ZA200901997B - Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes - Google Patents
Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes Download PDFInfo
- Publication number
- ZA200901997B ZA200901997B ZA200901997A ZA200901997A ZA200901997B ZA 200901997 B ZA200901997 B ZA 200901997B ZA 200901997 A ZA200901997 A ZA 200901997A ZA 200901997 A ZA200901997 A ZA 200901997A ZA 200901997 B ZA200901997 B ZA 200901997B
- Authority
- ZA
- South Africa
- Prior art keywords
- methyl
- azetidin
- ylcarbonyl
- benzamide
- het
- Prior art date
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- -1 Heteroaryl benzamide derivatives Chemical class 0.000 title claims description 378
- 238000011282 treatment Methods 0.000 title claims description 24
- 206010012601 diabetes mellitus Diseases 0.000 title description 13
- 239000012190 activator Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims description 115
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 86
- 150000003839 salts Chemical class 0.000 claims description 69
- 239000003814 drug Substances 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 230000001404 mediated effect Effects 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 239000000651 prodrug Substances 0.000 claims description 10
- 229940002612 prodrug Drugs 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- WIFSSWYPPHSSIV-UHFFFAOYSA-N azetidin-1-yl-(5-chloropyrazin-2-yl)methanone Chemical compound C1=NC(Cl)=CN=C1C(=O)N1CCC1 WIFSSWYPPHSSIV-UHFFFAOYSA-N 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 description 109
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical class NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 86
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 86
- 229910052757 nitrogen Inorganic materials 0.000 description 78
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 72
- 125000004433 nitrogen atom Chemical group N* 0.000 description 55
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- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 42
- 125000003373 pyrazinyl group Chemical group 0.000 description 42
- 125000001424 substituent group Chemical group 0.000 description 39
- 125000000335 thiazolyl group Chemical group 0.000 description 38
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- 125000004076 pyridyl group Chemical group 0.000 description 35
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- 229910052717 sulfur Inorganic materials 0.000 description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 23
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- 125000001309 chloro group Chemical group Cl* 0.000 description 21
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- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 20
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- 125000003282 alkyl amino group Chemical group 0.000 description 18
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- 125000003545 alkoxy group Chemical group 0.000 description 17
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 17
- 125000005843 halogen group Chemical group 0.000 description 17
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- 230000000694 effects Effects 0.000 description 13
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- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
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- FQUKZFSJTRQNCO-UHFFFAOYSA-N n-(1h-pyrazol-5-yl)benzamide Chemical compound C=1C=CC=CC=1C(=O)NC1=CC=NN1 FQUKZFSJTRQNCO-UHFFFAOYSA-N 0.000 description 1
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- NGSNKNGDGXSICN-UHFFFAOYSA-N n-pyrazin-2-ylbenzamide Chemical compound C=1C=CC=CC=1C(=O)NC1=CN=CC=N1 NGSNKNGDGXSICN-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
S—— HETEROARYL BENZAMIDE DERIVATIVES I N GLK mano Tin 00:0 === DIABETES V4 =—n This is a fresh application (i.e. a so-called divisional application) filed in terms of a Section 37 of the South African Patents Act 57/1978, in respect of part of the matter disclosed - in South African patent application 2008/00054 filed as a national phase PCT application on 2
January 2008 (i.e. the so-called parent application) based on PCT international application
PCT/GB2006/002471 filed on 3 July 2006. Co : The term "invention" is used herein to describe the subject matter of both the parent : and the fresh (divisional) applications. = The present invention relates to a group of benzoyl amino heterocyclyl compounds
Which are useful in the treatment or prevention of a disease or medical condition mediated through glucokinase (GLK or GK), leading to a decreased glucose threshold for insulin . secretion. In addition the compounds are predicted to lower blood glucose by increasing hepatic glucose uptake. Such compounds may have utility in the treatment of Type 2 ‘ diabetes and obesity. The invention also relates to pharmaceutical compositions comprising said compounds and to methods of treatment of diseases mediated by GLK : using said compounds.
In the pancreatic B-cell and liver parenchymal cells the main plasma membrane glucose transporter is GLUT2. Under physiological glucose concentrations the rate at which GLUT? transports glucose across the membrane is not rate limiting to the overall rate of glucose uptake in these cells. The rate of glucose uptake is limited by the rate of phosphorylation of glucose to glucose-6-phosphate (G-6-P) which is catalysed by glucokinase (GLK) [1]. GLK has a high (6-10mM) Km for glucose and is not inhibited by physiological concentrations of G-6-P [1]. GLK expression is limited to a few tissues and cell types, most notably pancreatic B-cells and liver cells (hepatocytes) [1]. In these cells | B
GLK activity is rate limiting for glucose utilisation and therefore regulates the extent of glucose induced insulin secretion and hepatic glycogen synthesis. These processes are - critical in the maintenance of whole body glucose homeostasis and both are dysfunctional in diabetes [2]. }
In one sub-type of diabetes, Maturity-Onset Diabetes of the Young Type 2 : (MODY-2), the diabetes is caused by GLK loss of function mutations [3, 4].
Hyperglycaemia in MODY-2 patients results from defective glucose utilisation in both the . pancreas and liver [5]. Defective glucose utilisation in the pancreas of MODY-2 patients results in a raised threshold for glucose stimulated {sulin secretion. Conversely, rare activating mutations of GLK reduce this threshold resulting in familial hyperinsulinism [6, -.35 6a, 7]. In addition to the reduced GLK activity observed in MODY-2 diabetics, hepatic glucokinase activity is also decreased in type 2 diabetics [8]. Importantly, global or liver selective overexpression of GLK prevents or reverses the development of the diabetic phenotype in both dietary and genetic models of the disease [9-12]. Moreover, acute
® treatment of type 2 diabetics with fructose improves glucose tolerance through stimulation of hepatic glucose utilisation [13]. This effect is believed to be mediated through a fructose induced increase in cytosolic GLK activity in the hepatocyte by the mechanism described below [13].
Hepatic GLK activity is inhibited through association with GLK regulatory protein (GLKRP). The GLK/GLKRP complex is stabilised by fructose-6-phosphate (F6P) binding to the GLKRP and destabilised by displacement of this sugar phosphate by fructose-1-phosphate (F1P). FIP is generated by fructokinase mediated phosphorylation of dietary fructose. Consequently, GLK/GLKRP complex integrity and hepatic GLK activity is regulated in a nutritionally dependent manner as F6P is dominant in the post-absorptive state whereas F1P predominates in the post-prandial state. In contrast to the hepatocyte, the pancreatic (B-cell expresses GLK in the absence of GLKRP. Therefore, B-cell GLK activity is regulated extensively by the availability of its substrate, glucose. Small molecules may activate GLK either directly or through destabilising the GLK/GLKRP complex. The former class of compounds are predicted to stimulate glucose utilisation in both the liver and the pancreas whereas the latter are predicted to act selectively in the liver. However, compounds with either profile are predicted to be of therapeutic benefit in treating Type 2 diabetes as this disease is characterised by defective glucose utilisation in both tissues.
GLK, GLKRP and the Karp channel are expressed in neurones of the hypothalamus, a region of the brain that is important in the regulation of energy balance and the control of food intake [14-18]. These neurones have been shown to express orectic and anorectic neuropeptides [15, 19, 20] and have been assumed to be the glucose-sensing neurones within the hypothalamus that are either inhibited or excited by changes in ambient glucose concentrations [17, 19, 21,22]. The ability of these neurones to sense changes in glucose levels is defective in a variety of genetic and experimentally induced models of obesity [23-28]. Intracerebroventricular (icv) infusion of glucose analogues, that are competitive inhibitors of glucokinase, stimulate food intake in lean rats [29, 30].
In contrast, icv infusion of glucose suppresses feeding [31]. Thus, small molecule activators of GLK may decrease food intake and weight gain through central effects on
GLK. Therefore, GLK activators may be of therapeutic use in treating eating disorders, including obesity, in addition to diabetes. The hypothalamic effects will be additive or
So
~ hii Ce ® 7.200970199, -3- synergistic to the effects of the same compounds acting in the liver and/or pancreas in normalising glucose homeostasis, for the treatment of Type 2 diabetes. Thus the
GLK/GLKRP system can be described as a potential “Diabesity” target (of benefit in both
Diabetes and Obesity).
GLK is also expressed in specific entero-endocrine cells where itis believed to control the glucose sensitive secretion of the incretin peptides GIP (glucose-dependent d insulinotropic polypeptide) and GLP-1 (Glucagon-Like Peptide-1) from gut K-cellsand L- cells respectively (32, 33, 34). Therefore, small molecule activators of GLK may have additional beneficial effects on insulin secretion, b-cell function and survival and body weight as a consequence of stimulating GIP and GLP-1 secretion from these entero- endocrine cells.
In WO00/58293 and WO01/44216 (Roche), a series of benzylcarbamoyl compounds are described as glucokinase activators. The mechanism by which such compounds activate GLK is assessed by measuring the direct effect of such compounds in an assay in which GLK activity is linked to NADH production, which in turn is measured optically - see details of the in vitro assay described hereinafter. Compounds of the present invention may activate GLK directly or may activate GLK by inhibiting the interaction of
GLKRP with GLK. ) Further GLK activators have been described in W(Q03/095438 (substituted phenylacetamides, Roche), W003/055482 (carboxamide and sulphonamide derivatives,
Novo Nordisk), W02004/002481 (arylcarbonyl derivatives, Novo Nordisk), and in
W003/080585 (amino-substituted benzoylaminoheterocycles, Banyu).
Our International application Number: WO03/000267 describes a group of benzoyl amino pyridyl carboxylic acids which are activators of the enzyme glucokinase (GLK).
Our International application Number: WO03/015774 describes compounds of the
Formula (A):
Neg wl, Sc A (R3),
A) wherein R? is a substituted heterocycle other than a carboxylic acid substituted pyridyl.
®
International application W02004/076420 (Banyu) describes compounds which are generally a subset of those described in W003/015774, wherein for example R! is an (substituted) alkyl ether and R? is (substituted) phenoxy.
We have surprisingly found a small group of compounds, generally a selected subgroup of those described in WO 03/015774, which have generally superior potency for the GLK enzyme, and more advantageous physical properties, including, for example, higher aqueous solubility, higher permeability, and/or lower plasma protein binding. :
Consequently, such compounds having a balance of these properties would be expected to display higher plasma free drug levels and superior in vivo efficacy after oral dosing as determined, for example, by activity in Oral Glucose Tolerance Tests (OGTTs). Therefore this group of compounds would be expected to provide superior oral exposure at a lower dose and thereby be particularly suitable for use in the treatment or prevention of a disease or medical condition mediated through GLK. The compounds of the invention may also have superior potency and/or advantageous physical properties (as described above) and/or favourable toxicity profiles and/or favourable metabolic profiles in comparison with other : GLK activators known in the art, as well as those described in WO 03/015774,
Thus, according to the first aspect of the invention there is provided a compound of
Formula (I):
R—0 H
N— ~< (=) | | M wherein:
R! is selected from isopropyl, but-2-yl, cyclopentyl, 1,1,1-trifluoroprop-2-yl, 1,3- difluoroprop-2-yl, but-1-yn-3-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-hydroxybut-2- yl, tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl, 1-methoxybut-2-y1, 2- hydroxyprop-1-yl, 2-methoxyprop-1-yl, 2-hydroxybut-1-y], 2-methoxybut-1-yl, 1- fluoromethoxyprop-2-yl, 1,1-difluoromethoxyprop-2-yl and 1-trifluoromethoxyprop-2-yl;
®
HET-1lisa5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on any nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R” and/or on 1 or 2 available carbon atoms bya substituent independently selected from RS,
HET-2 is a 5- or 6- membered heteroaryl ring, containing 1,2 or 3 ring hetereoatoms independently selected from O, S and N; which ring is substituted on an available carbon atom by a substituent selected from R?, and is optionally further substituted on 1 or 2 available carbon atoms by a substituent independently selected from R? and/or on an available nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R'%
R? is selected from —C(O)NR*R® and -SO,;NR'R’;
R? is selected from methyl, trifluoromethyl and halo;
R*and R® together with the nitrogen atom to which they are attached forma 4 to 7 membered saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in addition to the linking N atom) independently selected from O, N and S, wherein a -CHj- group can optionally be replaced by a -C(O)- and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(0), group; which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from R® and/or on an available nitrogen atom by a substituent selected from R®; or
R*and R® together with the nitrogen atom to which they are attached forma 6-10 membered bicyclic saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further nitrogen atom (in addition to the linking N atom), wherein a -CH,- group can optionally be replaced by a -C(O)-; which ring is optionally substituted on an available carbon by 1 substituent selected from hydroxy and R? or on an available nitrogen atom by methyl;
Ris independently selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1- 4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl and di(1-4C)alkylamino(1-4C)alkyl,
R'is independently selected from (1-4C)alkyl, halo(1-4C)alkyl, dihalo(1-4C)alkyl, - trihalo(1-4C)alkyl, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-
® 4C)alkyl, amino(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl and di(1-4C)alkylamino(1- 4C)alkyl;
R® is selected from hydroxy, (1-4C)alkoxy, (1-4C)alkyl, aminocarbonyl, (1- 4C)alkylaminocarbonyl, di(1-4C)alkylaminocarbonyl, ( 1-4C)alkylamino, di(1- 4Calkylamino, (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl and —S(O)p(1-4C)alkyl;
R’ is selected from (1-4C)alkyl, -C(O)(1-4C)alkyl, aminocarbonyl, (1- 4C)alkylaminocarbonyl, di( 1-4C)alkylaminocarbonyl, (1-4C)alkoxy(1-4C)alkyl, hydroxy (1-4C)alkyl and ~S(O)p(1-4C)alkyl;
R" is selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1- 4C)alkyl, -C(0O)(1-4C)alkyl, benzyl, and (1-4C)alkylsulfonyl; p is (independently at each occurrence) 0, 1 or 2; or a salt thereof.
In another aspect of the invention there is provided a compound of formula (I) as hereinbefore defined wherein R' is selected from isopropyl, but-2-yl, 1,1,1-trifluoroprop- 2-yl, 1,3-difluoroprop-2-yl, but-1-yn-3-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1- hydroxybut-2-yl, tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl, 1-methoxybut- 2-yl, 1-fluoromethoxyprop-2-yl, 1,1-diflucromethoxyprop-2-yl and 1- trifluoromethoxyprop-2-yl; or a salt thereof. : :
In another aspect of the invention there is provided a compound of formula (I) as hereinbefore defined wherein R' is selected from isopropyl, but-2-yl, 1,1,1-trifluoroprop- 2-yl, 1,3-difluoroprop-2-yl, but-1-yn-3-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1- hydroxybut-2-yl, tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl, 1-methoxybut- 2-yl, 2-hydroxyprop-1-yl, 2-methoxyprop-1-yl, 2-hydroxybut-1-yl, 2-methoxybut-1-yl, 1- fluoromethoxyprop-2-yl, 1,1-diflucromethoxyprop-2-yl and 1-trifluoromethoxyprop-2-yt; or a salt thereof.
In another aspect of the invention there is provided a compound of formula I) as . hereinbefore defined wherein R® is halo; or a salt thereof. :
In another aspect of the invention there is provided a compound of formula Das hereinbefore defined wherein R’ is independently selected from (1-4C)alkyl, hydroxy(1- 4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl, amino( 1-4C)alkyl, (1- 4C)alkylamino(1-4C)alkyl and di(1-4C)alkylamino(1-4C)alkyl; or a salt thereof,
®
It will be appreciated that, where definitions of heterocylyl groups HET-1 and h
HET-2 encompass heteroaryl rings which may be substituted on nitrogen, such substitution may not result in charged quaternary nitrogen atoms, removal of aromaticity of the ring or unstable structures. It will be appreciated that the definitions of HET-1 and HET-2 are not intended to include-any O-O, O-S or S-S bonds. It will be appreciated that the definitions of HET-1 and HET-2 are not intended to include unstable structures.
It will be understood that any single carbon atom in HET-1 may only be substituted by one group R® in order to maintain aromaticity of the ring. Up to two different carbon atoms in a HET-1 ring may be substituted by an R® group, each of which may be the same or different, provided the structure thereby formed is stable and aromatic.
It will be understood that any single carbon atom in HET-2 may only be substituted by one group R? in order to maintain aromaticity of the ring. Up to two different carbon atoms in a HET-2 ring may be substituted by an R® group, each of which may be the same or different, provided the structure thereby formed is stable and aromatic.
It will be understood that R® can be present on any or all available carbon atoms in the heterocyclic ring formed by NR*R?; each carbon atom can be substituted with 1 or 2 R® groups which may be the same or different, provided the structure thereby formed is stable (so, for example, it is not intended to cover gem-dihydroxy substitution).
It will be understood that where a compound of the formula (I) contains more than one group R’, they may be the same or different.
It will be understood that where a compound of the formula (I) contains more than one group R?, they may be the same or different.
A similar convention applies for all other groups and substituents on a compound of formula (I) as hereinbefore defined. N
Compounds of Formula (I) may form salts which are within the ambit of the invention. Pharmaceutically acceptable salts are preferred although other salts may be useful in, for example, isolating or purifying compounds.
In another aspect, the invention relates to compounds of formula (I) as hereinabove defined orto a pharmaceutically acceptable salt.
In this specification the generic term “alkyl” includes both straight-chainand ~~. branched-chain alkyl groups. However references to individual alkyl groups such as : “propyl” are specific for the straight chain version only and references to individual oo i
® branched-chain alkyl groups such as #-butyl are specific for the branched chain version only. For example, “(1-4C)alkyl” includes methyl, ethyl, propyl, isopropyl and t-butyl. An analogous convention applies to other generic terms.
For the avoidance of doubt, reference to the group HET-1 containing a nitrogen in the 2-position, is intended to refer to the 2-position relative to the amide nitrogen atom to which the group is attached. For example, HET-1 encompasses but is not limited to the following structures:
ChE Tha Todo 0 o NTN 0 N~7
Suitable examples of HET-1 as a 5- or 6-membered, C-linked heteroaryl ring as hereinbefore defined, include thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl and triazolyl.
Suitable examples of HET-2 include thienyl, furyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl and triazolyl. Further suitable examples of HET-2 include aromatic heterocycles where a ring nitrogen or sulfur atom has been oxidised but aromaticity has been preserved, for example a pyridine N-oxide. Further suitable examples of HET-2 include thiazolyl, pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl.
Suitable examples for a 4-7 membered ring formed by R* and R® together with the nitrogen to which they are attached, as hereinbefore defined, include morpholino, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, homopiperazinyl, homo-morpholino, homo-thiomorpholino (and versions thereof wherein the sulfur is oxidised to an SO or
S(O) group) and homo-piperidinyl. A further suitable example is thiomorpholino (and versions thereof wherein the sulfur is oxidised to an SO or (0), group).
Suitable examples for a 6-10 membered bicyclic heterocyclic ring formed by R* and R® together with the nitrogen to which they are attached, as hereinbefore defined, are bicyclic saturated or partially unsaturated heterocyclyl ring such as those illustrated by the structures shown below (wherein the dotted line indicates the point of attachment to the rest of the molecule and wherein R represents the optional substituents for carbon or : nitrogen defined hereinbefore): ; A y aN ’ ’ N re N ~ : | N
R \.. [2,2,1) - uy . ~ reg
AR R ~ . N vd — N ke 12,2,2] 321] Rr [4,1,0] [4,2,0]
R
ID Oo 9 “ N [3.2.0] “BAO a . - ¥ -N & N—| >
N
[3,1,1] AL y On BN oa gags 2,1,1] 13,1,0] [1.1.1]
In particular such a ring system is a [2,2,1] system such as
RAN .
N .
A> (7-azabicyclo[2.2.1]hept-7-y1).
In another embodiment, such a ring system is a [2.1. 1] system such as
® ’ (2-azabicyclo[2.1.1Thex-2-yl).
Examples of (1-4C)alkyl include methyl, ethyl, propyl, isopropyl, butyl and tert- butyl; examples of (3-6C)cyecloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; examples of halo include fluoro, chloro, bromo and iodo; examples of halo(1- 4C)alkyl include fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoropropyl and fluorobutyl; examples of dihalo(1-4C)alkyl include difluoromethyl, 1,1-difluoroeth-2-yl, 1,2-difluoroeth-2-yl, 1,1-dichloroeth-2-yl, 1,2-dichloroeth-2-yl, and 1, 1-difluoroprop-3-yi; examples of trihalo(1-4C)alkyl include trifluoromethyl and 1,1,1-trifluoroeth-2-y; examples of hydroxy(1-4C)alkyl include hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxyisopropyl and 4- hydroxybutyl; examples of (1-4C)alkoxy(1-4C)alkyl include methoxymethyl, ethoxymethyl, tert-butoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, methoxypropyl, 2- methoxypropyl and methoxybutyl; example of (1-4C)alkoxy include methoxy, ehtoxy, | Propoxy, isopropxy, butoxy and tert-butoxy; examples of (1-4C)alkylS(O)p(1-4C)alkyl (where p is 0, 1 or 2) include methylsulfinylmethyl, ethylsulfinylmethyl, ethylsulfinylethyl, methylsulfinylpropyl, methylsulfinylbutyl, methylsulfonylmethyl, ethylsulfonylmethyl, ethylsulfonylethyl, methylsulfonylpropyl, methylsulfonylbuty], methylthiomethyl, ethylthiomethyl, ethylthioethyl, methylthiopropyl, and methylthiobutyl; examples of (1-4C)alkylsulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl and tert-butylsulfonyl; examples of =S(0)p(1-4C)alkyl include (1- 4C)alkylsulfonyl, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, tert- : butylsulfinyl, methylthio, ethylthio, propylthio, isopropylthio and tert-butylthio; examples of amino(1-4C)alkyl include aminomethyl, aminoethyl, 2-aminopropyl, 3-aminopropyl, 1- aminoisopropyl and 4-aminobutyl; examples of (1-4C)alkylamino(1-4C)alkyl include (N- methyl)aminomethyl, (N-ethyl)aminomethyl, 1-((N-methyl)amino)ethyl, 2-(N- ~ methyl)amino)ethyl, (N-ethyl)aminoethyl, (N -methyl)aminopropyl, and 4-(N- methyl)amino)butyl; examples of di(1-4C)alkylamino(1-4C)alkyl include
® dimethylaminomethyl, methyl(ethyl)aminomethyl, methyl(ethyl)aminoethyl, (N,N- diethyaminoethyl, (N,N-dimethyl)aminopropyl and (N,N-dimethyl)aminobutyl; examples : of _C(0)(1-4C)alkyl and (1-4C)alkylcarbonyl include methylcarbonyl, ethylcarbonyl, propylcarbony! and tert-butyl carbonyl; examples of (1-4C)alkylamino include methylamino, ethylamino, propylamino, isopropylamino, butylamino and tert-butylamino; examples of di(1-4C)alkylamino include dimethylamino, diethylamino, N-methyl-N- ethylamino, dipropylamino, N-isopropyl-N-methyamino and dibutylamino; examples of (1-4C)alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl and tert- butylaminocarbonyl; examples of di(1-4C)alkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, dipropylaminocarbonyl, N-isopropyl-N-methyaminocarbonyl and dibutylaminocarbonyl.
It is to be understood that, insofar as certain of the compounds of Formula (I) defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of stimulating GLK directly or inhibiting the
GLK/GLKRP interaction. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. It is also to be understood that certain compounds may exist in tautomeric forms and that the invention also relates to any and all tautomeric forms of the compounds of the invention which activate GLK.
It is also to be understood that certain compounds of the formula (1) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. Itis to be understood that the invention encompasses all such solvated forms which activate GLK.
In another aspect, the invention relates to compounds of formula (I) as hereinabove defined or to a pro-drug thereof. Suitable examples of pro-drugs of compounds of formula (I) are in-vivo hydrolysable esters of compounds of formula (I). Therefore in another aspect, the invention relates to compounds of formula (I) as hereinabove defined or to an in-vivo hydrolysable ester thereof.
In one embodiment of the invention are provided compounds of formula (I), in an
® alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (I), in a further alternative embodiment are provided in-vivo hydrolysable esters of compounds of formula (I), and in a further alternative embodiment are provided pharmaceutically-acceptable salts of in-vivo hydrolysable esters of compounds of formula @.
The compounds of the invention may be administered in the form of a pro-drug.
A pro-drug is a bioprecursor or pharmaceutically acceptable compound being degradable in the body to produce a compound of the invention (such as an ester or amide of a compound of the invention, particularly an in-vivo hydrolysable ester).
Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in
Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen; ©) H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H.
Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); "e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and f) N. Kakeya, ef al., Chem Pharm Bull, 32, 692 (1984).
The contents of the above cited documents are incorporated herein by reference.
Examples of pro-drugs are as follows. An in-vivo hydrolysable ester of a compound of the invention containing a carboxy or a hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically-acceptable esters for carboxy include C; to Cgalkoxymethyl esters for example methoxymethyl, C; to C salkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidy] esters,
C; to CgeycloalkoxycarbonyloxyCi to Csalkyl esters for example : 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, for example 5-methyl-1,3-dioxolen-2-onylmethyl; and (1-6C)alkoxycarbonyloxyethyl esters.
An in-vivo hydrolysable ester of a compound of the invention containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and a-acyloxyalkyl ethers and related compounds which as
® a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of a-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and | phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
A suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for : example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically-acceptable salt of a benzoxazinone derivative : of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
In a further aspect of the invention there is provided a compound of formula 0 which is a compound of formula (IA), or a salt thereof:
R~—0 H
WDE he >
AQ
:
Ia) : wherein each of X!, X? and X is independently selected from CH, N, S and O;
X* is absent (to make a 5-membered ring) or is selected from CH, N, Oand S; provided that at least one of X', X?, X> and X* is CH and provided that there are no 0-0, O-S or S-S bonds within the ring;
R’, if present, is selected from methyl, trifluoromethyl and halo;
R', R? and HET-1 are as defined for a compound of formula (I).
It will be understood that the dotted circle inside the ring containing X' to X* (that is, the HET-2 ring) is intended to indicate that the ring is aromatic, although the precise number and position of the double bonds will be dependent on the nature of X' to X*.
References herein to a compound of formula (I) should generally be understood to apply equally to a compound of formula (IA), whether explicitly stated or not, unless the context indicates otherwise.
Particular examples of compounds of formula (I) and (IA) include compounds of formulae (IB), (IC) and/or (ID): 1 1
R—O H R—O H
N 0) 0) \—0 \\—0
R — R —
N N as) Ic - 1
N— 0] / \,—O
R? —N @m) wherein R', R? and HET-1 are as defined for a compound of formula (I).
Preferred values of each variable group are as follows. Such values may be used where appropriate with any of the values, definitions, claims, aspects or embodiments defined hereinbefore or hereinafter. In particular, each may be used as an individual limitation on the broadest definition of formula (I) or (IA). Further, each of the following values may be used in combination with one or more of the other following values to limit the broadest defintion of formula (I) or (IA) or to limit any narrower definitions of formula (D or (IA) in any of the aspects hereinbefore or hereinafter. Where appropriate each of the following values may also be used to limit any definition within formulae (IB), (IC) and/or ao).
(1) R! is of sub-formula X:
NK
X) wherein R* is selected from methyl, ethyl, trifluoromethyl, ethynyl, hydroxymethyl, hydroxyethyl, methoxymethyl, fluoromethoxymethyl, diflucromethoxymethyl and trifluoromethoxymethyl; preferably R* is selected from methyl, ethyl, trifluoromethyl, ethynyl, hydroxymethyl, hydroxyethyl, methoxymethyl, fluoromethoxymethyl and difluoromethoxymethyl (2) R! is of sub-formula Y: yf :
Re . wherein R” is selected from hydroxymethyl and methoxymethyl : 3) R'is 1-hydroxyprop-2-yl and the configuration is preferably (S), that is R'-O- is: 0%
HOY
(4) R'is 1-methoxyprop-2-yl and the configuration is preferably (S), that is R!-O- is: 0% ~ oY (5) R! is selected from isopropyl, 1,3-difluoroprop-2-yl, but-1-yn-3-yl, 1-hydroxyprop-2- yl, hydroxybut-3-yl and 1-methoxyprop-2-yl (6) R'is 1,1,1-trifluoroprop-2-yl, 1-flucromethoxyprop-2-yl, 1,1-difluoromethoxyprop-2- yl or 1-trifluoromethoxyprop-2-yl (MH R'is I-fluoromethoxyprop-2-yl, 1,1-diflucromethoxyprop-2-yl or 1- trifluoromethoxyprop-2-yl, particularly 1-fluoromethoxyprop-2-y1 or 1,1- difluoromethoxyprop-2-yl @®) R'is 1,1-difluoromethoxyprop-2-yl, particularly with the stereochemistry:
A
F NE
Rls tetrahydrofuryl or tetrahydropyranyl (10) R'is tetrahydrofuryl in the (S) configuration, that is: oe
Oo (ADR's tetrahydrofuryl in the (R) configuration, that is;
FF
O
(12)R'is 4-tetrahydropyranyl: :
SN
13)R'is 2-hydroxy-but-3-yl and the configuration is preferably such that R'-O- is:
HO
(4) R'is 1-hydroxybut-2-yl or 1-methoxybut-2-yl (15) R' is selected from isopropyl, but-2-yl, 1,1,1-trifluoroprop-2-yl, 1,3-difluoroprop-2- yl, but-1-yn-3-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, tetrahydrofuryl, : tetrahydropyranyl, 1-methoxyprop-2-yl, 1-fluoromethoxyprop-2-yl, 1,1- difluoromethoxyprop-2-yl and 1-trifluoromethoxyprop-2-yl (16) Ris selected from 2-hydroxyprop-1-yl, 2-methoxyprop-1-yl, 2-hydroxybut-1-y1 and 2-methoxybut-1-yl (17) R! is selected from isopropyl, 1,3-difluoroprop-2-yl, but-2-yl, 1-hydroxyprop-2-yl, 2- hydroxybut-3-yl, 1,1-difluoromethoxyprop-2-yl, tetrahydrofuryl, 1-hydroxybut-2-yl and 1- methoxyprop-2-yl
(18) R! is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl, but-2-yl, 1- ~ hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1,1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl, 1-hydroxybut-2-yl and 1-methoxyprop-2-yl (19) R! is selected from tetrahydrofuryl, 1-difluoromethoxyprop-2-yl, 1,3-difluoroprop-2- yl, and 2-hydroxybut-3-yl (20) R' is selected from isopropyl, tetrahydrofuryl, 1-hydroxyprop-2-yl and 1- methoxyprop-2-yl
QDR! is selected from 1-hydroxyprop-2-yl and 1-methoxyprop-2-yl, for example (2.5)-1- hydroxyprop-2-yl and (25)-1-methoxyprop-2-yl (22)R! is selected from isopropyl, but-2-yl, cyclopentyl, 1,1,1-trifluoroprop-2-yl, 1,3- difluoroprop-2-yl, but-1-yn-3-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-hydroxybut-2- yl, tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl, 1-methoxybut-2-yl, 2- hydroxyprop-1-yl, 2-methoxyprop-1-yl, 2-hydroxybut- 1-yl, 2-methoxybut-1-yl, 1- fluoromethoxyprop-2-yl and 1,1-difluoromethoxyprop-2-yl (23)R' is selected from isopropyl, but-2-yl, cyclopentyl, 1,1,1-trifluoroprop-2-yl, 1,3- difluoroprop-2-yl, but-1-yn-3-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-hydroxybut-2- yl, tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl, 1-methoxybut-2-yl, 2- hydroxyprop-1-yl, 2-methoxyprop-1-yl, 2-hydroxybut-1-yl, 2-methoxybut-1-yl and 1,1- difluoromethoxyprop-2-yl (24) HET-1 is a 5-membered heteroaryl ring (25) HET-1 is a 6-membered heteroaryl ring (26) HET-1 is substituted with 1 or 2 substituents independently selected from R® (27) HET-1 is substituted with 1 substituent selected from R® (28) HET-1 is substituted with 1 substituent selected from R’ (29) HET-1 is unsubstituted (30) HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, and triazolyl (31) HET-1 is selected from thiazoly], isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and oxadiazolyl (32) HET-1 is selected from pyridyl, pyrazinyl, pyridaziny! and pyrimidinyl (33) HET-1 is selected from thiazolyl, pyrazolyl and oxazolyl
(34) HET-1 is selected from thiadiazolyl and oxadiazolyl (35) HET-1 is selected from 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl (36) HET-1 is selected from 1,2,4-oxadiazolyl and 1,2,4-oxadiazolyl (37) HET-1 is pyrazolyl, particularly N-methylpyrazolyl (38) HET-1 is pyrazinyl (39) HET-1 is selected from thiazolyl, pyrazoly], thiadiazolyl and pyrazinyl (40) HET-1 is selected from thiazolyl, pyrazolyl, and thiadiazolyl, optionally substituted with (1-4C)alkyl (41) HET-1 is pyrazolyl, particularly N-methylpyrazolyl (42) HET-1 is pyrazolyl (optionally substituted with ethyl, isopropyl or 1 or 2 methyl), thiazolyl (optionally substituted with methyl), pyrazinyl (optionally substituted with methyl), pyridyl (optionally substituted by fluoro), isoxazolyl (optionally substituted with methyl) and thiadiazolyl (optionally substituted with methyl) (43) HET-1 is pyrazolyl (optionally substituted with ethyl, isopropyl, difluoromethyl, or 1 : or 2 methyl), thiazolyl (optionally substituted with methyl), pyraziny! (optionally substituted with methyl), pyridyl (optionally substituted by fluoro), isoxazolyl (optionally substituted with methyl) and thiadiazolyl (optionally substituted with methyl) (44) HET-1 is selected from pyrazinyl (optionally substituted with methyl), pyrazolyl (optionally substituted on carbon by methyl), methylthiadiazolyl (particularly 1,2,4- thiadiazol-5-yl, more particularly 3-methyl-1,2,4-thiadiazol-5-yl), thiazolyl (optionally substituted with methyl), pyridyl (optionally substituted by fluoro) and isoxazolyl (45) HET-1 is N-difluoromethylpyrazoly! (46) HET-1 is 5-methylpyrazin-2-yl (47) HET-1 is pyrazolyl (optionally substituted with ethyl, isopropyl, difluoromethyl, or 1 or 2 methyl), thiazolyl (optionally substituted with methyl), pyraziny! (optionally substituted with methyl), pyridyl (optionally substituted by fluoro), isoxazolyl (optionally - substituted with methyl) and thiadiazolyl (optionally substituted with methyl); and
R' is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl, but-2-yl, 1- hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1,1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl, 1-hydroxybut-2-yl and I-methoxyprop-2-yl; when HET-1 is pyrazolyl unsubstituted on nitrogen (ie NH-pyrazolyl), particularly R'is selected from 1- methoxyprop-2-yl, isopropyl, and tetrahydrofuryl
® (48) HET-1 is pyrazolyl (optionally substituted on carbon with methyl), thiazolyl (optionally substituted with methyl), pyraziny! (optionally substituted with methyl), pyridy] (optionally substituted by fluoro), isoxazolyl and methylthiadiazolyl (particularly 3-methyl-1,2,4-thiadiazol-5-yl);
R! is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl, but-2-yl, 1- hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1,1-diflucromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl, 1-hydroxybut-2-y1 and 1-methoxyprop-2-yl; when HET-1 is pyrazolyl, particularly R' is selected from 1-methoxyprop-2-yl, isopropyl, and tetrahydrofury! : (49) HET-1 is methylpyrazinyl and R! is selected from 1-hydroxyprop-2-yl and 1- methoxyprop-2-yl, for example (25)-1-hydroxyprop-2-yl and (2S)-1-methoxyprop-2-yl (50) HET-1 is pyrazolyl and R! is selected from isopropyl, tetrahydrofuryl and 1- methoxyprop-2-yl, for example (25)-1-methoxyprop-2-yl (51) Réis selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl and di(1-4C)alkylamino(1- 4C)alkyl : (52) RSis selected from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl, : methoxymethyl, aminomethyl, N-methylaminomethy], dimethylaminomethyl (53) R%is selected from (1-4C)alky}, halo, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl, and di(1- = 4C)alkylamino(1-4C)alkyl (54) RSis selected from methyl, ethyl, bromo, chloro, fluoro, hydroxymethyl and methoxymethyl (55) Ris selected from methyl, ethyl, chloro and fluoro (56) R%is methyl or fluoro, preferably methyl (57) Ris selected from methyl, ethyl, bromo, chloro, fluoro, aminomethyl, N- methylaminomethyl, dimethylaminomethyl, hydroxymethyl and methoxymethyl (58) R®is selected from methyl, ethyl, aminomethyl, N-methylaminomethyl, dimethylaminomethyl, hydroxymethyl and methoxymethyl (59) Ris selected from methyl, ethyl, isopropyl and methoxymethy1 (60) when 2 substituents R® are present, both are selected from methyl, ethyl, bromo, chloro and fluoro; preferably both are methyl (61) Ris selected from (1-4C)alky1S(O)p(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl and di(1-4C)alkylamino(1-4C)alkyl
_ (62) Ris selected from (1-4C)alkyl, hydroxy(1-4C)alkyl and di(1 -4C)alkylamino(1- 4C)alkyl (63) R'is selected from methyl, ethyl, hydroxymethyl, methoxymethyl, aminomethyl, N-methylaminomethy], dimethylaminomethyl (64) Ris selected from (1-4C)alkyl, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1- 4C)alkylS(0)p(1-4C)alkyl, amino(1-4C)alkyl, (1-4Calkylamino(1-4C)alkyl, and di(1- 4C)alkylamino(1-4C)alkyl (65) R'is selected from methyl, ethyl, aminomethyl, N-methylaminomethyl, and dimethylaminomethyl (66) Ris selected from methyl, ethyl, hydroxymethyl! and methoxymethyl (67) Ris selected from methyl, isopropyl and ethyl (68) R'is selected from methyl, isopropyl, difluoromethyl and ethyl (69) Ris selected from isopropyl and difluoromethyl, particularly difluoromethyl (70) R'is selected from methyl and ethyl (71) Ris methyl (72) R'is selected from methyl, ethyl, aminomethyl, N-methylaminomethyl, dimethylaminomethyl, hydroxymethyl and methoxymethyl (73) Riis selected from methyl, ethyl, isopropyl and methoxymethyl (74) when R’ is selected from halo(1-4C)alkyl, dihalo(1-4C)alky! and trihalo( 1-4C)alkyl, each halo is selected from chloro and fluoro, and is in particular fluoro. (75) when R’ is selected from halo(1-4C)alkyl, dihalo(1-4C)alkyl and trihalo(1-4C)alkyl,
R’ is particularly selected from fluoromethyl, difluoroethyl, difluoromethyl and trifluoromethyl (76) HET-2 is a 5-membered ring : (77) HET-2 is a 6-membered ring (78) HET-2 is selected from thienyl, furyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl and oxadiazolyl (79) HET-2 is selected from thienyl, furyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl and oxadiazolyl (80) HET-2 is selected from pyridyl, pyrazinyl, thiazoly] and thienyl (81) HET-2is selected from pyridyl, pyrazinyl and thiazolyl
(82) HET-2 is selected from pyridyl, pyrazinyl, pyridazinyl and thiazolyl (83) HET-2 is selected from pyridyl and pyrazinyl (84) HET-2 is pyrazinyl (85) HET-2 is substituted with a substituent selected from R® (86) HET-2 has one nitrogen substituent selected from R'® (87) R? is chloro or fluoro (88) R? is chloro (89) R? is fluoro (90) R? is chloro or methyl (91) R? is fluoro, chloro or methyl (92) R? is <C(O)NR*R’ (93) R? is -SO,NR*R® (94) R* and R® together with the nitrogen atom to which they are attached form a 4 membered ring (95)R*andR’ together with the nitrogen atom to which they are attached form a 5 membered ring (96) R* and R® together with the nitrogen atom to which they are attached form a 6 membered ring (97) R* and R® together with the nitrogen atom to which they are attached form a 7 membered ring (98) R* and R’ together with the nitrogen atom to which they are attached form a fully saturated ring (99) R* and R® together with the nitrogen atom to which they are attached form a ring selected from morpholino, piperidinyl, piperazinyl, pyrrolidinyl and azetidinyl (100) R* and R° together with the nitrogen atom to which they are attached form a ring selected from pyrrolidinyl, morpholino and azetidinyl (101) R* and R® together with the nitrogen atom to which they are attached form a ring selected from 7-azabicyclo[2.2.1Thept-7-yl, pyrrolidinyl, morpholino and azetidinyl (102) R* and R® together with the nitrogen atom to which they are attached form an azetidinyl ring (103) R* and R® together with the nitrogen atom to which they are attached form an azetidinyl or pyrrolidinyl ring
(104) R* and R® together with the nitrogen atom to which they are attached form an unsubstituted ring (105) R* and R® together with the nitrogen atom to which they are attached form an ring mono-substituted either with a substituent R® or with a substituent R® (106) R*and R® together with the nitrogen atom to which they are attached form a 6-10 membered bicyclic saturated or partially unsaturated ring (107) R® is selected from hydroxy, (1-4C)alkoxy, (1-4C)alkyl (108) R® is selected from hydroxy, methoxy and methyl (109) R’ is selected from (1-4C)alky! and —C(O)(1-4C)alkyl (110) R%is azetidinylcarbonyl or pyrrolidinylcarbonyl, preferably azetidinylcarbonyl (109) RY is (1-4C)alkyl (111) R" is (3-6C)cycloalkyl (112) RY is hydroxy(1-4C)alky! or (1-4C)alkoxy(1-4C)alkyl (113) R'is -C(0)(1-4C)alkyl : 15 (114) R'is benzyl (115) R' is (1-4C)alkylsulfonyl (116) Ris (1-4C)alkyl or benzyl
According to a further feature of the invention there is provided the following preferred groups of compounds of the invention:
In one aspect of the invention there is provided a compound of formula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:
R' is selected from isopropyl, but-2-yl, 1,1,1-trifluoroprop-2-yl, 1,3-difluoroprop-2-yl, but-1-yn-3-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl, 1-fluoromethoxyprop-2-yl and 1,1-difluoromethoxyprop-2-yl;
HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on any nitrogen atom (provided it is not thereby quaternised) by a methyl or ethyl group and/or on 1 or 2 available carbon atoms by a methyl or ethyl group;
HET-2 is a 5- or 6- membered heteroaryl ring, containing 1, 2 or 3 ring hetereoatoms independently selected from O, S and N; which ring is substituted on an available carbon
_ atom by a substituent selected from R?, and is optionally further substituted on 1 or 2 : available carbon atoms by a substituent independently selected from R} and/or on an available nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R'?;
RZis selected from ~C(O)NR'R’ and -SO,NR‘R?:
R? is selected from halo;
R* and R® together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in addition to the linking N atom) independently selected from O, N and S, wherein a -CH,- group can optionally be replaced by a -C(O)- and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O), group; which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from R® and/or on an available nitrogen atom by a substituent selected from R%;
R® is selected from hydroxy, (1-4C)alkoxy and (1-4C)alkyl;
Ris selected from (1-4C)alkyl, -C(0)(1-4C)alkyl, and -S(O)p(1-4C)alkyl;
R'? is selected from (1-4C)alkyl, -C(0)(1-4C)alkyl, benzyl, and (1-4C)alkylsulfonyl; p is (independently at each occurrence) 0, 1 or 2.
In one aspect of the invention there is provided a compound of formula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:
R' is selected from isopropyl, but-2-yl, 1,1,1-triflucroprop-2-yl, 1,3-difluoroprop-2-yl, but-1-yn-3-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl, 2-hydroxyprop-1-yl, 2-methoxyprop-1-yl, 2-hydroxybut-1-yl, 2- methoxybut-1-yl, 1-fluoromethoxyprop-2-y! and 1,1-difluoromethoxyprop-2-yl;
HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on any nitrogen atom (provided it is not thereby quaternised) by a methyl or ethyl group and/or on 1 or 2 available carbon atoms by a methyl or ethyl group;
HET-2 is a 5- or 6- membered heteroaryl ring, containing 1, 2 or 3 ring hetereoatoms independently selected from O, S and N; which ring is substituted on an available carbon atom by a substituent selected from R? and is optionally further substituted on 1 or 2 available carbon atoms by a substituent independently selected from R® and/or on an available nitrogen atom (provided it is not thereby quatemised) by a substituent selected from R'C,
Ris selected from ~C(O)NR'R® and -SO,NR*R’;
R3 is selected from halo; R*and R’ together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 : : further heteroatoms (in addition to the linking N atom) independently selected from O, N and S, wherein a -CHa- group can optionally be replaced by a -C(O)- and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O), group; which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from R® and/or on an available nitrogen atom by a substituent selected from R’;
RE is selected from hydroxy, (1-4C)alkoxy and (1-4C)alkyl;
R’ is selected from (1-4C)alkyl, -C(O)(1-4C)alkyl, and —S(O)p(1-4C)alkyl;
RY is selected from (1-4C)alkyl, -C(O)(1-4C)alkyl, benzyl, and (1-4C)alkylsulfonyl; pis (independently at each occurrence) 0, 1 or 2.
In another aspect of the invention there is provided a compound of formula @) or (LA) as hereinbefore defined, or a salt thereof, wherein:
R! isselected from isopropyl, but-2-yl, cyclopentyl, 1,1,1-trifluoroprop-2-yl, 1,3- : difluoroprop-2-yl, but-1-yn-3-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl, 2-hydroxyprop-1-yl, 2-methoxyprop-1-yl, 2- hydroxybut-1-yl, 2-methoxybut-1-yl, 1-fluoromethoxyprop-2-yl and 1,1- difluoromethoxyprop-2-yl; :
HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on any nitrogen atom (provided it is not thereby quaternised) by a methyl, ethyl or isopropyl group and/or on 1 or 2 available carbon atoms by a methyl, ethyl or fluoro group;
HET-2 is a 5- or 6- membered heteroaryl ring, containing 1, 2 or 3 ring hetereoatoms independently selected from O, S and N; which ring is substituted on an available carbon : 30 atom by a substituent selected from R2, and is optionally further substituted on 1 or 2 available carbon atoms by a substituent independently selected from R® and/or on an
©.2009/9 available nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R19;
R? is selected from ~C(O)NR‘R® and -SO,NR'R’;
R? is selected from halo;
R*and R® together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in addition to the linking N atom) independently selected from O, N and S, wherein a -CH,- group can optionally be replaced by a -C(O)- and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O), group; which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from R® and/or on an available nitrogen atom by a substituent selected from R’;
R® is selected from hydroxy, (1-4C)alkoxy and (1-4C)alkyl;
R? is selected from (1-4C)alkyl, -C(O)(1-4C)alkyl, and —S(0)p(1-4C)alkyl;
R' is selected from (1-4Cjalkyl, -C(O)(1-4C)alkyl, benzyl, and (1-4C)alkylsulfonyl; pis (independently at each occurrence) 0, 1 or 2.
In another aspect of the invention there is provided a compound of formula (I) or (TA) as hereinbefore defined, or a salt thereof, wherein:
R! is selected from isopropyl, but-2-yl, cyclopentyl, 1,1,1-trifluoroprop-2-yl, 1,3- difluoroprop-2-yl, but-1-yn-3-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl, 2-hydroxyprop-1-yl, 2-methoxyprop-1-yl, 2- hydroxybut-1-yl, 2-methoxybut-1-yl, 1-fluoromethoxyprop-2-yl and 1,1- difluoromethoxyprop-2-yl;
HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on any nitrogen ator (provided it is not thereby quaternised) by a methyl, ethyl or isopropyl group and/or on 1 or 2 available carbon atoms by a methyl, ethyl or fluoro group;
HET-2 is a 5-or 6- membered heteroaryl ring, containing 1, 2 or 3 ring hetereoatoms independently selected from O, S and N; which ring is substituted on an available carbon atom by a substituent selected from R?, and is optionally further substituted on 1 or 2 available carbon atoms by a substituent independently selected from R> and/or on an available nitrogen atom (provided it is not thereby quaternised) by a substituent selected from R19,
R? is selected from ~C(O)NRR’ and -SO,NRR?;
R? is selected from methyl and halo;
R*andR’ together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in addition to the linking N atom) independently selected from O, N and S, wherein a -CH,- group can optionally be replaced by a -C(O)- and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O), group; which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from R® and/or on an available nitrogen atom by a substituent selected from R’;
R3 is selected from hydroxy, (1-4C)alkoxy and (1-4C)atkyl;
R? is selected from (1-4Calkyl, -C(0)(1-4C)alkyl, and —S(0)p(1-4C)alkyl;
R'? is selected from (1-4C)alkyl, -C(O)(1-4C)alkyl, benzyl, and (1-4C)alkylsulfonyl; pis (independently at each occurrence) 0, 1 or 2.
In another aspect of the invention there is provided a compound of formula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:
R! is selected from isopropyl, but-2-yl, cyclopentyl, 1,1,1-trifluoroprop-2-yl, 1,3- difluoroprop-2-yl, but-1-yn-3 1, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl, 2-hydroxyprop-1-yl, 2-methoxyprop-1-yl, 2- hydroxybut-1-yl, 2-methoxybut-1-yl, 1-fluoromethoxyprop-2-yl and 1,1- difluoromethoxyprop-2-yl;
HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atom in the 2- position and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; which ring is optionally substituted on any nitrogen atom (provided it is not thereby quaternised) by a methyl, ethyl or isopropyl group and/or on 1 or 2 available carbon atoms by a methyl, ethyl or fluoro group;
HET-2 is a 5- or 6- membered heteroaryl ring, containing 1,2 or 3 ring hetereoatoms independently selected from O, S and N; which ring is substituted on an available carbon atom by a substituent selected from R?, and is optionally further substituted on 1 or 2 available carbon atoms by a substituent independently selected from R?;
R? is selected from —C(O)NR*R® and -SO,NR'R’;
®
R? is selected from methyl and halo;
R* and R’ together with the nitrogen atom to which they are attached forma 4 to 7 membered saturated or partially unsaturated heterocyclyl ring, optionally containing 1 or 2 further heteroatoms (in addition to the linking N atom) independently selected from O, N and S, wherein a -CHy- group can optionally be replaced by a -C(0)- and wherein a sulphur atom in the ring may optionally be oxidised to a S(O) or S(O), group; or
R* and R® together with the nitro gen atom to which they are attached form a 6-10 membered bicyclic saturated or partially unsaturated heterocyclyl ring, optionally containing 1 further nitrogen atom (in addition to the linking N atom), wherein a -CH,- group can optionally be replaced by a -C(O)-.
In another aspect of the invention there is provided a compound of formula (I) or (TA) as hereinbefore defined, or a salt thereof, wherein:
R! is selected from isopropyl, but-2-yl, 1,3-difluoroprop-2-yl, 1-hydroxyprop-2-yl and 1- methoxyprop-2-yl and tetrahydrofuryl;
HET-lisan optionally substituted 5- or 6-membered heteroaryl ring as hereinbefore defined;
HET-2 is a substituted 5- or 6-membered heteroaryl ring as hereinbefore defined;
R? is -CONRR’;
R* and R® together form an azetidinyl, pyrrolidinyl or morpholino ring. ’
In another aspect of the invention there is provided a compound of formula (I) or (IA) as hereinbefore defined, or a-salt thereof, wherein:
R! is selected from isopropyl, 1,3-difluoroprop-2-yl, but-2-yl, 1-hydroxyprop-2-yl, 2- hydroxybut-3-yl, 1-difluoromethoxyprop-2-yl, tetrahydrofuryl, 1-hydroxybut-2-yl and 1- methoxyprop-2-yl; HET-1 is an optionally substituted 5- or 6-membered heteroaryl ring as hereinbefore defined;
HET-2 is a substituted 5- or 6-membered heteroaryl ring as hereinbefore defined;
R? is —-CONR'R’;
R* and R’ together form an azetidinyl, pyrrolidiny! or morpholino ring.
In another aspect of the invention there is provided a compound of formula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:
o ~28-
R! is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl, but-2-yl, 1- hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl, 1-hydroxybut-2-yl and 1-methoxyprop-2-yl;
HET-1 is an optionally substituted 5- or 6-membered heteroaryl ring as hereinbefore defined;
HET-2 is a substituted 5- or 6-membered heteroaryl ring as hereinbefore defined;
R? is ~CONR'R’;
R* and R? together form an azetidiny] or pyrrolidinyl ring. ‘In another aspect of the invention there is provided a compound of formula (I) or (1A) as hereinbefore defined, or a salt thereof, wherein:
R'is selected from isopropyl, 1,3-difluoroprop-2-yl, 1-hydroxyprop-2-yl and 1- methoxyprop-2-yl,
HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl and pyrazinyl, wherein R'is optionally substituted on carbon or nitrogen with a methyl or ethyl group;
HET-2 is selected from pyridyl, pyrazinyl, thiazolyl and thienyl, substituted by R? and optionally substituted by R%;
R? is fluoro or chloro;
R? is -CONR‘R’;
R* and R® together form an azetidinyl, pyrrolidiny! or morpholino ring.
In another aspect of the invention there is provided a compound of formula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:
R! is selected from isopropyl, 1,3-difluoroprop-2-yl, but-2-yl, 1-hydroxyprop-2-y, 2- hydroxybut-3-yl, 1-difluoromethoxyprop-2-yl, tetrahydrofuryl, 1-hydroxybut-2-yl and 1- methoxyprop-2-yl; HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl and pyrazinyl, wherein R' is optionally substituted with a methyl, isopropyl or ethyl group;
HET-2 is selected from pyridyl, pyrazinyl, thiazoly! and pyrimidinyl, substituted by R? and optionally substituted by rR?
R? is fluoro or chloro; :
R*is—CONR'R’;
R* and R® together form an azetidinyl, pyrrolidinyl or morpholino ring.
In another aspect of the invention there is provided a compound of formula @ or (1A) as hereinbefore defined, or a salt thereof, wherein:
R! is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl, but-2-yl, 1- hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl, 1-hydroxybut-2-y! and 1-methoxyprop-2-yl;
HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl, pyridyl, isoxazoly! and pyrazinyl, wherein R' is optionally substituted with a methyl, isopropyl or ethyl group and/or (on a carbon atom) by fluoro;
HET-2 is selected from pyridyl, pyrazinyl, pyridazinyl, thiazolyl and pyrimidinyl, substituted by R* and optionally substituted by R’;
R? is fluoro or chloro;
R? is ~CONR‘R?;
R* and R® to gether form an azetidinyl or pyrrolidinyl ring.
In another aspect of the invention there is provided a compound of formula @ or (IA) as hereinbefore defined, or a salt thereof, wherein:
R' is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl, but-2-yl, 1- hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl, 1-hydroxybut-2-yl and 1-methoxyprop-2-y;
HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl, pyridyl, isoxazolyl and pyrazinyl, wherein R' is optionally substituted with a methyl, isopropyl or ethyl group and/or (on a carbon atom) by fluoro;
HET-2 is selected from pyridyl, pyrazinyl, pyridazinyl, thiazoly! and pyrimidinyl, substituted by R? and optionally substituted by R, i
R’ is methyl, fluoro or chloro;
R*is—CONR‘R’;
R*and R® together form an azetidinyl, 7-azabicyclo[2.2.1]hept-7-yl, morpholino, or pyrrolidinyl ring.
In another aspect of the invention there is provided a compound of formula Dor (IA) as hereinbefore defined, or a salt thereof, wherein:
R! is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl, but-2-yl, 1- hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl, 1-hydroxybut-2-yl and 1-methoxyprop-2-yl;
®
HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl, pyridyl, isoxazolyl and pyrazinyl, wherein R' is optionally substituted with a methyl, isopropyl or ethy! group and/or (on a carbon atom) by fluoro;
HET-2 is selected from pyridyl, pyrazinyl, pyridazinyl, thiazolyl and pyrimidinyl, substituted by R? and optionally substituted by R>;
R3is methyl, fluoro or chloro;
R? is -CONR*R’;
R* and R® together form an azetidinyl or pyrrolidinyl ring.
In another aspect of the invention there is provided a compound of formula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:
R! is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl, but-2-yl, 1- : hydroxyprop-2-yl, 2-hydroxybut-3-yl, I-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl, 1-hydroxybut-2-yl and I-methoxyprop-2-yl;
HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl, pyridyl, isoxazolyl and pyrazinyl, wherein R'is optionally substituted on a nitrogen atom with methyl, difluoromethyl, isopropyl or ethyl and/or on a carbon atom by fluoro or methyl; provided that when HET-1 is pyrazolyl, R' is selected from 1-methoxyprop-2-yl, isopropyl, and tetrahydrofuryl,
HET-2 is selected from pyridyl, pyrazinyl, pyridazinyl, thiazolyl and pyrimidinyl, substituted by R? and optionally substituted by R>;
RPis methyl, fluoro or chloro;
R’ is -CONR'R’ or —SO,NRR’, particularly ~CONR'R’;
R* and R® together form an azetidinyl, 7-azabicyclo[2.2.1Thept-7-yl, morpholino, or pyrrolidinyl ring.
In another aspect, Aspect A, of the invention there is provided a compound of formula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:
R! is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl, but-2-yl, 1- hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl, 1-hydroxybut-2-yl and 1-methoxyprop-2-yl;
HET-1 is selected from pyrazinyl (optionally substituted with methyl), pyrazolyl (optionally substituted on carbon by methyl), methylthiadiazolyl (particularly 3-methyl- 1,2,4-thiadiazol-5-yl), thiazolyl (optionally substituted with methyl), pyridyl (optionally
@® substituted by fluoro) and isoxazolyl; provided that when HET-1 is pyrazolyl, particularly
R! is selected from 1-methoxyprop-2-yl, isopropyl, and tetrahydrofuryl;
HET-2 is selected from pyridyl, pyrazinyl, pyridazinyl, thiazolyl and pyrimidinyl, substituted by R? and optionally substituted by R’;
Riis methyl, fluoro or chloro;
R” is —-CONRR’ or -SO,NRR’, particularly ~CONR‘R’;
R*and R® together form an azetidinyl, 7-azabicyclo[2.2.1]hept-7-yl, morpholino, or oo pyrrolidinyl ring.
In another aspect, Aspect B, of the invention there is provided a compound of formula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:
R' is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl, but-2-yl, 1- hydroxyprop-2-yl, 2-hydroxybut-3 -yl, 1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl, 1-hydroxybut-2-yl and 1-methoxyprop-2-yl; : HET-1 is selected from pyrazinyl (optionally substituted with methyl), pyrazolyl (optionally substituted on carbon by methyl), methylthiadiazolyl (particularly 3-methyl- 1,2,4-thiadiazol-5-yl), thiazolyl (optionally substituted with methyl), pyridyl (optionally substituted by fluoro) and isoxazolyl; provided that when HET-1 is pyrazolyl, particularly : R' is selected from 1-methoxyprop-2-yl, isopropyl, and tetrahydrofuryl,
HET-2 is selected from pyridyl and pyrazinyl, substituted by R? and optionally substituted byR3 :
R?is methyl, fluoro or chloro;
R*is -CONR'R’ or -SO,NR*R’, particularly ~CONR’R’;
R*and R® together form an azetidinyl or pyrrolidinyl ring, particularly azetidinyl.
Particular compounds of Aspect B are those of formulae (IB), (IC) and/or (ID).
In another aspect, Aspect C, of the invention there is provided a compound of formula (IB), (IC) or (ID) as hereinbefore defined, or a salt thereof, wherein:
R! is selected from isopropyl, 1-hydroxyprop-2-yl, tetrahydrofuryl and l-methoxyprop-2- yl; (particularly R! is selected from isopropyl, (28)-1-hydroxyprop-2-y], tetrahydrofuryl and (28)-1-methoxyprop-2-yl); HET-1 is methylpyrazinyl,
R? is ~CONRR’;
R*and R® together form an azetidiny! ring.
Qo
In another aspect, Aspect D, of the invention there is provided a compound of formula (IB) as hereinbefore defined, or a salt thereof, wherein:
R! is selected from isopropyl, 1-hydroxyprop-2-yl, tetrahydrofuryl and 1-methoxyprop-2- : yl; (particularly R' is selected from isopropyl, (28)-1-hydroxyprop-2-yl, tetrahydrofuryl and (2S)-1-methoxyprop-2-yl);
HET-1 is methylpyrazinyl;
R? is ~-CONR‘R’;
R* and R® together form an azetidinyl ring.
In another aspect, Aspect E, of the invention there is provided a compound of formula (IB), (IC) or (ID) as hereinbefore defined, or a salt thereof, wherein:
R' is selected from isopropyl, tetrahydrofuryl and 1-methoxyprop-2-yl (particularly (2S)- 1-methoxyprop-2-yl);
HET-1 is pyrazolyl; ~ R?is-CONR'R>;
R*and R® together form an azetidinyl ring,
In another aspect, Aspect F, of the invention there is provided a compound of - formula (IB) as hereinbefore defined, or a salt thereof, wherein:
R' is selected from isopropyl, tetrahydrofuryl and 1-methoxyprop-2-yl (particularly (2S)-
I-methoxyprop-2-yl); HET-1 is pyrazolyl,
R?is -CONR‘R’;
R* and R’ together form an azetidinyl ring.
In another aspect of the invention there is provided a compound of formula (I) (or 1A) as hereinbefore defined, or a salt thereof, wherein:
R'is selected from isopropyl, but-2-yl, 1,3-difluoroprop-2-yl, 1-hydroxyprop-2-yl and 1- methoxyprop-2-y! and tetrahydrofuryl;
HET-1 is an optionally substituted 5- or 6-membered heteroaryl ring as hereinbefore defined;
HET-2 is an optionally substituted 5- or 6-membered heteroaryl ring as hereinbefore defined;
R? is —-SO,NR'R;
R*and R® together form an azetidinyl, pyrrolidiny] or morpholino ring.
®
In another aspect of the invention there is provided a compound of formula (I) (or
IA) as hereinbefore defined, or a salt thereof, wherein:
R'is selected from isopropyl, 1,3-difluoroprop-2-yl, 1-hydroxyprop-2-yl and 1- methoxyprop-2-yl,
HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl and pyrazinyl, wherein R! is optionally substituted on carbon or nitrogen with a methyl or ethyl group; :
HET-2 is selected from pyridyl, pyrazinyl, thiazolyl and thienyl, substituted by R? and optionally substituted by R?;
R? is fluoro or chloro ;
R%is -SO,NR‘R%;
R*and R® together form an azetidinyl, pyrrolidiny] or morpholino ring.
In another aspect of the invention there is provided a compound of formula (I) (or
IA) as hereinbefore defined, or a salt thereof, wherein:
R' is selected from isopropyl, 1,3-difluoroprop-2-yl, but-2-yl, 1-hydroxyprop-2-yl, 2- hydroxybut-3-yl, 1-difluoromethoxyprop-2-yl, tetrahydrofuryl, 1-hydroxybut-2-yl and 1- methoxyprop-2-yl;
HET-1 is an optionally substituted 5- or 6-membered heteroaryl ring as hereinbefore : defined; :
HET-2 is an optionally substituted 5- or 6-membered heteroaryl ring as hereinbefore defined;
R? is ~SO,NR*R’,;
R* and R® together form an azetidinyl, pyrrolidinyl or morpholino ring.
In another aspect of the invention there is provided a compound of formula (I) (or
IA) as hereinbefore defined, or a salt thereof, wherein: 25° R! is selected from isopropyl, 1,3-difluoroprop-2-yl, but-2-yl, 1-hydroxyprop-2-vyl, 2- hydroxybut-3-yl, 1-difluoromethoxyprop-2-yl, tetrahydrofuryl, 1-hydroxybut-2-yl and 1- methoxyprop-2-yl;
HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl and pyrazinyl, wherein R! is optionally substituted with a methyl, isopropyl or ethyl group;
HET-2 is selected from pyridyl, pyrazinyl, thiazolyl and pyrimidinyl, substituted by R? and optionally substituted by R®;
R? is fluoro or chloro; :
° 7.2009/014g,
R? is ~SO,NR'R’;
R*and R® together form an azetidinyl, pyrrolidiny! or morpholino ring.
In another aspect of the invention there is provided a compound of formula (I) (or
IA) as hereinbefore defined, or a salt thereof, wherein:
R! is selected from isopropyl, 1,3-difluoroprop-2-yl, but-2-yl, 1-hydroxyprop-2-yl, 2- hydroxybut-3-yl, 1-difluoromethoxyprop-2-yl, tetrahydrofuryl, I-hydroxybut-2-yl and 1- methoxyprop-2-yl;
HET-! is selected from thiazolyl, pyrazolyl, thiadiazolyl and pyrazinyl, wherein R! is optionally substituted with a methyl, isopropyl or ethyl group;
HET-2 is selected from pyridyl, pyrazinyl, thiazolyl and pyrimidiny], substituted by R* and optionally substituted by R?;
R3 is fluoro or chloro;
R? is —-CONR'R’ or -SO,NRR’;
R*and R® together form an azetidinyl, pyrrolidinyl or morpholino ring.
In one aspect of the invention there is provided a compound of formula @ (or1a) as hereinbefore defined, or a salt thereof, wherein:
R'is selected from 1-fluoromethoxyprop-2-yl and 1,1-difluoromethoxyprop-2-yl;
HET-1 is an optionally substituted 5- or 6-membered heteroaryl ring as hereinbefore defined; HET-2 is an optionally substituted 5- or 6-membered heteroaryl ring as hereinbefore defined;
R? is -CONR'R’;
R*and R® together form an azetidinyl, pyrrolidinyl or morpholino ning.
In another aspect of the invention there is provided a compound of formula @ (or
IA) as hereinbefore defined, or a salt thereof, wherein:
R'is selected from 1-fluoromethoxyprop-2-yl and 1,1-difluoromethoxyprop-2-yl;
HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl and pyrazinyl, wherein R! is optionally substituted on carbon or nitrogen with a methyl or ethyl group;
HET-2 is selected from pyridyl, pyrazinyl, thiazolyl and thienyl, substituted by R? and optionally substituted by R%;
R3 is fluoro or chloro;
R? is ~-CONR'R?,
®
R*and R® together form an azetidinyl, pyrrolidiny] or morpholino ring.
In one aspect of the invention there is provided a compound of formula (I) (or 1A) as hereinbefore defined, or a salt thereof, wherein:
R'is selected from 1-fluoromethoxyprop-2-yl and 1,1-difluoromethoxyprop-2-yl;
HET-1 is an optionally substituted 5- or 6-membered heteroaryl ring as hereinbefore defined;
HET-2 is an optionally substituted 5- or 6-membered heteroaryl ring as hereinbefore defined; :
R?is ~SO,NR'R’;
R*andR’ together form an azetidinyl, pyrrolidinyl or morpholino ring.
In another aspect of the invention there is provided a compound of formula (I) (or
TA) as hereinbefore defined, or a salt thereof, wherein:
R'is selected from 1-fluoromethoxyprop-2-yl and 1,1-difluoromethoxyprop-2-yl;
HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl and pyrazinyl, wherein R! is optionally substituted on carbon or nitrogen with 2 methyl or ethyl group; :
HET-2 is selected from pyridyl, pyrazinyl, thiazolyl and thienyl, substituted by R* and optionally substituted by R®; : R3 is fluoro or chloro;
R?is —SO,NR‘R’;
R*andR’ together form an azetidinyl, pyrrolidiny! or morpholino Ting.
Further preferred compounds of the invention are each of the Examples (and salts thereof), each of which provides a further independent aspect of the invention. In further aspects, the present invention also comprises any two or more compounds of the Examples (and salts thereof).
Particular compounds of the invention include any one or more of: 3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1 S)-2-hydroxy-1-methylethyl]oxy}-
N-1,3-thiazol-2-ylbenzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-y1]oxy} -5-{[(1S)-2-hydroxy-1- methylethyljoxy}-N-1,3-thiazol-2-ylbenzamide; ~ 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-ylJoxy}-5-{[(1 S)-2-hydroxy-1-methylethyl]oxy}-
N-1,3-thiazol-2-ylbenzamide;
3-{[5-(azetidin- [-ylcarbonyl)pyridin-3-ylJoxy}-5-{[(1 S)-2-hydroxy-1-methylethylJoxy}-
N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[6-(azetidin- 1-ylcarbonyl)pyridin-3-ylJoxy}-5-{[(1S) -2-hydroxy-1-methylethyl]oxy}-
N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-ylJoxy}-5- {[(1S)-1-methyl-2- (methyloxy)ethyljoxy}-N-(1-methyl-1 H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl] oxy }-5-{[(18)-1-methyl-2- (methyloxy)ethyljoxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy} -5-[(1-methylethyl)oxy]-N-1,3-thiazol-2- ylbenzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy }-5-[(1-methylethyl)oxy]-N-1,3- thiazol-2-ylbenzamide ; 3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yljoxy}-5-[(1 -methylethyl)oxy]-N-(1-methyl-1H- pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1 -methylethyl)oxy]-N-(1- methyl-1H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-ylJoxy}-5-{[(1S)-1 -methyl-2- (methyloxy)ethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-y1Joxy}-5-{[(1 S)-1-methyl-2- (methyloxy)ethylJoxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1 -methyl-2- (methyloxy)ethylJoxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyridin-3-yljoxy}-5-{[(1S)-1 -methyl-2- (methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyridin-3-ylJoxy}-5-[(1 -methylethyl)oxy]-N-(1-methyl-18- pyrazol-3-yl)benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-ylJoxy}-5-[(1-methylethyl)oxy]-N-1,3-thiazol-2- ylbenzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-ylJoxy}-5-[(1-methylethyl)oxy] -N-(1-methyl-1H- pyrazol-3-yl)benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-ylJoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethyljoxy}-N-1,3-thiazol-2-ylbenzamide;
® 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-ylJoxy}-5-{[(1S)-1-methyl-2- : (methyloxy)ethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-ylJoxy}-5-[(1-methylethyl)oxy]-N-(3-methyl-1,2,4- thiadiazol-5-yl)benzamide; 3-{[5-(azetidin-1-ylsulfonyl)pyridin-2-ylJoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethylJoxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-ylJoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethyljoxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-yljoxy}-5-[(1 -methylethyl)oxy]-N-(1-methyl- 1H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yljoxy}-5-{[(1 S)-2-hydroxy-1-methylethyl]oxy}-
N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[3-chloro-5 ~(morpholin-4-ylcarbonyl)pyridin-2-ylJoxy} -5-{[(1S)-2-hydroxy-1- methylethylJoxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide; and 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yljoxy}-5- {[2-fluoro-1- (fluoromethyl)ethyljoxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide; and/or 3-{[5-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-ylJoxy}-5-{[( 1 S)- 1-methyl-2- : (methyloxy)ethylJoxy}-N-(1-methyl-1H-pyrazol-3-yDbenzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yljoxy }-5-{[(1S)-1 -methylpropyljoxy}-N- (1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-ylJoxy }-5-{[(1S)-1-methylpropyljoxy}-N-(1- methyl-1H-pyrazol-3-yl)benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yljoxy}-5-{[(1S)-1 -methylpropyljoxy}-N-(1- methyl-1H-pyrazol-3-yl)benzamide; 3-{[2-(azetidin-1-ylcarbonyl)pyrimidin-S-yl]oxy}-5-[(1 -methylethyl)oxy]-N-(1-methyl- 1H-pyrazol-3-yl)benzamide; 3-{[2-(azetidin-1-ylcarbonyl)pyrimidin-5-ylJoxy}-5-{[(1S)- 1-methyl-2- (methyloxy)ethylJoxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[2-fluoro-1-(flucromethyl)ethyljoxy} - N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-ylJoxy}-5-{[2-fluoro-1-(flucromethyl)ethyl] oXy}-
N-(1-methyl-1H-pyrazol-3-yl)benzamide;
: 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-ylJoxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H- pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yljoxy}-5-( {(18)-2- [(difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1 -methyl-1H-pyrazol-3-yl)benzamide;
3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-({(1 S)-2-[(difluoromethyl)oxy]-1- methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yljoxy}-5-({(1 S)-2-[(difluoromethyl)oxy]-1- methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-ylJoxy}-5-({(1 S)-2-[(difluoromethyl)oxy]-1-
methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3 ~chloropyridin-2-ylJoxy}-5-{[(1R,2R)-2-hydroxy-1- methylpropyljoxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
-3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yljoxy}-5 -{[(185,2S)-2-hydroxy-1- methylpropyl]oxy}-N-(1-methyl-1H- pyrazol-3-yl)benzamide;
3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1-ethyl-1 H-pyrazol-3-yl)-5- {{(18)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-ethyl-1 H-pyrazol-3-yl)-5-{[(1S)-1- methyl-2-(methyloxy)ethyl]oxy } benzamide; : 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yljoxy}-N-(1-ethyl-1 H-pyrazol-3-yl1)-5-{[(1S)-1-
methyl-2-(methyloxy)ethyl]oxy }benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yljoxy}-5-{[(1 S)-2-hydroxy-1- methylethyl]oxy}-N-[1-(1-methylethyl)- 1H-pyrazol-3-yl]benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yljoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethyl]Joxy}-N-1H-pyrazol-3-ylbenzamide;
3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yI]oxy}-N-(1-methyl- 1H-pyrazol-3-yl)-5- [(3S)-tetrahydrofuran-3-yloxy]benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-methyl-1 H-pyrazol-3 -y1)-5-[(3S)- tetrahydrofuran-3-yloxy]benzamide; 3-{[5-(azetidin- 1-ylcarbonyl)pyrazin-2-yl] oxy }-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-
tetrahydrofuran-3-yloxy]benzamide; 3-{[4-(azetidin- 1-ylcarbonyl)-1,3-thiazo}-2-ylJoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;
® 3-{[4~(azetidin-1-ylcarbonyl)-1,3-thiazol-2-ylJoxy}-5-[(1 -methylethyl)oxy]-N-(1-methyl- 1H-pyrazol-3-yl)benzamide; 3-{ [5-(azetidin-1-ylcarbonyl)pyrazin-2-ylJoxy}-5-{[(1S)-1 -(hydroxymethyl)propylloxy}-
N-(1-methyl-1H-pyrazol-3-yl)benzamide; and/or 3-{[2-(azetidin-1-ylcarbonyl)pyrimidin-5-ylJoxy}-5-{[(1S)-1 -methyl-2- (methyloxy)ethylJoxy}-N-1,3-thiazol-2-ylbenzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yljoxy}-5 -(cyclopentyloxy)-N-(1-methyl-1H- pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yljoxy} -5-(cyclopentyloxy)-N-( 1-methyl- 1H-pyrazol-3-yl)benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yI]oxy}-5-(cyclopentyloxy)-N-(1 -methyl-1H- pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R,2R)-2-hydroxy-1- methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yljoxy}-5-{[(1S,2S)-2-hydroxy-1- : methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-ylJoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethyljoxy}-N-(5-methylpyrazin-2-yl)benzamide; 3-{[5 (azetidin- 1-ylcarbonyl)-3-chloropyridin-2-ylJoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethylJoxy}-N-(5-methylpyrazin-2-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-ylJoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethyljoxy}-N-(5-methylpyrazin-2-yl)benzamide; - 3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-ylJoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide; 3-{[4-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-ylJoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide; 3-{[5-(azetidin- 1-ylcarbonyl)-4-methyl-1,3-thiazol-2-ylJoxy}-5-{[(1S)-1 -methyl-2- (methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-4-methyl-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethylJoxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-ylJoxy} -5-[( 1-methylethyl)oxy] -N-(5- methylpyrazin-2-yl)benzamide;
®
3-{[5-(azetidin-1 -ylcarbonyl)pyrazin-2-ylJoxy}-5-[(1 -methylethyl)oxy)-N-(5- methylpyrazin-2-yl)benzamide; 3-{[5-(azetidin-1 -ylcarbonyl)pyridin-2-yl] 0xy}-5-[(1-methylethyl)oxy]-N-(5- methylpyrazin-2-yl)benzamide; 3-{[5-(azetidin-1 -ylcarbonyl)-4-methyl-1,3-thiazol-2 -yljoxy}-5-[(1-methylethyl)oxy}-N- (5-methylpyrazin-2-yl)benzamide; 3-{[6-(azetidin- 1-ylcarbonyl)pyridin-3 -ylJoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethyl]oxy} -N-(5-methylpyrazin-2-yl)benzamide; 3-{[6-(azetidin-1 -ylcarbonyD)pyridin-3-yl]oxy}-5 -[(1-methylethyl)oxy]-N-(5- methylpyrazin-2-yl)benzamide ; 3-{[5-(azetidin-1-ylcarbonyl) -3-chloropyridin-2-yIJoxy}-5-{[(1 S)-1-methyl-2- (methyloxy)ethylJoxy}-N-1 H-pyrazol-3-ylbenzamide; 3-{[5-(azetidin-1 -ylcarbonyl)-3-chloropyridin-2-y1] 0xy }-5-{[(1S)-1-methyl-2- (methyloxy)ethyl]Joxy}-N-1,3-thiazol-2-ylbenzamide 5 3-{[5-(azetidin-1-ylcarbonyl)-3 -chloropyridin-2-ylJoxy}-5-{[(1S)-1 -methyl-2- (methyloxy)ethyloxy} -N-pyridin-2-ylbenzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3 -chloropyridin-2-yljoxy}-N-(1 -ethyl-1H-pyrazol-3-yl)-5- [(1-methylethyl)oxy]benzamide; 3-{[5-(azetidin-1 -ylcarbonyl)pyrazin-2-yl]oxy}-N-(1 -ethyl-1H-pyrazol-3-yl)-5-[(1-
methylethyl)oxy]benzamide; 3-{{5-(azetidin-1 -ylcarbonyl)pyrazin-2-yl]oxy}-N-[1 ~(1-methylethyl)-1H-pyrazol-3 -yl}-5- {[(18)-1 -methyl-2-(methyloxy)ethyljoxy }benzamide; 3-{[6-(azetidin- 1-ylcarbonyl)pyridin-3 -ylJoxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5 -[(1- methylethyl)oxy]benzamide;
3-{[6-(azetidin-1 -ylcarbonyl)pyridin-3-ylJoxy}-5-{[(18)-1 -methyl-2- (methyloxy)ethyl]oxy}-N-pyridin-2-ylbenzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl] oxy}-N-isoxazol-3-yl-5-{[(1S)-1-methyl-2- (methyloxy)ethyljoxy} benzamide; 3-{[5-(azetidin-1 -ylcarbonyl)-3-chloropyridin-2-yl] oxy}-5-[(1-methylethyl)oxy]-N-(3-
methyl-1,2,4-thiadiazol-5-y])benzamide; 3-{[6-(azetidin-1 -ylcarbonyl)pyridin-3-ylJoxy}-5-[(1 -methylethyl)oxy]-N-1H-pyrazol-3- ylbenzamide;
®
3-{[6-(azetidin-1-ylcarbonyl)pyridin-3 -yljoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethylJoxy}-N-1H-pyrazol-3 -ylbenzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl] oxy }-5-[(1-methylethyl)oxy]-N-1H-pyrazol-3- ylbenzamide;
3-{[5-(azetidin-1 -ylearbonyl)pyrazin-2-yljoxy}-5-{[(1S)-1 -methyl-2- (methyloxy)ethyl]oxy}-N-1H-pyrazol-3 -ylbenzamide; 3-{[5-(azetidin-1 -ylearbonyl)-3-chloropyridin-2-ylJoxy}-5-[(1 -methylethyl)oxy]-N-1H- pyrazol-3-ylbenzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3 -chloropyridin-2-yljoxy}-N~(1,5-dimethyl-1H-pyrazol-3-
yD-5-{[(1S)-1 -methyl-2-(methyloxy)ethyl]oxy}benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3 -chloropyridin-2-y1] oxy }-N-(1,5-dimethyl-1H-pyrazol-3- yD-5-{[2-fluoro-1-(fluoromethyl)ethyl] oxy }benzamide; 3-{[6-(azetidin-1 -ylcarbonyl)pyridazin-3-y1] oxy }-5-{[(1S)-1-methyl-2- (methyloxy)ethyljoxy}-N-(1-methyl-1 H-pyrazol-3-yl)benzamide;
3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl] oxy }-N-(4-methyl-1,3-thiazol-2-yI)-5-[(3S)- tetrahydrofuran-3-yloxyJbenzamide; 3-{[5-(azetidin-1 -ylcarbonyl)pyrazin-2-yljoxy}-N-(5-methyl-1,3 -thiazol-2-y1)-5-[(3S)- tetrahydrofuran-3-yloxy]benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl] oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(3S)-
tetrahydrofuran-3-yloxy]benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl] 0xy}-N-[1-(1-methylethyl)-1H-pyrazol-3-y1}-5- [(3S)-tetrahydrofuran-3-yloxy]benzamide; 3-{[5 ~(azetidin-1 -ylcarbonyl)pyrazin-2-yljoxy}-N-1H-pyrazol-3-yl-5 -[(3S)- tetrahydrofuran-3-yloxy]benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2 -ylJoxy}-N-(1,5-dimethyl- 1H-pyrazol-3-yl)-5 -[(3S)- tetrahydrofuran-3-yloxy]benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3 ~chloropyridin-2-yljoxy}-N-(4-methyl-1,3-thi azol-2-yl)-5- [(3S)-tetrahydrofuran-3-yloxy]benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3 -chloropyridin-2-yljoxy}-N-(5-methyl-1,3 -thiazol-2-yl)-5- [(3S)-tetrahydrofuran-3-yloxy]benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-ylJoxy} -N-(5-methylpyrazin-2-y1)-5- [(3S)-tetrahydrofuran-3-yloxy]benzamide;
_
3-{[5-(azetidin-1-ylcarbonyl)-3 -chloropyridin-2-ylJoxy}-N-(1-ethyl-1H-pyrazol-3 -yD-5- [(3S) -tetrahydrofuran-3-yloxy]benzamide; 3-{[5-(azetidin-1 -ylearbony!)-3-chloropyridin-2-yljoxy} -N-[1-(1-methylethyl)-1H- pyrazol-3-yl}-5-[(3S)-tetrahydrofuran-3 -yloxy]benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3 -chloropyridin-2-ylJoxy}-N-1H-pyrazol-3 -yl-5-[(3S)- tetrahydrofuran-3-yloxy]benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3 -ylJoxy}-N-(5-methylpyrazin-2-yl)-5- [(3S)- tetrahydrofuran-3 -yloxy]benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl] oxy}-N-(5-methylpyrazin-2-yl)-5-[(3S)- tetrahydrofuran-3-yloxy]benzamide; 3-{[6-(azetidin-1-ylearbonyl)pyridin-3 -ylJoxy}-N-(5-fluoropyridin-2-y1)-5- [(3S)- tetrahydrofuran-3-yloxy]benzamide; 3-{[3-chloro-5-(pyrrolidin-1 -ylearbonyl)pyridin-2-ylJoxy}-5-{(1 -methylethyl)oxy]-N-(5- methylpyrazin-2-yl)benzamide; 3-{[3-chloro-5-(pyrrolidin-1 -ylcarbonyl)pyridin-2-ylJoxy} -5-{[(1S)-1-methyl-2- (methyloxy)ethyljoxy}-N-(5 -methylpyrazin-2-yl)benzamide; 3-{[3-chloro-5-(pyrrolidin-1 -ylcarbonyl)pyridin-2-ylJoxy}-N-(1 -methyl-1H-pyrazol-3-yl)- 5-[(3S)-tetrahydrofuran-3-yloxy]benzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-ylJoxy}-N ~(1-methyl-1H-pyrazol-3-yl)-5- ‘ (tetrahydro-2H-pyran-4-yloxy)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3 ~chloropyridin-2-ylJoxy}-N-(1-methyl-1 H-pyrazol-3-y1)-5- (tetrahydro-2H-pyran-4-yloxy)b enzamide; 3-{[5-(azetidin-1-ylcarb onyl)pyrazin-2-yljoxy}-N-(5 -methylpyrazin-2-yl)-5-(tetrahydro- 2H-pyran-4-yloxy)benzamide; 3-5 -(azetidin- 1-ylcarbonyl)-3-chloropyridin-2-yl] 0Xy }-N-(5-methylpyrazin-2 -yD-5- (tetrahydro-2H-pyran-4-yloxy)benzamide ; 3-{[6-(azetidin-1 -ylearbonyl)pyridin-3-ylJoxy}-N-(1-methyl-1 H-pyrazol-3-yl)-5- (tetrahydro-2H-pyran-4-yloxy)benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl] oxy}-N-(5 -methylpyrazin-2-yl)-5-(tetrahydro- 2H-pyran-4-yloxy)benzamide; and 3-{[6-(azetidin-1-yloarbonyl)pyridin-3-yl]oxy) -N-(1-methyl- IE-pyrazol-3 y1)-5-[(3R)- tetrahydrofuran-3-yloxy]benzamide; and/or
® 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3 -ylJoxy}-N-isoxazol-3-y1-5-[(3S)-tetrahydrofuran-3- yloxy]benzamide; 3-{[5-(azetidin-} -ylearbonyl)pyrazin-2-yljoxy} -N-pyrazin-2-yl-5-[(3S)-tetrahydrofuran-3- yloxylbenzamide; : 3-{[5-(azetidin-1 -ylcarbonyl)pyrazin-2-yljoxy} -N-(5-fluoropyridin-2-yl)-5-[(3S)- tetrahydrofuran-3-yloxy]benzamide; 3-{[5-(azetidin-1 -ylcarbonyl)pyrazin-2-yljoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethyl]oxy}-N-pyridin-2-ylbenzamide; 3-{[5-(azetidin-1 -ylcarbonyl)pyrazin-2-yljoxy}-N-isoxazol-3 -yl-5-{[(1S)-1-methyl-2- (methyloxy)ethylJoxy}benzamide; 3-{[5-(azetidin-1 -ylcarbonyl)pyrazin-2-yljoxy}-5-{[(1S)-1 -methyl-2- (methyloxy)ethyl]oxy }-N-(4-methyl-1 ,3-thiazol-2-yl)benzamide; 3-{[5-(azetidin-1 -ylcarbonyl)pyrazin-2-ylJoxy}-5-{[(1S)-1 -methyl-2- (methyloxy)ethyl]oxy}-N-(5-methyl-1,3-thiazol-2 -y)benzamide; 3-{[5-(azetidin-1 -ylcarbonyl)pyrazin-2-yljoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethylloxy} -N-pyrazin-2-ylbenzamide; 3-{[5-(azetidin- 1-ylcarbonyl)pyrazin-2-yljoxy}-5-[(1 -methylethyl)oxy] -N-pyrazin-2- ylbenzamide; 3-{[6-(azetidin- 1-ylcarbonyl)pyridin-3-yl] oxy }-5-{[(15)-1-methyl-2- (methyloxy)ethylJoxy} ~N-pyrazin-2-ylbenzamide; : 3-{[5-(azetidin-1-ylcarb onyl)-3-chloropyridin-2-yljoxy}-5-[(1 -methylethyDoxy]-N- pyrazin-2-ylbenzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3 ~chloropyridin-2-ylJoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethyl]oxy}-N-pyrazin-2-ylbenzamide; 3-43 -chloro-5-(morpholin-4-ylcarbonyl)pyridin-2-ylJoxy} -N-(1-methyl-1H-pyrazol-3-yl)- 5-[(3S)-tetrahydrofuran-3-yloxy]benzamide; 3-{[5-(7-azabicyclo[2.2.1]hept-7-ylcarbonyl)-3 -chloropyridin-2-yljoxy}-N-(1-methyl- 1H- pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide; and 3-{[5-(azetidin-1-ylcarbonyl)-4-methyl-1 ,3-thiazol-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3- yl)-5-[(3S)-tetrahydrofuran-3 -yloxyJbenzamide; and/or 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yljoxy}-5- {[(1S)-2-hydroxy-1-methylethyl]Joxy}-
N-(5-methylpyrazin-2-yl)benzamide; | :
3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-y] oxy}-5-{[(18S)-2-hydroxy-1-methylethyljoxy}-
N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide ; : 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2 -ylJoxy}-5-{[(18S)-2-hydroxy-1- methylethylJoxy }-N-( 5-methylpyrazin-2-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3 -chloropyridin-2-yljoxy}-5-{[(1S)-2-hydroxy-1- methylethyl]oxy}-N-(3-methyl-1 ,2,4-thiadiazol-5-yl)benzamide; 3-{[5-(azetidin-1 -ylcarbonyl)-3-chloropyridin-2-yljoxy}-5-{[(1 S)-2-hydroxy-1- methylethylJoxy}-N-pyrazin-2-ylbenzamide; 3-{[5-(azetidin-1 -ylearbonyl)-3-chloropyridin-2-yljoxy}-5-{ [(1 S)-2-hydroxy-1- methylethylloxy} -N-pyridin-2-ylbenzamide; 3-{[5-(azetidin-1 -ylearbonyl)pyridin-2-y1] oxy}-5-{[(1S)-2-hydroxy-1-methylethyljoxy}-
N-(3-methyl-1,2,4-thiadiazol-5-y])benzamide;
N-(1-methyl-1H-pyrazol-3-y1)-3-{[6-(pyrrolidin-1 -ylearbonyl)pyridin-3-ylJoxy}-5-[(3S)- tetrahydrofuran-3-yloxy]benzamide; : 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-y1] oxy }-N-pyrazin-2-yl-5-[(3S)-tetrahydrofuran-3- yloxy]benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3 -ylJoxy}-N-(5-methyl-1H-pyrazol-3-y1)-5-[ (3S)- tetrahydrofuran-3-yloxy]benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl] oxy }-N-1H-pyrazol-3-y1-5-[(3S)- tetrahydrofuran-3-yloxy]benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3 -chloropyridin-2-y1joxy}-5-{[2-fluoro-1- (fluoromethyl)ethyljoxy}-N-(5 -methylpyrazin-2-yl)benzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3 -chloropyridin-2-yljoxy}-5-{[2-fluoro-1- (fluoromethyl)ethyl]oxy }-N-1H-pyrazol-3-ylb enzamide; 3-{[5-(azetidin-1-ylcarbonyl)-3 -chloropyridin-2-ylJoxy}-5-{[2-fluoro-1- (fluoromethyl)ethyl]oxy }-N-(5-methyl-1H-pyrazol-3 -ylbenzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yljoxy}-5- { [2-fluoro- 1-(fluoromethyl)ethyljoxy}-
N-1H-pyrazol-3-ylbenzamide; 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yljoxy}-5-{[2-fluoro-1 ~(fluoromethyl)ethyl]oxy}-
N-(5-methylpyrazin-2-yl)benzamide; 3-{[5-(azetidin- 1-ylcarbonyl)pyrazin-2-yljoxy}-5 -{[(1S)-2-hydroxy-1 -methylethylloxy}-
N-(5-methylpyrazin-2-yl)benzamide;
® 3-{ [5-(azetidin-1-ylcarbonyl)pyrazin-2-yljoxy}-5 ~({(18)-2-[(difluoromethyl)oxy]-1- methylethyl}oxy)-N-1H-pyrazol-3-ylb enzamide; 3-{[5-(azetidin-1-ylsulfonyl)-4-methyl-1 ,3-thiazol-2-ylJoxy}-5-{[(1S)-1-methyl-2- (methyloxy)ethyl]oxy}-N-(5 -methylpyrazin-2-yl)benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3 -y1Joxy}-N-[1-(difluoromethyl)-IH-pyrazol-3 -yl]-5- [3 S)-tetrahydrofuran-3-yloxy]benzamide; 3-{[5-(azetidin-1 -ylearbonyl)pyrazin-2-yljoxy} -N-[1-(difluoromethy1)-1H-pyrazol-3 -yl}-5- {[(1S)-1-methyl-2-(methyloxy) ethyl]oxy}benzamide; 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3 -yljoxy}-N-[1-(difluoromethyl)-1H-pyrazol-3 -yl]-5- {[(19)-1 -methyl-2-(methyloxy)ethyIjoxy }benzamide; and/or 3-{[5-(azetidin-1 -ylcarbonyl)pyrazin-2-yljoxy}-5-{[(1R)-1 -methyl-2- (methyloxy)ethyl] oxy }-N-(5-methylpyrazin-2-yl)benzamide; 3-{[6-(azetidin-1 -ylcarbonyl)pyridin-3-y1loxy} -5-{[(1R)-1-methyl-2- (methyloxy)ethyl] oxy }-N-(5-methylpyrazin-2-yl)benzamide; or a salt thereof,
A further feature of the invention is a pharmaceutical composition comprising a : compound of Formula (I), (IA), (IB), (IC) or (ID) as defined above, or a pharmaceutically- acceptable salt thereof, together with a pharmaceutically-acceptable diluent or carrier.
According to another aspect of the invention there is provided the a compound of
Formula (I), (TA), (IB), (IC) or (ID) or a pharmaceutically-acceptable salt thereof as defined above for use as a medicament.
According to another aspect of the invention there is provided the a compound of
Formula (I), (IA), (IB), (IC) or (ID) or a pharmaceutically-acceptable salt thereof as defined above for use as a medicament for treatment of a disease mediated through GLK, in particular type 2 diabetes.
Further according to the invention there is provided the use a compound of Formula @, (1A), (IB), (IC) or (ID) or a pharmaceutically-acceptable salt thereof in the preparation of a medicament for treatment of a disease mediated through GLK, in particular type 2 diabetes.
The compound is suitably formulated as a pharmaceutical composition for use in this way.
According to another aspect of the present invention there is provided a method of treating GLK mediated diseases, especially diabetes, by administering an effective amount of a compound of Formula (I), (IA), (IB), (IC) or (ID) or a pharmaceutically-acceptable salt thereof, to a mammal in need of such treatment.
Specific diseases which may be treated by a compound or composition of the invention include: blood glucose lowering in Type 2 Diabetes Mellitus without a serious risk of hypoglycaemia (and potential to treat type 1), dyslipidemia, obesity, insulin resistance, metabolic syndrome X, impaired glucose tolerance.
As discussed above, thus the GLK/GLKRP system can be described as a potential “Diabesity” target (of benefit in both Diabetes and Obesity). Thus, according to another aspect of the invention there is provided the use of a compound of Formula (I), (IA), (IB), (IC) or (ID) or a pharmaceutically-acceptable salt thereof, in the preparation of a medicament for use in the combined treatment or prevention, particularly treatment of diabetes and obesity.
According to another aspect of the invention there is provided the use of a compound of Formula (I), (IA), (IB), (IC) or (ID) or a pharmaceutically-acceptable salt thereof, in the preparation of a medicament for use in the treatment or prevention, particularly treatment of obesity.
According to another aspect of the invention there is provided the a compound of : 20 Formula (I), (IA), (IB), (IC) or (ID) ora pharmaceutically-acceptable salt thereof as : defined above for use as a medicament for treatment or prevention, particularly treatment of obesity. a.
According to a further aspect of the invention there is provided a method for the combined treatment of obesity and diabetes by administering an effective amount of a compound of Formula (I), (IA), (IB), (IC) or (ID) or a pharmaceutically-acceptable salt thereof, to a mammal in need of such treatment.
According to a further aspect of the invention there is provided a method for the treatment of obesity by administering an effective amount of a compound of Formula (J), (IA), (IB), (IC) or (ID) or a pharmaceutically-acceptable salt thereof, to a mammal in need of such treatment.
_
Compounds of the invention may be particularly suitable for use as pharmaceuticals because of advantageous physical and/or pharmacokinetic properties, and/or favourable toxicity profile and/or favourable metabolic profile.
Favourable toxicity profile may be demonstrated, for example, by use of an Ames test assay, and/or by testing against the hERG ion channel. A favourable metabolic profile may mean, for example, reduced rate of metabolism, leading to reduction in clearance of the compound from the body and hence increased exposure to the compound, or a favourable metabolic profile may mean, for example, not forming active metabolites (which might be considered undesirable in some circumstances).
For example, compounds of Aspects A to F may have favourable toxicological profiles.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration : (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). Dosage forms suitable for oral use are preferred.
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the
® gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexito] such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) orin a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
Claims (13)
1. A compound which is: 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-ylJoxy}-5-[(1-methylethyl)oxy]-N-1H-pyrazol-3- ylbenzamide; ! or a salt thereof. Ce I
2. A pharmaceutical composition comprising a compound according to Claim 1, or a pharmaceutically-acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
3. A compound according to Claim 1, or a pharmaceutically-acceptable salt thereof for use as a medicament.
4 A compound according to Claim 3, wherein the medicament is a medicament for : treatment of a disease mediated through GLK, in particular type 2 diabetes. DE
5. The use of a compound according to Claim 1, or a pharmaceutically-acceptable salt thereof, in the preparation of a medicament for treatment of a disease mediated through GLK.
6. The use of a compound according to Claim 1, or a pharmaceutically-acceptable salt thereof, in the preparation of a medicament for treatment of type 2 diabetes.
7. A process for the preparation of the compound of Claim 1 or a salt thereof, comprising reaction of 1-dimethylethyl 3-[({3-hydroxy-5-[(1- methylethyl)oxy]phenyl}carbonyl)amino]-/ H-pyrazole- 1 -carboxylate with 2-(azetidin-1- ylcarbonyl)-5-chloropyrazine; and thereafter if necessary forming a salt thereof.
8. A combination of a compound according to Claim 1, or a pharmaceutically acceptable salt, solvate or pro-drug thereof with one or more other substances and/or treatments. .
9. A compound as claimed in claim 1 or a salt thereof, substantially as herein described with reference to and/or as illustrated by any of the examples.
q -250- Nery
10. A pharmaceutical composition as claimed in claim 2, substantially as herein described with reference to and/or as illustrated by any of the examples.
11. The use as claimed in claim 5 or claim 6, substantially as herein described with reference to and/or as illustrated by any of the examples.
10 .
12. A process as claimed in claim 7, substantially as herein described with reference to and/or as illustrated by any of the examples.
13. A combination as claimed in claim 8, substantially as herein described with reference to and/or as illustrated by any of the examples. Dated on tl 1 of March 2909 \\ /| Adalns & Adams Applicants Patent Attorneys )
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GB0514173A GB0514173D0 (en) | 2005-07-09 | 2005-07-09 | Chemical compounds |
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ZA200901999A ZA200901999B (en) | 2005-07-09 | 2009-03-20 | Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes |
ZA200901998A ZA200901998B (en) | 2005-07-09 | 2009-03-20 | Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes |
ZA200901997A ZA200901997B (en) | 2005-07-09 | 2009-03-20 | Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes |
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ZA200901998A ZA200901998B (en) | 2005-07-09 | 2009-03-20 | Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes |
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GB (1) | GB0514173D0 (en) |
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GB0514173D0 (en) | 2005-08-17 |
ZA200901998B (en) | 2009-12-30 |
ZA200800054B (en) | 2009-07-29 |
CN101445505B (en) | 2016-04-20 |
CN101386618A (en) | 2009-03-18 |
CN101258150A (en) | 2008-09-03 |
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