R2 is chosen from wherein R10, R11, and R12 are independently chosen from -H, halogen, -OCH3, -OCF3, -CF3, C1-C4 alkyl, and phenyl; and L is a C0-C10 alkyl.

8. A compound, or salt thereof, according to claim 7, wherein:
R2 is chosen from wherein R10, R11, and R12 are independently chosen from -H, halogen, -OCH3, -OCF3, -CF3, and C1-C4 alkyl; and R15 and R16 are independently chosen from -H and C1-C4 alkyl.

9. A pharmaceutical composition comprising a compound according to claim 1, or salt thereof, and a pharmaceutically acceptable carrier.

10. A compound, or salt thereof, represented by Formula I, wherein:
Q is chosen from N and CH;

R1 is chosen from wherein R4 is chosen from , and -M-NR7R8;
wherein R5, R6, and R9 are independently chosen from -H, C1-C4 alkyl, -OH, -OCH3, halogen, and aminoalkyl;
R7 and R8 are independently chosen from -H, C1-C4 alkyl, and amino alkyl;
L1 is a C0-C10 alkyl optionally substituted with -OH, with a proviso that -OH cannot be bonded to a carbon atom that is also bonded to N;
M is C2-C10 alkyl optionally substituted with -OH, with a proviso that -OH cannot be bonded to a carbon atom that is also bonded to N;

R2 is chosen from wherein R10, R11, and R12 are independently chosen from -H, halogen, -OCH3, -OCF3, -CF3, C1-C4 alkyl, and phenyl; and L is a C0-C10 alkyl.

11. A compound, or salt thereof, according to claim 10, wherein:

R4 is chosen from wherein R5, R6, and R9 are independently chosen from -H, C1-C4 alkyl, -OH, -OCH3, halogen, and aminoalkyl;
R7 and R8 are independently chosen from -H, C1-C4 alkyl, and aminoalkyl; and R13 and R14 are independently chosen from -H, -OH, and C1-C4 alkyl, with a proviso that -OH cannot be bonded to a carbon atom that is also bonded to N.

12. A compound, or salt thereof, according to claim 11, wherein:
R5, R6, R7, and R8 are independently chosen from -H and C1-C4 alkyl;
R9 is -R17 -NR7R8; and wherein R17 is a C1-C4 alkyl.

13. A compound, or salt thereof, according to claim 12, wherein:
R4 is chosen from wherein R7 and R8 are independently chosen from -H and -CH3; and R18 is chosen from -H and -OH.

14. A compound, or salt thereof, according to claim 10, wherein:

R2 is chosen from wherein R10, R11 and R12 are independently chosen from -H, halogen, -OCH3, -OCF3, -CF3, and C1-C4 alkyl; and R15 and R16 are independently chosen from -H and C1-C4 alkyl.

15. A pharmaceutical composition comprising a compound according to claim 10, or salt thereof, and a pharmaceutically acceptable carrier.

16. A compound, or salt thereof, represented by Formula I, wherein:
Q is chosen from N and CH;

R1 is chosen from , and wherein R4 is chosen from wherein R5, R6, and R9 are independently chosen from -H, C1-C4 alkyl, -OH, -OCH3, halogen, and aminoalkyl;
R7 and R8 are independently chosen from -H, C1-C4 alkyl, and aminoalkyl; and R13 and R14 are independently chosen from -H, -OH, and C1-C4 alkyl, with a proviso that -OH cannot be bonded to a carbon atom that is also bonded to N;

R2 is chosen from wherein R10, R11, and R12 are independently chosen from -H, halogen, -OCH3, -OCF3, -CF3, and C1-C4 alkyl; and R15 and R16 are independently chosen from -H and C1-C4 alkyl.

17. A compound, or salt thereof, according to claim 16, wherein:
R5, R6, R7 , and R8 are independently chosen from -H and C1-C4 alkyl;
R9 is -R17 -NR7R8; and wherein R17 is a C1-C4 alkyl.

18. A compound, or salt thereof, according to claim 17, wherein:
R4 is chosen from wherein R7 and R8 are independently chosen from -H and -CH3; and R18 is chosen from -H and -OH.

19. A compound, or salt thereof, according to claim 17, wherein Q is N.

20. A compound, or salt thereof, according to claim 17, wherein Q is CH.

21. A pharmaceutical composition comprising a compound according to claim 16, or salt thereof, and a pharmaceutically acceptable carrier.

22. A method of treatment of a T-cell mediated disease comprising administering to a patient suffering therefrom a therapeutically effective amount of a compound, or salt thereof, according to any of claims 1, 10 and 16.

23. The method of claim 22 wherein the T-cell mediated disease is an autoimmune disease.

24. The method of claim 23 wherein the autoimmune disease is rheumatoid arthritis.

25. The method of claim 23 wherein the autoimmune disease is lupus erythematosus.

26. The method of claim 23 wherein the autoimmune disease is multiple sclerosis.

27. The method of claim 22 wherein the T-cell mediated disease is an inflammatory disease.

28. The method of claim 27 wherein the inflammatory disease is asthma.

29. The method of claim 27 wherein the inflammatory disease is inflammatory bowel disease.

30. The method of claim 22 wherein the T-cell mediated disease is transplant rejection.

31. A method of treatment of cancer comprising administering to a patient suffering therefrom a therapeutically effective amount of a compound, or salt thereof, according to any of claims 1, 10 and 16.

32. The method of claim 31 wherein the cancer is gastrointestinal cancer.

33. A method of treatment of diabetes comprising administering to a patient suffering therefrom a therapeutically effective amount of a compound, or salt thereof, according to any of claims 1, 10 and 16.