Patent Application
20170369492
The present invention relates to 1,3-substituted 2-amino-indole derivatives and analogues, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment or prevention of conditions having an association with the GPR43 receptor, such as diabetes mellitus, obesity and inflammatory bowel disease.
Targeting the release of anorectic and antidiabetic gut peptides is the focus of many ongoing drug development programs, as evidence is accumulating that enhanced secretion of Peptide YY (PYY) and Glucagon-Like Peptide-1 (GLP-1) from intestinal L-cells may translate into beneficial effects in subjects with diabetes and obesity.
Short chain fatty acids (SCFA), derived from bacterial fermentation of macrofibrous material reaching the distal gut are known to reach high concentrations under physiological conditions in the colons of healthy subjects. Non-digestible and fermentable dietary fibre, as well as SCFA themselves, have been shown to increase GLP-1 and PYY secretion in humans (Zhou et al., Am. J. Physiol. Endocrinol. Metab., 2008, vol. 295(5), pp. E1160-E1166), and enhanced PYY release has been proposed as a link between luminal SCFA and altered gut motility (Dumoulin et al., Endocrinology, 1998, vol. 139(9), pp. 3780-3786).
SCFA act as a local nutrient source, but can also trigger cell-specific signalling cascades by activation of the G-protein coupled free fatty acid receptors, GPR41 (FFAR3) and GPR43 (FFAR2) (Brown et al., J. Biol. Chem., 2003, vol. 278(13), pp. 11312-11319). The finding that both receptors are located in colonic L cells by immunostaining (Tazoe et al., Biomed. Res., 2009, vol. 30(3), pp. 149-156), suggests that short chain fatty acids may utilise this pathway to modulate L-cell function. In addition to L cells, GPR43 is also expressed in Islets of Langerhans, white adipose tissue, bone marrow and spleen.
GPR43 knockout mice have impaired glucose tolerance, with reduced insulin secretion and reduced GLP-1 secretion (Tolhurst et al., Diabetes, 2012, vol. 61, pp. 364-371). They have increased fat mass and a mild increase in food intake. From this it can be deduced that activation of the GPR43 receptor should lead to beneficial effects in the treatment of diabetes and obesity.
GPR43 is also expressed on a variety of immune cells, so may represent a potential treatment for certain inflammatory diseases and conditions (Bindels L B, Dewulf E M, Delzenne N M., Trends Pharmacol Sci., 2013, 34(4), Pp. 226-32; Macia L et al., Nat Commun, 2015, 6, article 6734; and Smith, P M et al, Science, 2013, 341 (6145), pp. 569-573).
There is therefore a need for compounds that activate the GPR43 receptor.
Certain 3-substituted 2-amino-indole analogues are known in the art. WO 2004/060893 describes a broad class of such compounds useful for treating a variety of diseases modulated by potassium channels. Other substituted indole analogues are known from WO 2012/064897, WO 2005/023818, WO 2011/140164, WO 2011/153553 and US 2014/0018361.
In accordance with the present invention, there is provided a compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
In the context of the present specification, unless otherwise stated, an “alkyl” substituent group or an alkyl moiety in a substituent group may be linear or branched. Examples of alkyl groups/moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, and n-hexyl.
A “haloalkyl” substituent group or a haloalkyl moiety in a substituent group refers to an alkyl group or moiety in which one or more, e.g. one, two, three, four or five, hydrogen atoms are replaced independently by halogen atoms, i.e. by fluorine, chlorine, bromine or iodine atoms. Examples of haloalkyl groups/moieties include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl.
A “hydroxyalkyl” substituent group or a hydroxyalkyl moiety in a substituent group refers to an alkyl group or moiety in which one or more, e.g. one, two, three, four or five, hydrogen atoms are replaced by hydroxyl groups, examples of which include —CH2OH, —CH2CH2OH, —CH2CH2CH2OH, —CH(OH)CH2OH, —CH(CH3)OH and —CH(CH2OH)2.
The term “(halo)phenylcarbonyl” denotes a phenylcarbonyl group which is optionally substituted with from 1 to 5 independently selected halogen atoms, an example of which is fluorophenylcarbonyl.
A “cycloalkyl” substituent group or a cycloalkyl moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, from 3 to 8 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless stated otherwise, a cycloalkyl substituent group or moiety may include monocyclic, bicyclic (e.g. fused or spiro) and polycyclic hydrocarbyl rings.
An “alkenyl” substituent group or an alkenyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon double bonds. Examples of alkenyl groups/moieties include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1,4-hexadienyl.
A “cycloalkenyl” substituent group or a cycloalkenyl moiety in a substituent group refers to an unsaturated hydrocarbyl ring having one or more carbon-carbon double bonds and containing, for example, from 3 to 8 carbon atoms, examples of which include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl and cyclohex-1,3-dien-1-yl. Unless stated otherwise, a cycloalkenyl substituent group or moiety may include monocyclic, bicyclic (e.g. fused or spiro) and polycyclic hydrocarbyl rings.
A “C6-C10 aryl” group refers to a group derived from an aromatic hydrocarbon containing from six to ten carbon atoms. The aryl group may be monocyclic or polycyclic (e.g. bicyclic) in which the two or more rings are fused, examples of which include phenyl, 1-naphthyl and 2-naphthyl. Also included within the scope of the term “aryl”, as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings as exemplified by indanyl and tetrahydronaphthyl. An aryl group may be bonded at any suitable ring atom.
A “heteroaryl” group is a 5- to 10-membered aryl group in which from 1 to 4 ring carbon atoms are replaced by heteroatoms independently selected from nitrogen, oxygen and sulphur. The heteroaryl group can be bonded at any suitable ring atom (i.e. at any carbon or heteroatom of the heteroaryl ring system). Examples of heteroaryl groups include the following:
The term “halogen” includes fluorine, chlorine, bromine and iodine.
When a group or moiety is described as being ‘unsaturated’, it should be understood that the group or moiety may be partially or fully unsaturated and thus may have aliphatic or aromatic properties.
For the purposes of the present invention, where a combination of moieties is referred to as one group, for example, arylalky or alkoxycarbonyl, the last mentioned moiety contains the atom by which the group is attached to the rest of the molecule. An example of an arylalkyl group is benzyl and an example of an alkoxycarbonyl group is —C(O)OCH3.
It will be appreciated that the invention does not encompass any unstable structures or any divalent —O—O—, —O—S— or —S—S— moieties. When any chemical moiety or group is described as being optionally substituted, it will be appreciated that the moiety or group may be either unsubstituted or substituted by one or more of the specified substituents. It will be appreciated that the number and nature of substituents will be selected so as to avoid sterically undesirable combinations.
In an embodiment of the invention, one of X4, X5, X6 and X7 is N, e.g. X4 is N or X7 is N.
In another embodiment of the invention, two of X4, X5, X6 and X7 are N, e.g.
X4 and X7 are N, X5 is CR5 and X6 is CR6, or
X5 and X7 are N, X4 is CR4 and X6 is CR6, or
X4 and X6 are N, X5 is CR5 and X7 is CR7, or
X6 and X7 are N, X4 is CR4 and X5 is CR5.
In a particular embodiment, X4 and X7 are N, X5 is CR5 and X6 is CR6.
As stated above, Q represents —O—, —S—, —SO—, —SO2—, —SO2NR—, —SO2(CH2)m— or —SO2O—. When Q represents an SO2NR—, —SO2(CH2)m— or —SO2O— group, the group will be attached to the central ring system through the sulphur atom.
In one embodiment of the invention, Q represents —SO2— or —SO2NR—.
R represents a hydrogen atom or a C1-C6, or C1-C4, or C1-C2 alkyl group. In one embodiment, R represents a hydrogen atom or a methyl group.
In a further embodiment, Q represents —SO2—.
As stated above, R1 and R2 each independently represent a hydrogen atom or a C1-C6, or C1-C4, or C1-C2 alkyl, C3-, C4-, C5- or C6-C8 cycloalkyl or C1-C6, or C1-C4, or C1-C2 alkoxycarbonyl group, each of which may be optionally substituted by at least one halogen atom, e.g. one, two, three or four halogen atoms independently selected from fluorine and chlorine atoms.
In one embodiment, R1 and R2 each independently represent a hydrogen atom or a C1-C6, or C1-C4, or C1-C2 alkyl, C3-C6 cycloalkyl or C1-C6, or C1-C4, or C1-C2 alkoxycarbonyl group, each of which may be optionally substituted by one or two halogen atoms independently selected from fluorine and chlorine atoms.
In another embodiment, R1 and R2 each independently represent a hydrogen atom.
In a further embodiment, one of R1 and R2 represents a hydrogen atom and the other of R1 and R2 represents a C1-C2 alkyl (such as methyl), C3-C6 cycloalkyl (such as cyclohexyl) or C1-C2 alkoxycarbonyl (such as methoxycarbonyl) group, each of which may be optionally substituted by one or two fluorine atoms.
Examples of R1 and R2 substituents include hydrogen atoms and methyl, 4,4-difluorocyclohexyl and methoxycarbonyl groups.
As stated above, R5 represents a saturated or unsaturated 3- to 10-membered (e.g. 3-, 4-, 5- or 6- to 7-, 8-, 9- or 10-membered) ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms) independently selected from nitrogen, oxygen and sulphur, wherein the 3- to 10-membered ring system is optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, cyano, C1-C6, or C1-C4, or C1-C2, alkyl, C1-C6, or C1-C4, or C1-C2 haloalkyl, C1-C6, or C1-C4, or C1-C2 hydroxyalkyl, C1-C6, or C1-C4, or C1-C2 alkoxy, C1-C6, or C1-C4, or C1-C2 haloalkoxy, C3-C6 cycloalkylC1-C6 alkoxy (e.g. cyclopropylC1-C6, or C1-C4, or C1-C2 alkoxy, specifically cyclopropylmethoxy), C1-C6 alkoxyC1-C6 alkyl (e.g. C1-C6, or C1-C4, or C1-C2 alkoxymethyl, specifically methoxymethyl), C1-C6, or C1-C4, or C1-C2 alkylC(O)NR14, phenyl, (halo)phenylcarbonyl, phenoxy, benzyl, benzyloxycarbonyl and a saturated or unsaturated 4- to 6-membered heterocyclyl group, which heterocyclyl group is itself optionally substituted by at least one C1-C6, or C1-C4, or C1-C2 alkyl group,
and when Q represents —SO2NR—, R3 may additionally represent a C1-C6, or C1-C4, or C1-C2 alkyl group optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), C1-C6, or C1-C4, or C1-C2 alkoxy, C1-C6 cycloalkyl, phenyl and a saturated or unsaturated 4- to 6-membered heterocyclyl group.
This R3 saturated or unsaturated 3- to 10-membered ring system may comprise one or more (e.g. one, two, three or four) ring heteroatoms independently selected from nitrogen, oxygen and sulphur. The ring system may be monocyclic or polycyclic (e.g. bicyclic) in which the two or more rings are fused, bridged or spiro. If the ring system is unsaturated, it may be partially or fully unsaturated. The ring system can be bonded to Q at any suitable ring atom (i.e. at any carbon or heteroatom of the ring system).
Examples of R5 saturated or unsaturated 3- to 10-membered ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptyl, azabicyclo[3.2.1]octanyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl), tetrahydrofuranyl, naphthyl, benzofuranyl, benzothienyl, benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, benzoxazolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, oxazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl), 2,3-dihydroindenyl, 1,4-oxazepanyl, azepanyl, 2,3-dihydrobenzofuranyl, 2,3-dihydroisoindolyl, tetrahydropyranyl, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridinyl, pyrazolyl, imidazo[1,2-a]pyridinyl, pyrazinyl, thiazolidinyl, indanyl, thienyl, isoxazolyl, pyridazinyl, pyrrolyl, furanyl, thiazolyl, isothiazolyl, indolyl, isoindolyl, imidazolyl, pyrimidinyl, benzimidazolyl, triazolyl, tetrazolyl and pyridinyl.
In one aspect, the R3 saturated or unsaturated 3- to 10-membered ring system is selected from phenyl, thienyl, cyclopropyl, cyclohexyl, pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, 1,4-oxazepanyl, azepanyl, thiomorpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 2,3-dihydroisoindolyl, azabicyclo[3.2.1]octanyl and 2,3-dihydro-1,4-benzodioxinyl.
If present in R3, a saturated or unsaturated 4- to 6-membered heterocyclyl substituent group contains from 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur, examples of which include azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxadiazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl and furanyl.
In one embodiment of the invention, R5 represents a saturated or 3-, 4-, 5- or 6-membered ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms) independently selected from nitrogen, oxygen and sulphur, wherein the 3-, 4-, 5- or 6-membered ring system is optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, cyano, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, C3-C6 cycloalkylC1-C2 alkoxy, C1-C2 alkoxyC1-C2 alkyl, C1-C2 alkylC(O)NR14—, phenyl, (halo)phenylcarbonyl, phenoxy, benzyl, benzyloxycarbonyl and a saturated or unsaturated 4- to 6-membered heterocyclyl group, which heterocyclyl group is itself optionally substituted by at least one, e.g. one or two, C1-C6, or C1-C4, or C1-C2 alkyl groups which may be the same or different to one another,
and when Q represents —SO2NR—, R3 may additionally represent a C1-C4 alkyl group optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), C1-C2 alkoxy, C3-C6 cycloalkyl, phenyl and a saturated or unsaturated 4- to 6-membered heterocyclyl group.
In another embodiment, R3 represents a saturated 4- to 6-membered ring system which may comprise one or two ring heteroatoms independently selected from nitrogen, oxygen and sulphur (e.g. cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, thiomorpholinyl or morpholinyl), wherein the saturated 4- to 6-membered ring system is optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C1-C2 alkoxy, C1-C2 haloalkoxy, C3-C6 cycloalkylC1-C2 alkoxy, C1-C2 alkoxyC1-C2 alkyl, C1-C2 alkylC(O)NR14—, phenyl, fluorophenylcarbonyl, phenoxy, benzyl and a saturated or unsaturated 4- to 6-membered heterocyclyl group, which heterocyclyl group is itself optionally substituted by at least one C1-C2 alkyl group.
In an alternative embodiment, R3 represents an unsaturated, e.g. aromatic, 6- to 10-membered ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms) independently selected from nitrogen, oxygen and sulphur, wherein the unsaturated 6- to 10-membered ring system is optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, C1-C6, or C1-C4, or C1-C2 alkyl, C1-C6, or C1-C4, or C1-C2 haloalkyl, C1-C6, or C1-C4, or C1-C2 alkoxy, C1-C6, or C1-C4, or C1-C2 haloalkoxy, benzyloxycarbonyl and a saturated or unsaturated 5- to 6-membered heterocyclyl group, which heterocyclyl group is itself optionally substituted by at least one, e.g. one or two, C1-C6, or C1-C4, or C1-C2 alkyl groups which may be the same or different to one another.
In a further embodiment, R3 represents a phenyl or pyridinyl group which is optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine or chlorine), cyano, C1-C2 alkyl, C1-C2 haloalkyl (e.g. trifluoromethyl), C1-C4 alkoxy, C1-C2 haloalkoxy (e.g. difluoromethoxy or trifluoromethoxy), benzyloxycarbonyl and a saturated or unsaturated 5- to 6-membered heterocyclyl group (e.g. morpholinyl), which heterocyclyl group is itself optionally substituted by at least one, e.g. one or two, C1-C6, or C1-C4, or C1-C2 alkyl groups which may be the same or different to one another.
In a still further embodiment, R5 represents phenyl optionally substituted by one or two substituents independently selected from fluorine, chlorine, cyano, methyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy and C1-C3 alkoxy.
In yet another embodiment, R3 represents an unsubstituted phenyl group.
In still another embodiment, when Q represents —SO2NR—, R3 represents a C1-C4 alkyl group optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), C1-C2 alkoxy, C3-C6 cycloalkyl, phenyl and a saturated or unsaturated 4- to 6-membered heterocyclyl group (e.g. oxetanyl, tetrahydrofuranyl or thiazolyl).
In a particular embodiment of the invention, R3 represents any one of the following moieties or is selected from a group containing any two or more of such moieties:
If present, R4, R5 and R6 each independently represent a hydrogen or a halogen atom, or a C1-C6, or C1-C4, or C1-C2 alkyl (e.g. methyl or ethyl), C1-C6, or C1-C4, or C1-C2 alkoxy (e.g. methoxy), C1-C6, or C1-C4, or C1-C2 alkylthio (e.g. methylthio), C1-C6, or C1-C4, or C1-C2 haloalkyl (e.g. trifluoromethyl), NR12R13 (e.g. dimethylamino), C3-C8 cycloalkyl (e.g. cyclopropyl or cyclohexyl) or C5-C8 cycloalkenyl (e.g. cyclohexenyl) group.
In an embodiment of the invention, R4 represents a hydrogen atom.
In an embodiment of the invention, R5 represents a hydrogen or halogen (e.g. chlorine) atom, or a C1-C6, or C1-C4, or C1-C2 alkyl (e.g. methyl or ethyl) group.
In an embodiment of the invention, R6 represents a hydrogen atom, or a C1-C6, or C1-C4, or C1-C2 alkyl (e.g. methyl or ethyl) group.
In a further embodiment, R5 and R6 each independently represent a hydrogen or chlorine atom or a methyl group.
As stated above, R7 represents a hydrogen or a halogen atom, hydroxyl, cyano, NR9R10, or a C1-C6, or C1-C4, or C1-C2 alkyl, C3-, C4- or C5- to C6-, C7- or C8-cycloalkyl, C2-C6 or C2-C4 alkenyl, C5-C8 or C5-C6 cycloalkenyl, C1-C6, or C1-C4, or C1-C2 alkoxy, C3-, C4- or C5- to C6-, C7- or C8-cycloalkyloxy, benzyloxy, 3- to 11-membered saturated heterocyclyl, 3- to 11-membered saturated heterocyclyloxy, C6-C10 aryl or heteroaryl group, each of which may be optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen, cyano, C1-C6, or C1-C4, or C1-C2 alkyl, C1-C6, or C1-C4, or C1-C2 alkoxy, C3-C8 or C3-C6 cycloalkyl, phenyl and a saturated or unsaturated 5- to 6-membered heterocyclyl group wherein each C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, phenyl or saturated or unsaturated 5- to 6-membered heterocyclyl substituent group may itself be optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy and C1-C6 cycloalkyl.
The R7 3- to 1-membered saturated heterocyclyl group or moiety contains from 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur. Furthermore, the group or moiety may be monocyclic or polycyclic (e.g. bicyclic) in which the two or more rings are fused, bridged or spiro. The R7 saturated heterocyclyl group can be bonded to the central ring system through any suitable ring atom (i.e. through any carbon or heteroatom of the heterocyclyl group). Examples of such 3- to 11-membered saturated heterocyclyl groups or moieties include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, azepanyl, oxazepanyl, tetrahydrofuranyl, tetrahydropyranyl, 6-azaspiro[2.5]octanyl, 6-oxa-9-azaspiro[4.5]decanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 4-oxa-7-azaspiro[2.5]octanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl and octahydrocyclopenta[b]morpholinyl.
The R7 heteroaryl group contains from 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur. The group may be monocyclic, or bicyclic in which the rings are fused together. Specific examples of R7 heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furyl, furazanyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, tetrazinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, quinolinyl, quinazolinyl, indolyl, 7-azaindolyl, indolizinyl, indazolyl, imidazo[1,2-a]pyridinyl and 7H-pyrrolo[2,3-d]pyrimidinyl. If present, the R7 saturated or unsaturated 5- to 6-membered heterocyclyl substituent group contains from 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur, examples of which include pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, oxadiazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl and furanyl.
In an embodiment of the invention, R7 represents a hydrogen or a halogen atom (e.g. fluorine, chlorine or bromine), hydroxyl, cyano, NR9R10, or a C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C5-C6 cycloalkenyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, benzyloxy, 3- to 11-membered saturated heterocyclyl, 3- to 6-membered saturated heterocyclyloxy, C6-C10 aryl or 5- to 6-membered heteroaryl group, each of which may be optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl and a saturated or unsaturated 5- to 6-membered heterocyclyl group wherein each C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl or saturated or unsaturated 5- to 6-membered heterocyclyl substituent group may itself be optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine or chlorine), C1-C3 alkyl (e.g. methyl), C1-C3 alkoxy (e.g. methoxy) and C3-C6 cycloalkyl (e.g. cyclopropyl).
In a second embodiment, R7 represents a hydrogen or a halogen atom (e.g. fluorine, chlorine or bromine), hydroxyl, cyano, NR9R10, or a C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C5-C6 cycloalkenyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, benzyloxy, 3- to 6-membered saturated heterocyclyl (e.g. azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl), 5- to 6-membered saturated heterocyclyloxy (e.g. tetrahydrofuranyloxy or tetrahydropyranyloxy), phenyl, pyrazolyl or pyridinyl group, each of which may be optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl and a saturated or unsaturated 5- to 6-membered heterocyclyl group (e.g. tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, pyrazolyl, thiazolyl and oxazolyl), wherein each C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl or saturated or unsaturated 5- to 6-membered heterocyclyl substituent group may itself be optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine or chlorine), C1-C3 alkyl (e.g. methyl), C2-C3 alkoxy (e.g. methoxy) and C3-C6 cycloalkyl (e.g. cyclopropyl).
If R7 represents a group NR9R10, then as stated above R9 and R10 each independently represent a hydrogen atom, or a C1-C6, or C1-C4, or C1-C2 alkyl or —(CH2)p—R11 group, each of which may be optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine or chlorine), C1-C3 alkyl (e.g. methyl) and C1-C3 alkoxy (e.g. methoxy).
As stated above, p is 0 or 1 and R11 represents C3-C6 cycloalkyl, phenyl or a saturated or unsaturated 5- to 6-membered heterocyclyl group. This R11 saturated or unsaturated 5-to 6-membered heterocyclyl group is as defined above for R7.
In one aspect, R9 and R10 each independently represent a hydrogen atom, or a C1-C4 alkyl or R11 group, each of which may be optionally substituted as previously defined.
In another aspect, R9 and R10 each independently represent a hydrogen atom, or a C1-C4 alkyl or R11 group selected from cyclopropyl, tetrahydrofuranyl and tetrahydropyranyl, each of which may be optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from fluorine and methyl.
In yet another aspect, one of R9 and R10 represents a hydrogen atom or a C1-C6 alkyl (e.g. methyl) group and the other of R9 and R10 represents a group —(CH2)—R11, each of which may be optionally substituted as previously defined.
In still another aspect, one of R9 and R10 represents a hydrogen atom or a methyl group, and the other of R9 and R10 represents a —(CH2)—R11 group optionally substituted as previously defined, wherein R11 is selected from oxazolyl, pyridinyl, dioxolanyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, cyclohexyl, furanyl, cyclopropyl and pyrazolyl.
In a third embodiment, R7 is represented by a group of formula:
wherein
In one embodiment, XA in formula (A) represents N.
In another embodiment, both XB moieties in formula (A) represent CH2.
In a further embodiment, in formula (A), one XP represents CH2 and the other XB represents CH(CH3), or one XB represents CH2 and the other XB represents a single bond.
In one embodiment, XC in formula (A) represents —O— or —S—.
In one embodiment, in formula (A), both R16 represent a hydrogen atom and at least one R17 is other than a hydrogen atom, or both R17 represent a hydrogen atom and at least one R is other than a hydrogen atom.
In another embodiment, in formula (A), at least one R16 is other than a hydrogen atom and at least one R17 is other than a hydrogen atom.
In one embodiment, if present in formula (A), each R18 represents a hydrogen atom and n is 2.
In one embodiment, if present in formula (A), each R19 represents a hydrogen atom and q is 2, 3 or 4.
In one embodiment, if present in formula (A), each R20 represents a hydrogen atom and t is 2, 3 or 4.
In a fourth embodiment, R7 is represented by a group of formula (A) wherein
In a fifth embodiment, R7 is represented by a group of formula (A) wherein
In a sixth embodiment, R7 represents a hydrogen or a halogen atom (e.g. fluorine, chlorine or bromine), hydroxyl, cyano, NR9R10 (e.g. methylamino or dimethylamino), or a C1-C6, or C1-C4, or C1-C2 alkoxy or benzyloxy group.
In a particular embodiment of the invention, R7 represents any one of the following moieties or is selected from a group containing any two or more of such moieties: hydrogen, bromine and chlorine atoms and (1-methylcyclopropyl)methoxy, (2,2-difluorocyclopropyl)methoxy, (2,6-dimethyloxan-4-yl)oxy, (2-methylcyclopropyl)methoxy, (2R)-2-(methoxymethyl)pyrrolidin-1-yl, (2R)-2-methylmorpholin-4-yl, (2R)-2-phenylmorpholin-4-yl, (2R,5R)-2,5-dimethylmorpholin-4-yl, (2R,6R)-2,6-dimethylmorpholin-4-yl, (2S)-2-methylmorpholin-4-yl, (2S)-2-phenylmorpholin-4-yl, (2S,5S)-2,5-dimethylmorpholin-4-yl, (3,3-difluorocyclobutyl)methoxy, (3R)-oxolan-3-yloxy, (3S)-oxolan-3-yloxy, (4,4-difluorocyclohexyl)oxy, (4-methyl-1,3-thiazol-2-yl)methoxy, (dimethyl-1,3-oxazol-4-yl)methoxy, (E)-2-cyclopropylethenyl, 1-(pyridin-2-yl)ethoxy, 1,4-oxazepan-4-yl, 1-cyclopentylethoxy, 1-cyclopropylethoxy, 1H-pyrazol-1-yl, 1-phenylethoxy, 2-(2-methylpropy)morpholin-4-yl, 2-(methoxymethyl)morpholin-4-yl, 2-(propan-2-yl)morpholin-4-yl, 2-(trifluoromethyl)morpholin-4-yl, 2,2-diethylmorpholin-4-yl, 2,2-dimethylmorpholin-4-yl, 2,2-dimethylpyrrolidin-1-yl, 2,5-dimethylmorpholin-4-yl, 2,6-dimethylthiomorpholin-4-yl, 2-cyano-morpholin-4-yl, 2-cyclopropylethyl, 2-cyclopropylmorpholin-4-yl, 2-ethyl-2-methylmorpholin-4-yl, 2-ethylmorpholin-4-yl, 2-ethylthiomorpholin-4-yl, 2-methoxyethoxy, 2-methylmorpholin-4-yl, 2-methylphenyl, 2-methylpiperidin-1-yl, 2-methylthiomorpholin-4-yl, 2-oxa-6-azaspiro[3.5]nonan-(6-yl, 3-(1H-pyrazol-1-yl)piperidin-1-yl, 3,3-difluoropiperidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 3,3-dimethylpyrrolidin-1-yl, 3,5-dimethyl-1H-pyrazol-1-yl, 3-ethoxypiperidin-1-yl, 3-methoxypiperidin-1-yl, 3-methoxypyrrolidin-1-yl, 3-methylmorpholin-4-yl, 3-methylphenyl, 3-methylpiperidin-1-yl, 4-(cyclopropylmethoxy)piperidin-1-yl, 4-(methoxymethyl)piperidin-1-yl, 4,4-difluorocyclohex-1-en-1-yl, 4,4-difluorocyclohexyl, 4,4-difluoropiperidin-1-yl, 4-fluoropiperidin-1-yl, 4-methoxypiperidin-1-yl, 4-methylphenyl, 4-methylpiperidin-1-yl, 4-oxa-7-azaspiro[2.5]octan-7-yl, 5-oxa-8-azaspiro[3.5]nonan-8-yl, 6-azaspiro[2.5]octan-6-yl, 6-oxa-9-azaspiro[4.5]decan-9-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, azepan-1-yl, azetidin-1-yl, benzyloxy, cyclobutoxy, cyclohex-1-en-1-yl, cyclohexyl, cyclohexylmethoxy, cyclohexyloxy, cyclopent-1-en-1-yl, cyclopentyl, cyclopentylmethoxy, cyclopentyloxy, cyclopropylmethoxy, ethylamino, morpholin-4-yl, N-(1,3-dioxolan-2-ylmethyl)-N-methyl-amino, N-(2,2-difluoroethyl)-N-methyl-amino, N-(2,2-dimethyloxan-4-yl)-N-methyl-amino, N-(cyclohexylmethyl)-N-ethylamino, N-(cyclopropylmethyl)-4-N-(oxolan-2 ylmethyl)-amino, N-(cyclopropylmethyl)-amino, N,N-diethylamino, N-[(2-methoxyphenyl)methyl]-N-methyl-amino, N-[(3-chlorophenyl)methyl]-N-methyl-amino, N-cyclopropyl-N-methyl-amino, N-ethyl-4-N-(furan-2-ylmethyl)-amino, N-ethyl-4-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-amino, N-ethyl-N-(oxan-4-ylmethyl)-amino, N-ethyl-N-methyl-amino, N-methyl-4-[(5-methyl-1,2-oxazol-3-yl)methyl]-amino, N-methyl-N-(oxan-2-ylmethyl)-amino, N-methyl-N-(oxan-4-yl)-amino, N-methyl-N-(propan-2-yl)-amino, N-methyl-N-(pyridin-2-ylmethyl)-amino, octahydrocyclopenta[b]morpholin-4-yl, oxan-2-ylmethoxy, oxan-3-ylmethoxy, oxan-4-ylmethoxy, oxan-4-yloxy, oxolan-3-ylmethoxy, pentan-3-yloxy, phenyl, piperidin-1-yl, prop-1-en-2-yl, propan-2-yl, pyridin-3-yl, pyridin-4-yl, pyrrolidin-1-yl, hydroxyl, cyano, methoxy, ethoxy, benzyloxy, N-methylamino and N-dimethylamino.
As stated above, either R8 represents a saturated 3- to 8-membered ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms) independently selected from nitrogen, oxygen and sulphur, wherein the 3- to 8-membered ring system is optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl and C1-C6, or C1-C4, or C1-C2 alkyl, or R8 represents a C1-C6, or C1-C4, or C1-C2 alkyl group optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from phenyl and C3-C6 cycloalkyl, the cycloalkyl group itself being optionally substituted by at least one C1-C6, or C1-C4, or C1-C2 alkyl group.
This R8 saturated 3- to 8-membered ring system may comprise one or more (e.g. one, two, three or four) ring heteroatoms independently selected from nitrogen, oxygen and sulphur. The ring system may be monocyclic or bicyclic in which the two or more rings are fused, bridged or spiro, and is attached to the nitrogen atom of the central ring system through a ring carbon atom. Examples of such ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, azepanyl, oxazepanyl and bicyclo[2.2.1]heptanyl.
In an embodiment of the invention, R8 represents a saturated 4- to 7-membered ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms) independently selected from nitrogen, oxygen and sulphur, wherein the 4- to 7-membered ring system is optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl and C1-C2 alkyl, or R8 represents a C1-C6, or C1-C4, or C1-C2 alkyl group optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from phenyl and C3-C6 cycloalkyl, the cycloalkyl group itself being optionally substituted by at least one (e.g. one or two independently selected) C1-C2 alkyl groups.
In one aspect, R8 represents a C4-C6 cycloalkyl group optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from fluorine, hydroxyl and methyl.
In another aspect, R8 represents a C1-C2 alkyl group optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from phenyl and C3-C6 cycloalkyl, the cycloalkyl group itself being optionally substituted by one or two independently selected C1-C2 alkyl groups.
In a particular embodiment of the invention, R8 represents any one of the following moieties or is selected from a group containing any two or more of such moieties:
As stated above, R12 and R13 each independently represent a hydrogen atom or a C1-C6, or C1-C4, or C1-C2 alkyl (e.g. methyl) group.
In an embodiment of the invention, R12 and R13 both represent a methyl group.
As stated above, R14 represents a hydrogen atom or a C1-C6, or C1-C4, or C1-C2 alkyl (e.g. methyl) group.
In an embodiment of the invention, R14 represents a methyl group.
In an embodiment of the invention, the compound of formula (I) is one in which;
Examples of compounds of the invention include:
It should be noted that each of the chemical compounds listed above represents a particular and independent aspect of the invention.
The present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises,
(a) when NR1R2 represents NH2, reacting a compound of formula
wherein L1 represents a leaving group (e.g. a halogen atom or trifluoromethanesulphonate group) and X4, X5, X6, X7, Q and R3 are as defined in formula (I), with a compound of formula (III), H2NR8, or a salt thereof (e.g. a hydrochloride salt) wherein R8 is as defined in formula (I); or
(b) when NR1R2 represents NH2, reacting a compound of formula
wherein L2 represents a leaving group (e.g. a halogen atom or trifluoromethanesulphonate group) and X4, X5, X6, X7 and R8 are as defined in formula (I), with a compound of formula
wherein Q and R3 are as defined in formula (I);
wherein any of compounds (II), (III), (IV) or (V) may optionally be protected;
and optionally thereafter carrying out one or more of the following procedures:
In process (a) the compound of formula (II) may conveniently be combined with an amine of formula (III) or a salt thereof in the presence of a base such as triethylamine or ethylbis(propan-2-yl)amine, in a solvent such as anhydrous N-methylpyrrolidone, to arrive at a compound of formula (I). Typically the reaction mixture is heated, e.g. to around 170° C. under microwave irradiation.
Process (b) may conveniently be carried out by combining the compound of formula (IV) with the substituted acetonitrile of formula (V) in the presence of a base such as sodium hydride or sodiobis(trimethylsilyl)amine, and a metal catalyst such as Pd(o), typically where the metal catalyst is in the form of a transition metal complex such as tetrakis(triphenylphosphine) palladium and/or di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]-phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium, in a solvent such as 1,2-dimethoxyethane, dioxane or 2-methyloxalane, typically where the solvent is anhydrous, to arrive at a compound of formula (I). Typically the reaction mixture is heated, e.g. to around 70-150° C. under conventional heating or microwave irradiation. Optionally the Pd(o) catalyst may be formed in situ, e.g. from Pd(I) acetate and 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane.
Compounds of formula (II) may be prepared by reacting a compound of formula
wherein each L3 independently represents a leaving group (e.g. a halogen atom or trifluoromethanesulphonate group) and X4, X5, X6 and X7 are as defined above, with a compound of formula (V) as defined above. The reaction is conveniently carried out in the presence of a base such as sodium hydride, and a metal catalyst such as Pd(o), typically where the metal catalyst is in the form of a transition metal complex such as tetrakis(triphenylphosphine) palladium, in a solvent such as anhydrous 1,2-dimethoxyethane, to arrive at a compound of formula (II) which may or may not be isolated. Typically the reaction mixture is heated, e.g. to around 70-140° C. under conventional heating or microwave irradiation.
In one embodiment, a compound of formula (I) or a salt or a protected form thereof, may be converted into another compound of formula (I) or a salt or a protected form thereof.
For example, a compound of formula (I) or a salt or a protected form thereof, where R1 and R2 are both hydrogen, may be converted into another compound of formula (I) or a salt or a protected form thereof where one or both of R1 and R2 are not hydrogen, typically by treatment with a compound of formula R1-L and/or R2-L, where R1 and R2 are as previously defined but not hydrogen and L is as previously defined for L1.
In one convenient procedure, a compound of formula (I) or a salt thereof, where R1 and R2 are both hydrogen, may be combined with a compound of formula (C1-C6 alkyl)-L′, where L′ is a leaving group such as a chlorine, bromine or iodine atom, in the presence of a base such as butyllithium, and a solvent such as anhydrous THF. Typically the reaction mixture is cooled, e.g. to about 0° C.
In another convenient procedure, a compound of formula (I) or a salt thereof, where R1 and R are both hydrogen, may be combined with a compound of formula L″-COO—(C1-C6 alkyl), where L″ is a leaving group such as a chlorine, bromine or iodine atom, in the presence of a base such as ethylbis(propan-2-yl)amine, and a solvent such as anhydrous dichloromethane. Typically the reaction mixture is heated, e.g. to about 30-50° C.
Substituents R4, R5, R6 and R7 may also be modified and/or replaced after the formation of a compound of formula (I).
For example, where R4, R5, R6 or R7 represents a halogen atom selected from chlorine, bromine or iodine, the halogen atom may be substituted to arrive at an alternate compound of formula (I).
Where the new substituent requires carbon-carbon bond formation, in a convenient procedure a compound of formula (I) where, for example, R7 represents a chlorine, bromine or iodine atom, may be combined with a boric acid derivative such as R7a—B(OH)2, R7a—B(pinacole ester) or R7a—BF3—K+ where R7a represents the replacement R7 bonded to the boron atom via a carbon-boron bond, in the presence of a base such as potassium carbonate, caesium carbonate or potassium phosphate, and a metal catalyst such as Pd(o), typically where the metal catalyst is in the form of a transition metal complex such as tetrakis(triphenylphosphine) palladium or di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]-phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium. A solvent such as a dioxane/water mixture may be used and the reaction mixture is typically heated, e.g. to around 100-160° C. under conventional heating or microwave irradiation.
Where the new substituent requires carbon-nitrogen bond formation, in a convenient procedure a compound of formula (I) where, for example, R7 represents a chlorine, bromine or iodine atom, may be combined with a primary or secondary amine of formula R7aH, where R7a represents the replacement R7 and includes a nitrogen atom through which the R7a group is to be bonded to the remainder of the compound of formula (I). Examples of R7aH include morpholine, piperidine, pyrrolidine and substituted derivatives thereof. Optionally, the reaction is performed in the presence of an additional base such as triethylamine or ethylbis(propan-2-yl)amine. A solvent such as ethanol, anhydrous tetrahydrofuran, anhydrous N-methylpyrrolidone or anhydrous N,N-dimethylformamide may be used and the reaction mixture is typically heated, e.g. to around 60-200° C. under conventional heating or microwave irradiation.
In a similar procedure, where it is desired to form a carbon-nitrogen bond to a suitable ring nitrogen of a heterocyclic amine, a compound of formula (I) where, for example, R7 represents a chlorine, bromine or iodine atom, may be combined with the heterocyclic amine in the presence of a base such as sodium hydride and a solvent such as anhydrous N,N-dimethylformamide. The reaction mixture is typically heated, e.g. to around 200° C. under conventional heating or microwave irradiation.
Where the new substituent requires carbon-oxygen bond formation, in a convenient procedure a compound of formula (I) where, for example, R7 represents a chlorine, bromine or iodine atom, may be combined with the desired alcohol in the presence of a base such as sodium hydride and a solvent such as anhydrous tetrahydrofuran. The reaction mixture is typically heated, e.g. to around 60-120° C. under conventional heating or microwave irradiation.
The above procedures to substitute R4, R5, R6 or R7, where R4, R5, R6 or R7 initially represents a leaving group such as a chlorine, bromine or iodine atom, may also be applied to synthesise suitably substituted compounds of formula (IV) or (VI) prior to their reaction with compounds of formula (V). Likewise, they may be applied to the intermediates of formula (II) to replace substituents prior to reaction with an amine of formula (III) or a salt thereof.
The compounds of formula (V) where Q is —SO2— may conveniently be synthesised by reacting a compound of formula R3SO2Cl with a compound of formula ClCH2CN, in the presence of a reducing agent such as disodium sulfite, and a base such as sodium hydrogen carbonate, in a solvent such as a water/propan-2-ol or water/tetrahydrofuran mixture. The reaction mixture is typically heated, e.g. to around 100-120° C. under conventional heating or microwave irradiation.
In an alternate procedure, the compounds of formula (V) where Q is —SO2— and R3 is an amino group attached to the remainder of the compound via the nitrogen atom of the amino group, may be synthesised by reacting the corresponding amine R3H with cyanomethanesulfonyl chloride in the presence of a base such as triethylamine and a solvent such as anhydrous dichloromethane. Typically, the reaction is performed at a temperature of from 20-30° C.
Compounds of formulae (II), (IV), (V) and (VI) are either commercially available, are known in the literature or may be prepared using known techniques.
As already indicated, in the above processes certain functional groups such as phenol, hydroxyl or amino groups in the reagents may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the introduction and f/or removal of one or more protecting groups.
The protection and deprotection of functional groups is described in ‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie, Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1999).
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, benzenesulphonate (besylate), saccharin (e.g. monosaccharin), trifluoroacetate, sulphate, nitrate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, valerate, propanoate, butanoate, malonate, oxalate, 1-hydroxy-2-napthoate (xinafoate), methanesulphonate or p-toluenesulphonate salt.
In one aspect of the invention, compounds of formula (I) may bear one or more radiolabels. Such radiolabels may be introduced by using radiolabel-containing reagents in the synthesis of the compounds, or may be introduced by coupling the compounds to chelating moieties capable of binding to a radioactive metal atom. Such radiolabeled versions of the compounds may be used, for example, in diagnostic imaging studies.
Unless stated otherwise, any atom specified herein may also be an isotope of said atom. For example, the term “hydrogen” encompasses 1H, 2H and 3H. Similarly carbon atoms are to be understood to include 12C, 13C and 14C, nitrogen atoms are to be understood to include 14N and 15N, and oxygen atoms are to be understood to include 16O, 17O and 18O.
In a further aspect of the invention, compounds of formula (I) may be isotopically labelled. As used herein, an “isotopically labelled” compound is one in which the abundance of a particular nuclide at a particular atomic position within the molecule is increased above the level at which it occurs in nature.
In a still further aspect, the invention provides prodrugs of the compounds of formula (I). The term “prodrug” as used herein refers to a derivative of an active form of a compound which derivative, when administered to a subject, is gradually converted to the active form to produce a better therapeutic response and/or a reduced toxicity level. In general, prodrugs will be functional derivatives of the compounds disclosed herein which are readily convertible in vivo into the compound from which it is notionally derived. Prodrugs include, without limitation, acyl esters, carbonates, phosphates, and urethanes. These groups are exemplary and not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs. Prodrugs may be, for example, formed with available hydroxy, thiol, amino or carboxyl groups. For example, available NH2 groups in the compounds of the invention may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine). Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985.
Compounds of formula (I) and their salts may be in the form of hydrates or solvates which form an aspect of the present invention. Such solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.
Where compounds of formula (I) are capable of existing in stereoisomeric forms, it will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds and mixtures thereof including racemates. The use of tautomers and mixtures thereof also forms an aspect of the present invention. Enantiomerically pure forms are particularly desired.
Compounds of formula (I) and their salts may be amorphous or in a polymorphic form or a mixture of any of these, each of which forms an aspect of the present invention.
The compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as GPR43 receptor agonists and/or as positive allosteric modulators of the GPR43 receptor. Accordingly, they may be used in the treatment of obesity; diabetes, in particular diabetes mellitus such as diabetes mellitus type 1, diabetes mellitus type 2 and gestational diabetes; metabolic syndrome; atherosclerosis; irritable bowel syndrome; and autoimmune diseases including inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), rheumatoid arthritis and systemic lupus. The compounds may also be used in the treatment of asthma, liver fibrosis, non-alcoholic steatohepatitis (NASH), neuroinflammation, multiple sclerosis and colorectal cancer.
As used herein, the term “obesity” refers to a person who has a body mass index (BMI) of greater than or equal to 30 kg/m2. The BMI may be calculated by dividing a patient's weight in kilograms by the square of their height in metres (kg/m2).
Thus, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as hereinbefore defined, for use in therapy, in particular for the treatment of conditions whose development or symptoms are linked to GPR43 receptor activity.
The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as hereinbefore defined, for the preparation of a medicament for the treatment of conditions whose development or symptoms are linked to GPR43 receptor activity.
In the context of the present specification, the terms “therapy” and “treatment” also include “prophylaxis” unless there are specific indications to the contrary. The terms “therapeutic”, “therapeutically” and “treating” should be construed accordingly.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disorder or condition in question. Persons at risk of developing a particular disorder or condition generally include those having a family history of the disorder or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disorder or condition or those in the prodromal phase of a disorder.
In particular, the compounds of the invention (including pharmaceutically acceptable salts) may be used in the treatment of obesity and/or diabetes (including diabetes mellitus such as diabetes mellitus type 1, diabetes mellitus type 2 and gestational diabetes).
In one embodiment, the compounds of the invention (including pharmaceutically acceptable salts) may be used in the treatment of obese diabetics, including those suffering from diabetes mellitus type 1, diabetes mellitus type 2 or gestational diabetes.
In another embodiment, the compounds of the invention (including pharmaceutically acceptable salts) may be used in the treatment of inflammatory bowel disease.
The present invention also provides a method of treating obesity, diabetes (including diabetes mellitus such as diabetes mellitus type 1, diabetes mellitus type 2 and gestational diabetes) or inflammatory bowel disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, the daily dosage of the compound of the invention, if inhaled, may be in the range from 0.05 micrograms per kilogram body weight (μg/kg) to 100 micrograms per kilogram body weight (μg/kg). Alternatively, if the compound is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligrams per kilogram body weight (mg/kg), preferably from 0.01 to 1 mg/kg body weight
The compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
Therefore the present invention further provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention still further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceutics—The Science of Dosage Form Design”, M. E. Aulton, Churchill Livingstone, 1988.
Pharmaceutically acceptable adjuvants, diluents or carriers that may be used in the pharmaceutical compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral administration is preferred. The pharmaceutical compositions of the invention may contain any conventional non-toxic pharmaceutically acceptable adjuvants, diluents or carriers. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable diluents and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring and/or colouring agents may be added.
The pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.
Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (percent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.
The compounds of the invention (that is, compounds of formula (I) and pharmaceutically acceptable salts thereof) may also be administered in conjunction with other compounds used for the treatment of the above conditions, for example, biguanide drugs (for example Metformin), insulin (synthetic insulin analogues), oral antihyperglycemics (these are divided into prandial glucose regulators and alpha-glucosidase inhibitors) and sulfonylureas (for example, glimepiride, glibenclamide (glyburide), gliclazide, glipizide, gliquidone, chloropropamide, tolbutamide, acetohexamide, glycopyramide, carbutamide, glibonuride, glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide, tolcylamide and tolazamide). Preferably the sulfonylurea is glimepiride or glibenclamide (glyburide).
Alternatively, the compounds of the invention may be administered in combination with a dipeptidyl peptidase-4 (DPP IV) inhibitor (for example, alogliptin); or a phosphodiesterase-4 (PDE4) inhibitor (for example, rolipram, roflumilast or apremilast); or bupropion/naltrexone (“Contrave”); or lorcaserin hydrochloride (“Lorqess”); or phentermine/topiramate (“Qsymia”).
The present invention will now be further explained by reference to the following illustrative examples. In the illustrative examples, the compounds synthesised are both named and illustrated structurally. Whilst every effort has been made to ensure that the chemical names and the chemical structures are consistent, if any inconsistencies occur the illustrated chemical structure should be taken to be correct, unless the illustrated chemical structure is chemically impossible.
The methods used for the synthesis of the compounds of the invention are illustrated by the general schemes below and the preparative examples that follow. The starting materials and reagents used in preparing these compounds are available from commercial suppliers. These general schemes are merely illustrative of methods by which the compounds of this invention can be synthesised, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.
Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as stated and at 300.3K unless otherwise stated; the chemical shifts (δ) are reported in parts per million. Spectra were recorded using a Bruker 400 AVANCE instrument fitted with a 5 mm BBFO probe with instrument controlled by Bruker TopSpin 2.1 software, or by a Bruker 400 AVANCE-III instrument fitted with a 5 mm BBFO probe with instrument controlled by Bruker TopSpin 3.0 software, or by a Bruker 300 MHz AVANCE II instrument fitted with a 5 mm DUL probe with instrument controlled by Bruker TopSpin 1.3 software.
Purity was assessed using one or more of the following:
Compounds were purified using normal phase chromatography on silica, using Biotage or Isolute KP-Sil cartridges or Kinesis Telos Silica cartridges, or on basic silica, using Biotage or Isolute KP-NH cartridges, or by reverse phase chromatographic methods, using Biotage or Isolute KP-C18-HS cartridges or by SCX-2 catch-release cartridges, or by Preparative HPLC.
Preparative HPLC was performed using one or more of the following:
Mobile phases typically consisted of acetonitrile or methanol mixed with water containing either 0.1% formic acid or 0.1% ammonia, unless stated otherwise.
Room temperature in the following examples means the temperature ranging from 20° C. to 25° C.
The abbreviations used in the specific examples have the following meanings:
To a stirred solution of 2,3-dichloropyrazine (CAS 4858-85-9; 1.4 mL, 13 mmol) and 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 24 g, 13 mmol) in DMSO (8 mL) was added DBU (4.1 mL, 27 mmol). The reaction was subjected to microwave irradiation at 100° C. for 45 mins. The reaction mixture was diluted with water and brine and then extracted with ethyl acetate. The aqueous phase was extracted further with DCM. The combined organics were dried over MgSO4 and concentrated in vacuo. The crude product was loaded onto a plug of silica (10 g) and eluted using 0-100% EtOAc/petroleum ether. The product fractions were concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, DCM-d2) δ ppm 6.01 (s, 1H) 7.62-7.72 (m, 2H) 7.83-7.91 (m, 3H) 8.51-8.59 (m, 2H)
MS ES+: 294
To a stirred solution of 2,3-dichloropyrazine (CAS 4858-85-9; 360 μL, 3-4 mmol) and 2-(4-methylbenzenesulfonyl)acetonitrile (CAS 5697-44-9; 736 mg, 3.8 mmol) in acetonitrile (7 mL) was added DBU (620 μL, 4.1 mmol). The reaction was heated in a microwave at 80° C. for 30 min. The reaction mixture was evaporated to dryness and purified by column chromatography (C18-silica 0-30% Acetonitrile+0.05% NH3/Water+0.1% NH3) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.46 (s, 3H) 7.00 (s, 1H) 7.50 (d, J=1 Hz, 2H) 7.62 (d, J=1 Hz, 2H) 8.64-8.75 (m, 2H)
MS ES+: 308
To a stirred solution of 2,3-dichloropyrazine (CAS 4858-85-9; 156 μL, 1.50 mmol) and 2-(4-chlorophenylsulfonyl)acetonitrile (CAS 1851-09-8; 323 mg, 1.50 mmol) in DMF (1 mL) was added DBU (452 μL, 3.00 mmol). The reaction was heated in a microwave at 100° C. for 30 min. The reaction mixture was diluted with ammonium chloride solution, extracted with EtOAc/tetrahydrofuran (2:1), the combined organics dried (H frit) and evaporated to dryness. The crude product was purified by column chromatography silica (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 328
Prepared as described for 2-(4-chlorobenzenesulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 3), to a stirred solution of 2,3-dichloropyrazine (CAS 4858-85-9; 156 μL, 1.50 mmol) and 2-(4-fluorophenylsulfonyl)acetonitrile (CAS 32083-66-2; 299 mg, 1.50 mmol) in DMF (1 mL) was added DBU (452 μL, 3.00 mmol).
The reaction was heated in a microwave at 100° C. for 30 min. The crude product was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 312
Prepared as described for 2-(4-Chlorobenzenesulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 3), to a stirred solution of 2,3-dichloropyrazine (CAS 4858-85-9; 156 μL, 1.50 mmol) and 2-(4-isopropoxyphenylsulfonyl)acetonitrile (CAS 886499-39-4; 359 mg, 1.50 mmol) in DMF (1 mL) was added DBU (452 μL, 3.00 mmol). The reaction was then heated in a microwave at 100° C. for 30 min. The crude product was purified by column chromatography (silica, 0-40% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 352
Prepared as described for 2-(4-chlorobenzenesulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 3), to a stirred solution of 2,3-dichloropyrazine (CAS 4858-85-9; 156 μL 1.50 mmol) and 2-(thiophen-2-ylsulfonyl)acetonitrle (CAS 175137-62-9; 281 mg, 1.50 mmol) in DMF (1 mL) was added DBU (452 μL, 3.00 mmol). The reaction was heated in a microwave at 100° C. for 30 min then 125° C. for 30 min. The crude product was purified by column chromatography (C18-silica, 0-30% Acetonitrile+0.05% NH3/Water+0.1% NH3) to afford the title compound.
MS ES+: 300.
To a stirred solution of cyclohexanone (CAS 108-94-1; 851 mg, 8.67 mmol) and 2-bromopyridin-3-amine (CAS 39856-58-1; 500 mg, 2.89 mmol) in DCM (8 mL) at 0° C. under N2 was added TiCl4 solution (1M in DCM, 3.18 mL, 3.18 mmol) dropwise. The reaction mixture was allowed to stir for 2 hours at rt and then cooled to 0° C. Sodium triacetoxyborohydride (1.8 g, 8.67 mmol) was added portionwise and then the reaction allowed to warm to rt and stirred over a weekend. The reaction mixture was quenched slowly into water and then extracted with DCM. The organic phase was separated and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-40% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 255
To a stirred solution of potassium tert-butoxide (3.5 g, 32 mmol) in propan-2-ol (25 mL) at 0° C. was added 2-(4-methylbenzenesulfonyl)acetonitrile (CAS 5697-44-9; 3.69 g, 18 mmol) and the resulting mixture stirred for 30 min. 2-chloro-3-nitropyridine (CAS 5470-18-8; 2.5 g 15.8 mmol) was added and the reaction mixture stirred at 65° C. for 6 h. The reaction mixture was allowed to cool and concentrated in vacuo. The resulting residue was taken up in water and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 25-30% EtOAc/hexane) to afford the title compound.
1H NMR (4 MHz, DMSO-d6) δ ppm 2.45 (s, 3H), 6.93 (s, 1H), 7.45-7.55 (m, 2H), 7.55-7.65 (m, 3H), 8.05-8.15 (m, 1H), 8.50-8.60 (m, 1H)
MS ES+: 318
A stirred suspension of 2-(4-methylbenzenesulfonyl)-2-(3-nitropyridin-2-yl)acetonitrile (Intermediate 8; 1.2 g, 11 mmol) and palladium on carbon (10% w/w) (60 mg, 0.55 mmol) in acetic acid (0.5 mL) and ethyl acetate (50 mL) was placed under an atmosphere of hydrogen. The reaction was stirred at rt for to h. The reaction was filtered and the filtrate concentrated in vacuo. The residue was taken up in water and neutralised with sat. aq. NaHCO3 solution and then extracted with ethyl acetate. The organics were dried (NaSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 2-5% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (s, 3H), 6.90-7.00 (m, 1H), 7.10 (s, 2H), 7.25-7.35 (m, 2H), 7.35-7.45 (m, 1H), 7.85-7.95 (m, 2H), 8.05-8.15 (m, 1H), 11.50 (s, 1H)
MS ES+: 304
A stirred suspension of 2-amino-3-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridin-1-ol (Intermediate 9; 400 mg) and palladium on carbon (10% w/w) (50 mg) in acetic acid (2 mL) and ethyl acetate (10 mL) was placed under an atmosphere of hydrogen at too psi. After 8 h the reaction was diluted with ethyl acetate and filtered. The filtrate was washed with sat. aq. NaHCO3 solution and the organic phase separated and dried (Na2SO4). The organic phase was concentrated in vacuo. The crude product was triturated with hexane and filtered to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H) 6.82-6.97 (m, 3H) 7.27-7.40 (m, 3H) 7.86-7.96 (m, 2H) 8.02-8.09 (m, 1H) MS ES+: 288
To a stirred solution of 2-chloro-3-iodopyridine (CAS 78607-36-0; 4.9 g, 20.5 mmol) in toluene(15 mL) was added potassium tert-butoxide (2.81 g, 25.0 mmol), Pd2dba3 (1.53 g, 1.70 mmol) and 2-(4-methylbenzenesulfonyl)acetonitrile (CAS 5697-44-9; 2.64 g, 14.6 mmol). The reaction was heated at 125° C. for 4 h. The reaction was poured onto ice and extracted with ethyl acetate. The organic phase was separated, dried and concentrated in vacuo. The crude product was purified by column chromatography (silica, 20-22% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H), 6.76 (s, 1H), 7.50-7.58 (m, 2H), 7.60-7.65 (m, 1H), 7.65-7.75 (m, 2H), 7.90-8.00 (m, 1H), 7.55-7.65 (m, 1H)
MS ES+: 307
A neat mixture of 2,3-dichloropyrazine (CAS 4858-85-9; 0.100 mL, 0.958 mmol), 2-((4-methoxyphenyl)sulfonyl)acetonitrile (CAS 132276-87-0; 220 mg, 0.958 mmol) and DBU (0.289 mL, 1.916 mmol) was heated to 85° C. for 1.5 h. The reaction mixture was treated with dilute citric acid and EtOAc. The phases were separated and the aqueous extracted with EtOAc. The combined organic extracts were then washed with dilute citric acid, water, sat. NaHCO3, sat. brine, dried (H-frit) and evaporated. The crude material was absorbed onto MgSO4 from DCM/MeOH and purified by column chromatography (silica, 0-40% EtOAc/petroleum ether) to afford the title compound. 1H NMR (400 MHz, DCM-d2) δ ppm 3.96 (s, 3H) 5.99 (s, 1H) 7.10 (d, J=9 Hz, 2H) 7.76 (d, J=9 Hz, 2H) 8.49-8.60 (m, 2H)
MS ES+: 324
To a stirred degassed solution of Pd(Ph3P)4 (0.058 g, 0.050 mmol) in anhydrous DME (1.5 mL) under an atmosphere of nitrogen was added a solution of 2-((4-methoxyphenyl)sulfonyl)acetonitrile (CAS 132276-87-0; 0.232 g, 1.10 mmol) and NaH (0.084 g, 2.10 mmol) in anhydrous DME (4 mL). The resulting mixture was stirred at room temperature for to min followed by the addition of 2-chloro-3-iodopyridine (CAS 78607-36-0; 00.239 g, 1 mmol). The reaction was heated in a microwave at 90° C. to 110° C. for 2.5 h. More Pd(Ph3P)4 (0.029 g, 0.025 mmol) was added and the reaction heated in a microwave at 115° C. to 120° C. for 1.5 h. The solvent was removed under reduced pressure and the residue was diluted with water, neutralised with 2 M aq. HCl solution and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10-40% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.90 (s, 3H) 5.72 (s, 1H) 7.03 (d, J=9 Hz, 2H) 7.33-7.45 (m, 1H) 7.74 (d, J=9 Hz, 2H) 7.89-7.99 (m, 1H) 8.41-8.55 (m, 1H) MS ES+: 323
To a stirred degassed solution of Pd(Ph3P)4 (0.116 g, 0.100 mmol) in anhydrous DME (1.5 mL) under an atmosphere of nitrogen was added a solution of 2-(phenylsulfonyl)acetonitrile (0.399 g, 2.20 mmol) and NaH (0.168 g, 4.20 mmol) in anhydrous DME (4 mL). The resulting mixture was stirred at room temperature for to min followed by the addition of 2-chloro-3-iodopyridine (0.479 g, 2.00 mmol). The reaction mixture was heated at 120° C. for 1.5 h. The solvent was removed under reduced pressure and the residue was diluted with water, neutralised with 2 M aq. HCl solution and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10-40% EtOAc/petroleum ether) to afford the title compound.
1H NMR (4 MHz, CHLOROFORM-d) δ ppm 5.73 (s, 1H) 7.36-7.45 (m, 1H) 7.56-7.71 (m, 2H) 7.76-7.86 (m, 1H) 7.87-7.94 (m, 2H) 7.95-8.03 (m, 1H) 8.45-8.60 (m, 1H)
MS ES+: 293
A stirred suspension of cyclohexanamine (CAS 108-91-8; 0.114 mL, 0.998 mmol), 4-chloro-5-iodopyrimidine (CAS 63558-65-6; 200 mg, 0.832 mmol) and Cs2CO3 (407 mg, 1.248 mmol) in N-methyl-2-pyrrolidinone (2 mL) was heated in a microwave at 100° C. for 1 h. The reaction mixture was poured into water and extracted with EtOAc (×2). The combined extracts were washed with water, dilute citric acid, water, sat. NaHCO3, sat. brine, dried (H-frit) and evaporated. The crude product was then purified by column chromatography (silica, 0-20% EtOAc/petroleum ether) to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.21-1.37 (m, 3H) 1.39-1.54 (m, 2H) 1.63-1.73 (m, 1H) 1.73-1.85 (m, 2H) 1.99-2.12 (m, 2H) 3.96-4.10 (m, 1H) 5.19 (br. s., 1H) 8.44 (s, 1H) 8.46 (s, 1H)
MS ES+: 304
To a stirred solution of 4-chloropyrimidin-5-amine (CAS 54660-78-5; 150 mg, 1.16 mmol) and cyclohexanone (CAS 108-94-1; 360 μL, 3.47 mmol) in DCM (5 mL) at 0° C. was added TiCl4 solution (1.0M in DCM, 1.27 mL, 1.27 mmol). The reaction was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (736 mg, 3.47 mmol) was then added portionwise. Stirring at rt was maintained for 2 h. The reaction mixture was poured into water and extracted with EtOAc (×2). The combined organic extracts were washed with water, sat. NaHCO3, sat.brine, dried (H-frit) and evaporated. The crude product was purified by column chromatography (silica, 0-15% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.21-152 (m, 5H) 1.62-1.96 (m, 3H) 1.99-2.17 (m, 2H) 3.29-3.47 (m, 1H) 4.11-4.27 (m, 1H) 8.06 (s, 1H) 8.33 (s, 1H)
MS ES+: 212
To a stirred solution of cyclohexanone (CAS 108-94-1; 1.34 g, 13.6 mmol) and 4-iodopyridin-3-amine (CAS 105752-11-2; 1 g, 4.55 mmol) in DCM (15 mL) at 0° C. under N2 was added TiCl4 solution (1.0M in DCM, 5.00 mL, 5.00 mmol) dropwise. The reaction mixture was allowed to stir at rt for 2 hours and then sodium triacetoxyborohydride (2.89 g, 13.6 mmol) was added portionwise. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was quenched slowly into water and then extracted with DCM. The organics were separated and concentrated. The crude product was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.49 (m, 4H) 1.56-1.76 (m, 4H) 1.89-1.97 (m, 2H) 3.42-3.53 (m, 1H) 4.28 (d, J=8 Hz, 1H) 7.48 (d, J=5 Hz, 1H) 7.65 (d, J=5 Hz, 1H) 7.90 (s, 1H)
MS ES+: 303
Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a stirred solution of 4,4-difluorocyclohexanone (CAS 22515-18-0; 2.33 g, 17.3 mmol) and 2-bromopyridin-3-amine (CAS 39856-58-1; 1 g, 5.78 mmol) in DCM (15 mL) at 0° C. under N2 was added TiCl4 solution (1M in DCM, 6.36 mL, 6.36 mmol) dropwise. The reaction was allowed to stir at room temperature for 2 h and then cooled to 0° C. Sodium triacetoxyborohydride (3.68 g, 17.3 mmol) was added portionwise and then the reaction stirred at room temperature for 72 h. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 291
A neat mixture of 3-bromo-4-fluoropyridine (200 mg 1.14 mmol) and cyclohexanamine (CAS 108-91-8; 650 μL, 5.68 mmol) was heated in a microwave at 120° C. for 45 min. The reaction mixture was dissolved in EtOAc and washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24-1.49 (m, 4H) 1.60-1.73 (m, 2H) 1.74-1.88 (m, 2H) 1.95-2.16 (m, 2H) 3.18-3.46 (m, 1H) 4.71 (br. s, 1H) 6.48 (d, J=6 Hz, 1H) 8.12 (d, J=6 Hz, 1H) 8.34 (s, 1H)
MS ES+: 255
To a stirred solution of 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-amine (Example 1; 0.135 g, 0.38 mmol) in anhydrous THF (5 mL) at −78° C. and under an atmosphere of nitrogen was added dropwise a solution of butyllithium (0.152 mL, 0.380 mmol) in hexanes (2.5 M). The resulting mixture was stirred at −78° C. for 10 min and then quenched at −78° C. by the addition of methyl carbonochloridate (0.294 ml, 3.80 mmol) and allowed to warm to room temperature. The reaction was partitioned between diethyl ether and water. The phases were separated and the aqueous extracted with diethyl ether. The combined organics were dried over MgSO4, filtered and concentrated in vacuo. Purification was performed by chromatography (preparative HPLC, 40-80% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (3 MHz, CHLOROFORM-d) δ ppm 1.18-1.48 (m, 3H) 1.65-1.99 (m, 5H) 2.40-2.67 (m, 2H) 3.76 (s, 6H) 4.04-4.29 (m, 1H) 7.39-7.65 (m, 3H) 8.07-8.25 (m, 2H) 8.38 (d, J=2 Hz, 1H) 8.66 (d, J=2 Hz, 1H)
MS ES+: 473
To a stirred solution of 3-bromo-2-chloro-6-methylpyridine 1-oxide (CAS 185017-76-9; 0.309 & 1.39 mmol) and difluorocyclohexanamine hydrochloride (CAS 675112-70-6; 0.309 g, 1.80 mmol) in NMP (3 mL) was added Cs2CO3 (1.22 g, 3.74 mmol) and the resulting mixture was heated at 110° C. to 140° C. for 6 h using a microwave reactor. The mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous extracted with ethyl acetate (×2) The combined organics were washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure.
The crude product was purified by column chromatography (silica, 20-100% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 321
To a stirred degassed solution of Pd(Ph3P)4 (18 mg, 0.016 mmol) in anhydrous DME (1 mL) under an atmosphere of nitrogen was added a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 62 mg, 0.343 mmol) and NaH, 60% dispersion in oil (26 mg, 0.654 mmol) in anhydrous DME (1 mL). The resulting mixture was stirred at room temperature for 10 min followed by addition of a solution of 3-bromo-2-((4,4-difluorocyclohexyl)amino)-6-methylpyridine 1-oxide (Intermediate 21; 1 mg, 0.311 mmol) in anhydrous DME (1 mL). The reaction mixture was heated at 120° C. for 1.5 h. The solvent was removed under reduced pressure and the residue was diluted with water, neutralised with 2 M aq. HCl solution and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) to afford the title compound.
MS ES+: 422
Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a stirred solution of 4-chloro-6-methoxypyrimidin-5-amine (CAS 15846-19-2; 0.15 g, 0.940 mmol) and cyclohexanone (CAS 108-94-1; 0.294 ml, 2.82 mmol) in anhydrous DCM (5 mL) under an atmosphere of nitrogen at 0° C. was added TiCl4 solution (1M in DCM, 3.66 mL, 3.66 mmol). The reaction was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (1.94 g, 9.15 mmol) was added portionwise and the reaction stirred at room temperature for 16 h. The crude product was purified by column chromatography (silica, 0-20% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 242
To stirred solution of cyclohexanone (CAS 108-94-1; 1060 mg, 10.8 mmol) and 4-bromo-6-chloropyridazin-3-amine (CAS 446273-59-2; 750 mg, 3.60 mmol) in THF (10 mL) at 0° C. under N2 was added titanium isopropoxide (IV) (1.16 mL, 3.96 mmol) dropwise. The reaction was allowed to stir at room temperature for 2 h and then cooled to 0° C. Sodium triacetoxyborohydride (4580 mg, 21.6 mmol) was added portionwise and then the reaction allowed to stir at room temperature. The reaction was poured into water and extracted with DCM. The organics were separated and concentrated.
The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound. MS ES+: 292
Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to stirred solution of 4,4-difluorocyclohexanone (CAS 22515-18-0; 1480 mg, 11.1 mmol) and 4-chloro-6-ethoxypyrimidin-5-amine (CAS 63291-59-8; 960 mg, 5.53 mmol) in DCM (15 mL) at 0° C. under N2 was added TiCl4 solution (1M in DCM, 6.08 mL, 6.08 mmol) dropwise. The reaction was allowed to stir at room temperature for 2 h and then cooled to 0° C. Sodium triacetoxyborohydride (2340 mg, 11.06 mmol) was added portionwise and then the reaction allowed to stir at room temperature overnight. The crude product was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.41 (m, 3H) 1.51-1.64 (m, 2H) 1.77-1.89 (m, 4H) 2.00-2.09 (m, 2H) 3.66-3.81 (m, 1H) 4.39-4.47 (m, 3H) 8.08 (s, 1H) MS ES+: 292
To a stirred solution of phenylmethanol (CAS 100-51-6; 791 mg, 7.32 mmol) in THF (10 mL) at 0° C. was added NaH, 60% dispersion in oil (0.305 g, 7.62 mmol) portionwise. The resulting suspension was allowed to stir for 15 minutes. 4,6-dichloropyrimidin-5-amine (CAS 5413-85-4; 1 g, 6.10 mmol) was then added slowly and the reaction allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into water and extracted with DCM. The phases were separated and the organics concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 5.45 (s, 2H) 5.49 (s, 2H) 7.31-7.36 (m, 1H) 7.38-7.44 (m, 2H) 7.47-7.52 (m, 2H) 7.92 (s, 1H) MS ES+: 236
Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to stirred solution of 4,4-difluorocyclohexanone (CAS 22515-18-0; 1.59 g, 11.9 mmol) and 4-(benzyloxy)-6-chloropyrimidin-5-amine (Intermediate 26; 1.4 g, 5.94 mmol) in DCM (15 mL) at 0° C. under N2 was added TiCl4 solution (1M in DCM, 6.53 mL, 6.53 mmol) dropwise. The reaction was allowed to stir at room temperature for 2 h and then cooled to 0° C. Sodium triacetoxyborohydride (2.52 g, 11.9 mmol) was added portionwise and then the reaction allowed to stir at room temperature overnight. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.74-1.82 (m, 2H) 1.89-1.98 (m, 2H) 2.26-2.39 (m, 2H) 2.40-2.46 (m, 2H) 3.64-3.78 (m, 1H) 4.47-4.53 (m, 1H) 5.47 (s, 2H) 7.30-7.46 (m, 3H) 7.46-7.54 (m, 2H) 8.12 (s, 1H)
MS ES+: 354
Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a stirred solution of 6-chloro-N4,N4-dimethylpyrimidine-4,5-diamine (CAS 130623-81-3; 560 mg, 3.24 mmol) and cyclohexanone (CAS 108-94-1; 1.016 mL, 9.73 mmol) in anhydrous DCM (18 mL) under an atmosphere of N2 at 0° C. was added dropwise TiCl4 solution (1M in DCM, 3.66 mL, 3.66 mmol). The reaction was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (1.94 g, 9.15 mmol) was added portionwise and the reaction stirred at room temperature for 16 h. The crude product was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 255
Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a stirred solution of 4-chloro-6-methoxypyrimidin-5-amine (CAS 15846-19-2; 200 mg, 1.25 mmol) and cyclopentanone (CAS 120-92-3; 0.33 mL, 3.76 mmol) in anhydrous DCM (6 mL) under an atmosphere of N2 at 0° C. was added dropwise TiCl4 solution (1M in DCM, 1.4 mL, 1.38 mmol). The reaction was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (797 mg, 3.76 mmol) was added portionwise and the reaction stirred at room temperature for 16 h. The crude product was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33-1.53 (m, 2H) 1.55-1.82 (m, 4H) 1.83-2.00 (m, 2H) 3.73 (d, J=9 Hz, 1H) 4.04 (s, 3H) 4.18-4.42 (m, 1H) 8.08 (s, 1H) MS ES+: 228
Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a stirred solution of 4-chloro-2-methoxypyridin-3-amine (CAS 934180-49-1; 250 mg, 1.58 mmol) and cyclohexanone (CAS 108-94-1; 309 mg, 3.15 mmol) in anhydrous DCM (10 mL) under an atmosphere of N2 at 0° C. was added dropwise TiCl4 solution (1M in DCM, 1.73 mL, 1.73 mmol). The reaction was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (668 mg, 3.15 mmol) was added portionwise and the reaction stirred at room temperature overnight. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.71 (m, 6H) 1.75-2.01 (m, 4H) 3.54-3.64 (m, 1H) 3.89 (s, 3H) 4.02-4.08 (m, 1H) 6.97 (d, J 6 Hz, 1H) 7.54 (d, J=6 Hz, 1H)
MS ES+: 241
Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a mixture of cyclohexanone (CAS 108-94-1; 2.68 g, 27.3 mmol) and 4-(benzyloxy)-6-chloropyrimidin-5-amine (Intermediate 26; 3.22 g, 13.66 mmol) in DCM (50 mL) at 0° C. under N2 was added dropwise TiCl4 solution (1M in DCM, 15 mL, 15 mmol) dropwise. The reaction was allowed to stir at room temperature for 2 h and then cooled to 0° C. Sodium triacetoxyborohydride (5.79 g, 27.3 mmol) was added portionwise and then the reaction allowed to stir at room temperature overnight. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 318
To a stirred solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 1.96 g, 100.8 mmol) in DME (3 mL) at 0° C. was added NaH, 60% dispersion in oil (866 mg, 21.7 mmol). After to minutes the resulting suspension was added to a degassed solution of Pd(Ph3P)4 (313 mg, 0.27 mmol) and Pd(amphos)2Cl2 (192 mg, 0.271 mmol) in DME (2 mL). The resulting suspension was allowed to stir at room temperature for 20 minutes. 4-(benzyloxy)-6-chloro-N-cyclohexylpyrimidin-5-amine (Intermediate 31; 3.44 g, 10.8 mmol) was then added and the reaction mixture subjected to microwave irradiation at 120° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organics were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 346
A suspension of 7-(benzenesulfonyl)-4-(benzyloxy)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 32; 2.6 g, 5.62 mmol) and Pd/C (598 mg, 0.562 mmol) in MeOH (20 mL) was stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered through a pad of celite and the resulting filtrate concentrated. The crude product was purified by column chromatography (silica, o-10% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.96 (m, 9H) 2.41-2.55 (m, 2H) 7.47-7.62 (m, 4H) 7.63-7.70 (m, 2H) 7.83 (s, 1H) 8.04-8.11 (m, 2H)
MS ES+: 373
A solution of 6-amino-5-cyclohexyl-7-(phenylsulfonyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (Intermediate 33; 2.1 g, 5.64 mmol) in POCl3 (8 mL, 86 mmol) was stirred at 80° C. overnight. The reaction mixture was allowed to cool and concentrated in vacuo. The crude residue was taken up in DCM and washed with water. The organics were separated and concentrated. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.44 (m, 3H) 1.58-1.65 (m, 1H) 1.76-1.91 (m, 4H) 2.25-2.38 (m, 2H) 4.83-4.99 (m, 1H) 7.51-7.68 (m, 5H) 8.04-8.11 (m, 2H) 8.42 (s, 1H)
MS ES+: 391
Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a stirred solution of cyclohexanone (CAS 108-94-1; 565 mg, 5.76 mmol) and 4-chloro-6-methoxy-2-methylpyrimidin-5-amine (CAS 88474-31-1; 500 mg, 2.88 mmol) in DCM (10 mL) at 0° C. under N2 was added TiCl4 solution (1M in DCM, 3.17 ml, 3.17 mmol) dropwise. The reaction was allowed to stir at room temperature for 2 h and then cooled to 0° C. Sodium triacetoxyborohydride (1.22 g, 5.76 mmol) was added portionwise and then the reaction allowed to stir at room temperature overnight. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.30 (m, 4H) 1.49-1.57 (m, 1H) 1.62-1.69 (m, 2H) 1.72-1.81 (m, 3H) 2.40 (s, 3H) 3.39-3.49 (m, 1H) 3.88-3.96 (m, 4H)
MS ES+: 256
Prepared as described for N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17), to a stirred solution of 4-chloro-6-methoxypyrimidin-5-amine (CAS 15846-19-2; 0.572 mL, 6.19 mmol) and oxan-4-one (CAS 29943-42-8; 0.33 mL, 3.76 mmol) in anhydrous DCM (6 mL) under an atmosphere of nitrogen at 0° C. was added dropwise TiCl4 solution (1M in DCM, 3.41 mL, 3.41 mmol). The reaction was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (1.31 g, 6.19 mmol) was added portionwise and the reaction stirred at room temperature over a weekend. The crude product was purified by column chromatography (silica, 50-100% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.53 (m, 2H) 1.69-1.77 (m, 2H) 3.26-3.35 (m, >2H due to overlap with water peak) 3.68-3.79 (m, 1H) 3.79-3.87 (m, 2H) 3.98 (s, 3H) 4.38 (d, J=10 Hz, 1H) 8.10 (s, 1H)
MS ES+: 244
A mixture of 2,3-dichloropyrazine (CAS 4858-85-9; 10 g, 67.1 mmol), cesium carbonate (24 g, 73.8 mmol) and malononitrile (CAS 109-77-3; 4.88 g, 73.8 mmol) in DMSO (150 mL) was stirred at 125° C. for 90 minutes then allowed to cool to rt. Cyclohexanamine (CAS 108-91-8; 150 mL, 1.31 mol) was added and the reaction mixture was stirred at 130° C. for 4 days. After cooling to rt, 2M sodium hydroxide solution (200 mL; 0.4 mol) was added and the mixture was stirred at 115° C. for 24 hr. After cooling the mixture was diluted with water and extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.33 (m, 1H) 1.35-1.47 (m, 2H) 1.64-1.78 (m, 3H) 1.81-1.89 (m, 2H) 2.37-2.49 (m, 2H) 4.32-4.44 (m, 1H) 7.08 (br. s., 1H) 7.42 (br. s., 1H) 7.77-7.89 (m, 3H) 8.04 (d, J=3 Hz, 1H)
MS ES+: 260.
A solution of 6-amino-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (Intermediate 37; 13.9 g, 53.6 mmol) in 50% aqueous sulfuric acid (100 mL) was heated at 100° C. for 2 h. The reaction mixture was allowed to cool to rt then poured into water and then basified to pH to with 2M NaOH. The resulting mixture was extracted with DCM (×3) and the organic extracts were concentrated in vacuo. The crude product was purified by column chromatography (C18-silica 5-95% methanol/water+0.1% formic acid) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.25-1.46 (m, 3H) 1.64-1.73 (m, 3H) 1.80-1.89 (m, 2H) 2.42-2.54 (m, 2H) 4.21-4.32 (m, 1H) 5.34 (s, 1H) 6.48 (br. s., 2H) 7.61 (d, J=3 Hz, 1H) 7.86 (d, J=3 Hz, 1H) 8.16 (s, 1H)
MS ES+: 217
A solution of 5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-amine formate (Intermediate 38; 5 g, 19.1 mmol) in DCM (0 mL) was treated with triethylamine (12.9 mL, 92 mmol) followed by phthaloyl dichloride (CAS 88-95-9; 4.93 g, 24.3 mmol). The reaction mixture was allowed to stir at rt for 3 hours then poured into water and extracted with DCM. The organic phase was separated and concentrated to yield the title compound, which was used without further purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.09 (m, 2H) 1.16-1.41 (m, 3H) 1.58-1.65 (m, 1H) 1.73-1.86 (m, 4H) 4.22-4.32 (m, 1H) 6.84 (s, 1H) 7.96-8.02 (m, 2H) 8.04-8.10 (m, 2H) 8.37-8.41 (m, 1H) 8.48-8.54 (m, 1H)
A solution of 2-{5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-yl}-2,3-dihydro-1H-isoindole-1,3-dione (Intermediate 39; 8.63 g, 24.9 mmol) and acetic anhydride (23.5 mL, 249 mmol) in dichloromethane (100 mL) was cooled to 0° C. then sulfuric acid (6.64 mL, 125 mmol) was added dropwise. After 2 h the reaction mixture was diluted with water and extracted with DCM. The organic phase was concentrated and then azeotroped with toluene to yield the title compound.
MS ES+: 427.
A solution of 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonic acid (Intermediate 40; 10.63 g, 24.9 mmol) in phosphorus oxychloride (50 mL, 536 mmol) was treated with phosphorus pentachloride (5.42 g, 26.0 mmol) and heated to 80° C. for 1.5 h. The reaction mixture was slowly quenched into warm water. The aqueous mixture was allowed to cool to rt and extracted with DCM. The organic phase was concentrated to yield the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.49 (m, 3H) 1.63-1.68 (m, 1H) 1.75-1.93 (m, 4H) 2.53-2.64 (m, 2H) 4.81 (s, 1H) 8.04-8.09 (m, 2H) 8.13-8.19 (m, 2H) 8.78 (d, J=2.27 Hz, 1H) 8.90 (d, J=2.53 Hz, 1H)
MS ES+: 445
To a stirred solution of 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonyl chloride (Intermediate 41; 100 mg, 0.225 mmol) in THF (1 mL) was added DMAP (28 mg, 0.225 mmol) and aniline (CAS 62-53-3; 42 mg, 0.450 mmol) and the reaction mixture allowed to stir at room temperature overnight. The reaction mixture was diluted with water and extracted with DCM. The organics were separated and concentrated. The crude material was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound. 1H NMR (40 MHz, DMSO-d6) δ ppm 1.19-1.28 (m, 1H) 1.30-1.47 (m, 2H) 1.56-1.69 (m, 1H) 1.72-1.81 (m, 3H) 2.40-2.48 (m, 3H) 4.52-4.65 (m, 1H) 6.84-6.93 (m, 1H) 6.96-6.70 (m, 2H) 7.06-7.12 (m, 2H) 8.01-8.10 (m, 2H) 8.11-8.17 (m, 2H) 8.57 (d, J=3 Hz, 1H) 8.69 (d, J=3 Hz, 1H) 10.67 (s, 1H)
MS ES+: 502
To a stirred solution of 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonyl chloride (Intermediate 41; 1 mg, 0.225 mmol) in THF (1 mL) was added DMAP (28 mg, 0.225 mmol) and pyridin-3-amine (CAS 462-08-8; 42 mg, 0.450 mmol). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with water and extracted with DCM. The crude material was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 503
A mixture of silver trifluoromethanesulfonate (45 mg, 0.173 mmol), 4-methoxybenzene-1-sulfonyl chloride (36 mg, 0.173 mmol) and 2-{5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-yl}-2,3-dihydro-1H-isoindole-1,3-dione (Intermediate 39; 30 mg, 0.087 mmol) in nitrobenzene (0.5 mL) was subjected to microwave heating to 120° C. for 40 minutes. The reaction mixture was partitioned between water and DCM then the organic phase was concentrated in vacuo and the residue was purified by column chromatography on silica (silica, 5-50% EtOAc/petroleum ether) to afford the title compound.
1H NMR (4 MHz, DMSO-d6) δ ppm 1.22-1.32 (m, 2H) 1.32-1.46 (m, 2H) 1.60-1.67 (m, 1H) 1.70-1.85 (m, 5H) 3.81 (s, 3H) 4.63-4.74 (m, 1H) 7.08-7.16 (m, 2H) 7.89-7.96 (m, 1H) 8.04-8.10 (m, 1H) 8.14-8.21 (m, 2H) 8.60 (d, J=2 Hz, 1H) 8.72 (d, J=2 Hz, 1H)
MS ES+: 517.
Intermediates 45 to 54 were prepared by analogous methods and the data are given in Table 1. Where reactions failed to proceed to completion, further sulfonyl chloride was added and the temperature was increased (up to 150° C.) as required. Conventional heating in a sealed tube could also be employed.
To a stirred solution of 2-(benzenesulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 1; 50 g, 170 mmol) and cyclohexanamine (CAS 108-91-8; 97 mL, 850-mmol) in DMSO (100 mL) was added triethylamine (26 mL, 190 mmol). The reaction was heated thermally at 170° C. for 48 h. More cyclohexanamine (97 mL, 850 mmol) and triethylamine (26 mL, 190 mmol) were added and the reaction heated thermally at 185° C. for 24 h. The reaction was allowed to cool and diluted with brine. The resulting mixture was extracted with ethyl acetate and the organics washed with water and then with water/brine (1:1). The organics were dried (MgSO4) and concentrated in vacuo. The crude product was loaded onto a plug of silica (10 g) and eluted using 0-50% EtOAc/petroleum ether. Product fractions were concentrated and this purification process repeated another 3 times. The product fractions were concentrated. The resulting residue was recrystallised from hot ethanol to afford the title compound.
1H NMR (40 MHz, DMSO-d6) δ ppm 1.20-1.29 (m, 1H) 1.33-1.48 (m, 2H) 1.62-1.76 (m, 3H) 1.77-1.88 (m, 2H) 2.39-2.48 (m, 2H) 4.33-4.47 (m, 1H) 7.52-7.64 (m, 5H) 7.86-7.91 (m, 1H) 8.01-8.07 (m, 2H) 8.07-8.12 (m, 1H)
MS ES+: 357
A neat mixture of 2-(3-chloropyrazin-2-yl)-2-(4-methylbenzenesulfonyl)acetonitrile (Intermediate 2; 109 mg, 0.35 mmol) and cycloheptanamine (CAS 5452-35-7; 1.13 mL, 8.85 mmol) was heated in a microwave at 170° C. for 1 h and 45 mins. The reaction mixture was evaporated and purified by column chromatography (preparative HPLC, 40-80% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.75 (m, 8H), 2.32 (s, 3H), 2.35-2.47 (m, 2H) 2.95-3.07 (m, 2H) 4.45-4.60 (br. m., 1H) 7.33 (d, J=8 Hz, 2H) 7.54 (br. s., 2H) 7.82 (d, J=3 Hz, 1H) 7.91 (d, J=8 Hz, 2H) 8, (d, J=3 Hz, 1H)
MS ES+: 385
Prepared as described for 5-cycloheptyl-7-[(4-methylbenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine (Example 2), a neat mixture of 2-(3-chloropyrazin-2-yl)-2-(4-methylbenzenesulfonyl)acetonitrile (Intermediate 2; 109 mg, 0.35 mmol) and cyclohexanamine (CAS 108-91-8; 1.01 mL, 8.85 mmol) was heated in a microwave at 170° C. for 1 h and 45 mins. The reaction mixture was evaporated and purified by column chromatography (preparative HPLC, 30-70% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.31 (m, 1H) 1.32-1.48 (m, 2H) 1.60-1.76 (m, 3H) 1.77-1.87 (m, 2H) 2.33 (s, 3H) 2.37-2.48 (m, 2H) 4.32-4.44 (m, 1H) 7.35 (d, J=8 Hz, 2H) 7.57 (s, 2H) 7.88 (d, J=3 Hz, 1H) 7.92 (d, J=8 Hz, 2H) 8.08 (d, J=3 Hz, 1H)
MS ES+: 371
Prepared as described for 5-cycloheptyl-7-[(4-methylbenzene)sulfonyl]-5H-pyrrolo[2,3-b]pyrazin-6-amine (Example 2), a neat mixture of 2-(3-chloropyrazin-2-yl)-2-(4-methylbenzenesulfonyl)acetonitrile (Intermediate 2; 109 mg, 0.35 mmol) and cyclopentanamine (CAS 1003-03-8; 0.873 mL, 8.85 mmol) was heated in a microwave at 170° C. for 1 h and 45 mins. The reaction mixture was evaporated and purified by column chromatography (preparative HPLC, 30-70% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.69-1.85 (m, 2H) 1.96-2.16 (m, 4H) 2.21-2.35 (m, 2H) 2.40 (s, 3H) 4.80-4.92 (m, 1H) 6.08 (br. &, 2H) 7.27-7.33 (m, 2H) 7.92 (d, J=3 Hz, 1H) 8.10 (d, J=8 Hz, 2H) 8.26 (d, J=3 Hz, 1H)
MS ES+: 357
A stirred solution of 2-(4-chlorophenylsulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 3; 218 mg 0.664 mmol) and cyclohexanamine (CAS 108-91-8; 228 μL, 1.99 mmol) in N-methyl-2-pyrrolidinone (1.3 mL) was heated in a microwave at 170° C. for 2 h. More cyclohexanamine (228 μL, 1.99 mmol) was then added and the reaction was heated in a microwave at 170° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with brine and water, dried (H frit) and evaporated to dryness. The crude product was purified by column chromatography (silica, 0-30% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24-1.54 (m, 3H) 1.74-1.83 (m, 1H) 1.84-1.93 (m, 2H) 1.93-2.01 (m, 2H) 2.29-2.46 (m, 2H) 4.17-4.33 (m, 1H) 6.14 (br. s., 2H) 7.46 (d, J=9 Hz, 2H) 7.95 (d, J=3 Hz, 1H) 8.16 (d, J=9 Hz, 2H) 8.25 (d, J=3 Hz, 1H)
MS ES+: 391
A stirred solution of 2-(3-chloropyrazin-2-yl)-2-(4-fluorophenylsulfonyl)acetonitrile (Intermediate 4; 101 mg, 0.324 mmol) and cyclohexanamine (CAS 108-91-8; 111 μL, 0.972 mmol) in N-methyl-2-pyrrolidinone (650 μL) was heated in a microwave at 170° C. for 2 h. More cyclohexanamine (200 μL, 1.75 mmol) was added and the reaction heated in a microwave at 170° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with brine and water, dried (H fit) and evaporated to dryness. The crude product was purified by column chromatography (silica, 0-30% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, METHANOL-d4) δ ppm 1.26-1.57 (m, 3H) 1.69-1.83 (m, 3H) 1.86-1.98 (m, 2H) 2.48-2.64 (m, 2H) 4.25-4.38 (m, 1H) 7.19-7.27 (m, 2H) 7.90 (d, J=3 Hz, 1H) 8.03 (d, J=3 Hz, 1H) 8.10-8.18 (m, 2H)
MS ES+: 375
A stirred solution of 2-(3-chloropyrazin-2-yl)-2-(4-isopropoxyphenylsulfonyl)acetonitrile (Intermediate 5; 204 mg, 0.580 mmol) and cyclohexanamine (CAS 108-91-8; 199 μL, 1.74 mmol) in N-methyl-2-pyrrolidinone (1.1 mL) was heated in a microwave at 170° C. for 2 h. More cyclohexanamine (200 μL, 1.75 mmol) was added and the reaction heated in a microwave at 170° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with brine and water, dried (H frit) and evaporated to dryness. The crude product was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (d, J=6 Hz, 6H) 1.32-1.48 (m, 2H) 1.62-1.76 (m, 3H) 1.77-1.87 (m, 2H) 2.36-2.49 (m, 3H) 4.32-4.44 (m, 1H) 4.62-4.73 (m, 1H) 7.03 (d, J=9 Hz, 2H) 7.54 (br. s, 2H) 7.88 (d, J=3 Hz, 1H) 7.94 (d, J=9 Hz, 2H) 8.08 (d, J=3 Hz, 1H)
MS ES+: 415
A stirred solution of 2-(3-chloropyrazin-2-yl)-2-(thiophen-2-ylsulfonyl)acetonitrile (Intermediate 6; 74 mg, 0.247 mmol) and cyclohexanamine (CAS 108-91-8; 282 μl, 2.47 mmol) in DMSO (120 μL) was heated in a microwave at 170° C. for 2.5 h. The reaction mixture was diluted with DMSO and purified by column chromatography (preparative HPLC, 30-70% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (4 MHz, METHANOL-d4) δ ppm 1.29-1.59 (m, 3H) 1.71-1.86 (m, 3H) 1.90-1.99 (m, 2H) 2.52-2.67 (m, 2H) 4.28-4.40 (m, 1H) 7.06-7.11 (m, 1H) 7.68-7.73 (m, 1H) 7.81-7.85 (m, 1H) 7.93 (d, J=3 Hz, 1H) 8.06 (d, J=3 Hz, 1H)
MS ES+: 363
To a stirred solution of solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 555 mg, 3.07 mmol) in DME (3 mL) at 0° C. under a flow of N2 was added sodium hydride (60% dispersion in oil, 223 mg, 5.57 mmol) and the resulting suspension allowed to stir for to minutes. In a separate flask Pd(Ph3P)4 (CAS 014221-01-3; 161 mg, 0.139 mmol) in DME (3 mL) was degassed with N2. The suspension of pre-formed sodium salt of 2-(benzenesulfonyl)acetonitrile was added to the second vessel. After stirring for a further 10 minutes 2-bromo-N-cyclohexylpyridin-3-amine (Intermediate 7; 711 mg, 2.79 mmol) was added and the reaction mixture subjected to microwave irradiation at 120° C. for 1.5 h. The reaction mixture was poured into water and extracted with ethyl acetate and then the organics washed with brine. The organics were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-500% EtOAc/DCM) to afford crude product. The crude product was triturated with hot IPA and then filtered and dried to afford the title compound.
1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.13-1.37 (m, 1H) 1.38-1.54 (m, 2H) 1.73-1.85 (m, 1H) 1.86-2.16 (m, 6H) 3.91-4.04 (m, 1H) 5.88 (br. s., 2H) 6.89-6.98 (m, 1H) 7.40-7.59 (m, 4H) 8.13-8.20 (m, 2H) 8.22-8.30 (m, 1H)
MS ES+: 356
To a stirred solution of 3-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridin-2-amine (Intermediate 10; 250 mg, 0.7 mmol) in DMF (10 mL) was added DBU (264 mg, 1.4 mmol) and cyclopentyl bromide (194 mg, 1.0 mmol). The reaction was heated in a sealed tube at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The organics were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (preparative HPLC, 5-95% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.71 (m, 2H) 1.90-2.02 (m, 6H) 2.32 (s, 3H) 4.84-4.92 (m, 1H) 6.87-6.94 (m, 1H) 7.13 (s, 2H) 7.33 (d, J=8 Hz, 2H) 7.48-7.55 (m, 1H) 7.95 (d, J=8 Hz, 2H) 8.11-8.18 (m, 1H)
MS ES+: 356
A stirred solution of 2-(2-chloropyridin-3-yl)-2-(4-methylbenzenesulfonyl)acetonitrile (Intermediate 11; 600 mg, 2.0 mmol), triethylamine (500 mg, 4.9 mmol) and cyclohexanamine (CAS 108-91-8; 2.43 g, 24.5 mmol) in DMSO (5 mL) was heated to 160° C. for 3 hours in a microwave. The reaction was poured onto ice and extracted with ethyl acetate. The organic phase was concentrated in vacuo. The resulting residue was purified by column chromatography (preparative HPLC, 5-95% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.33 (m, 2H) 1.34-1.48 (m, 3H) 1.60-1.71 (m, 3H) 1.78-1.87 (m, 2H) 2.33 (s, 3H) 4.29-4.40 (m, 1H) 6.96-7.09 (m, 3H) 7.32-7.36 (m, 2H) 7.70-7.74 (m, 1H) 7.80-7.85 (m, 2H) 7.92-7.98 (m, 1H)
MS ES+: 370
To a stirred solution of 2,3-dichloropyrazine (CAS 4858-85-9; 1.8 g, 12.1 mmol) and 2-(cyclohexanesulfonyl)acetonitrile (CAS 797036-54-5; 2.7 g, 14.4 mmol) in DMSO (2 mL) was added DBU (1.85 g, 12.1 mmol) and the reaction heated in a microwave to 130° C. for 3 h. To the resulting solution was added triethylamine (600 mg, 59 mmol) and cyclohexanamine (CAS 108-91-8; 6 g, 60.5 mmol) and the reaction heated in a microwave to 170° C. for 3 h. The reaction was poured onto ice and extracted with ethyl acetate. The organic phase was concentrated in vacuo. The resulting residue was purified by column chromatography (preparative HPLC, 5-95% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.30 (m, 4H) 1.33-1.49 (m, 4H) 1.55-1.63 (m, 1H) 1.66-1.80 (m, 5H) 1.80-1.98 (m, 4H) 2.39-2.49 (m, 2H) 3.09-3.24 (m, 1H) 4.32-4.44 (m, 1H) 7.31-7.43 (m, 2H) 7.91 (d, J=3 Hz, 1H) 8.09 (d, J=3 Hz, 1H)
MS ES+: 363
To a stirred solution of 2-(3-chloropyrazin-2-yl)-2-((4-methoxyphenyl)sulfonyl)acetonitrile (Intermediate 12; 136 mg, 0.420 mmol) and 4,4-difluorocyclohexanamine hydrochloride (CAS 675112-70-6; 433 mg, 2.52 mmol) in N-methyl-2-pyrrolidinone (2 mL) was added triethylamine (0.410 mL, 2.94 mmol). The reaction was then heated in a microwave to 180° C. for 2 h. The reaction mixture was partitioned between water and EtOAc. The phases were separated and the aqueous extracted with EtOAc. The combined organic extracts were then washed with water, dilute citric acid, water, sat. NaHCO3, sat. brine, dried (H-frit) and evaporated. The crude material was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.87-2.11 (m, 4H) 2.24-2.40 (m, 2H) 2.75-2.93 (m, 2H) 3.86 (s, 3H) 4.29-4.44 (m, 1H) 6.20 (br. s., 2H) 6.99 (d, J=9 Hz, 2H) 7.96 (d, J=3 Hz, 1H) 8.11 (d, J=9 Hz, 2H) 8.22 (d, J=3 Hz, 1H)
MS ES+: 423
To a stirred solution of 2-(2-chloropyridin-3-yl)-2-((4-methoxyphenyl)sulfonyl)acetonitrile (Intermediate 13; 210 mg, 0.651 mmol) in N-methyl-2-pyrrolidinone (1 mL) was added a solution of 4,4-difluorocyclohexanamine hydrochloride (CAS 675112-70-6; 670 mg, 3.90 mmol) and triethylamine (0.635 mL, 4.55 mmol) in N-methyl-2-pyrrolidinone (2 mL) and the resulting mixture heated at 165-175° C. for 20 h. The reaction mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous extracted with ethyl acetate. The combined organics were washed with dilute citric acid, water, sat. aq. sodium bicarbonate solution and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-40% EtOAc/petroleum ether). Further purification was performed by column chromatography (preparative HPLC, 40-80% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (4 MHz, CHLOROFORM-d) δ ppm 1.81-2.16 (m, 4H) 2.21-2.49 (m, 2H) 2.53-2.89 (m, 2H) 3.84 (8, 3H) 4.56-4.92 (m, 1H) 5.68 (br. s., 2H) 6.86-7.14 (m, 3H) 7.77-7.99 (m, 3H) 8.00-8.15 (m, 1H)
MS ES+: 422
To a stirred solution of 2-(2-chloropyridin-3-yl)-2-(phenylsulfonyl)acetonitrile (Intermediate 14; 100 mg, 0.342 mmol) in N-methyl-2-pyrrolidinone (1 mL) was added a solution of cyclohexanamine (CAS 108-91-8; 0.234 mL, 2.05 mmol) and triethylamine (0.048 mL, 0.342 mmol) in N-methyl-2-pyrrolidinone (1 mL) and the resulting mixture heated at 170° C. for 5 h using a microwave reactor. The reaction mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous extracted with ethyl acetate. The combined organics were washed with dilute citric acid, water, sat aq. sodium bicarbonate solution and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-40% EtOAc/petroleum ether). Further purification was performed by column chromatography (preparative HPLC, 40-80% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.20-1.56 (m, 3H) 1.72-2.00 (m, 5H) 2.14-2.51 (m, 2H) 4.49 (br. s., 1H) 5.70 (br. s., 2H) 6.89-7.16 (m, 1H) 7.40-7.56 (m, 3H) 7.82-7.91 (m, 1H) 7.92-8.00 (m, 2H) 8.03-8.11 (m, 1H)
MS ES+: 356
A stirred solution of N-cyclohexyl-5-iodopyrimidin-4-amine (Intermediate 15; 139 mg, 0.459 mmol) and Pd(Ph3P)4 (26.5 mg, 0.023 mmol) dry DME (2 mL) was degassed with N2. In a separate vial 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 91 mg, 0.504 mmol) was dissolved in dry DME (2 mL), degassed and cooled to 0° C. NaH, 60% dispersion in oil (36.7 mg, 0.917 mmol) was added and stirred 5 min. The solution of iodopyrimidine and Pd catalyst was then added via cannula, rinsing with further dry DME. The reaction mixture was then heated in a microwave at 110° C. for 1 h. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water, sat. brine, dried (H-frit) and evaporated. The crude material was then purified by column chromatography (silica, 0-40% EtOAc/petroleum ether) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.53 (m, 3H) 1.57-1.69 (m, 1H) 1.70-1.90 (m, 4H) 1.98-2.16 (m, 2H) 4.30-4.47 (m, 1H) 7.50-7.65 (m, 5H) 8.01-8.13 (m, 2H) 8.60 (s, 1H) 8.74 (s, 1H)
MS ES+: 357
Prepared as described for 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-2-amine (Example 15), a stirred solution of 2-(2-chloropyridin-3-yl)-2-(phenylsulfonyl)acetonitrile (Intermediate 14; 239 mg, 0.816 mmol), 4,4-difluorocyclohexanamine hydrochloride (CAS 675112-70-6; 662 mg, 4.90 mmol) and triethylamine (0.8 mL, 5.71 mmol) in N-methyl-2-pyrrolidinone (2. mL) was heated at 170° C. for 5 h using a microwave reactor. The crude product was purified by column chromatography (silica, 0-40% EtOAc/petroleum ether). Further purification was performed by column chromatography (preparative HPLC, 40-80% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.82-2.14 (m, 4H) 2.17-2.46 (m, 2H) 2.58-2.87 (m, 2H) 4.49-4.90 (m, 1H) 5.76 (s, 2H) 6.97-7.14 (m, 1H) 7.39-7.63 (m, 3H) 7.76-7.93 (m, 1H) 7.97 (d, J=7 Hz, 2H) 8.04-8.14 (m, 1H)
MS ES+: 392
To a stirred degassed solution of 4-chloro-N-cyclohexylpyrimidin-5-amine (Intermediate 16; 209 mg, 0.987 mmol) in dry DME (2 mL) was added Pd(Ph3P)4 (29 mg, 0.025 mmol) and Pd(amphos)2Cl2 (18 mg, 0.025 mmol). In a separate vial, 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 197 mg, 1.09 mmol) was dissolved in dry DME (2 mL), degassed, cooled in ice and treated with NaH, 60% dispersion in oil (79 mg, 1.98 mmol). The second vial was stirred in ice for 5 min, then at rt for 5 min, under a gentle N2 stream. The solution of pyrimidine and Pd catalysts was then added via cannula, rinsing with further dry DME. The reaction heated in the microwave at 110° C. for 1 h. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water, sat. brine, dried (H-frit) and evaporated. The crude product was purified by column chromatography (silica, 50-90% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.53 (m, 3H) 1.57-1.69 (m, 1H) 1.70-1.90 (m, 4H) 1.98-2.16 (m, 2H) 4.30-4.47 (m, 1H) 7.50-7.65 (m, 5H) 8.01-8.13 (m, 2H) 8.60 (s, 1H) 8.74 (s, 1H)
MS ES+: 357
To a stirred solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 330 mg, 1.82 mmol) in DME (3 mL) at 0° C. under a flow of N2 was added NaH, 60% dispersion in oil (132 mg, 3.31 mmol) and the resulting suspension allowed to stir for 10 min. In a separate flask Pd(Ph3P)4 (96 mg, 0.083 mmol) in DME (3 mL) was degassed. The solution in the first flask was added to the solution of Pd(Ph3P)4 in DME. After stirring for a further to min N-cyclohexyl-4-iodopyridin-3-amine (Intermediate 17; 500 mg, 1.66 mmol) was added and the reaction mixture subjected to microwave irradiation at 120° C. for 1.5 h. The reaction mixture was poured into water and extracted with ethyl acetate and then the organics washed with brine. The organics were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (basic silica, 0-20% EtOAc/petroleum ether). The resulting solid was recrystallised from hot IPA/water to afford the title compound.
1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.28-1.42 (m, 1H), 1.44-1.59 (m, 2H), 1.78-1.89 (m, 1H), 1.92-2.12 (m, 4H), 2.12-2.30 (m, 2H), 3.94-4.10 (m, 1H), 5.89 (br. s., 2H), 7.45-7.62 (m, 4H), 7.89-8.07 (m, 2H), 8.17-8.22 (m, 1H), 8.68 (s, 1H)
MS ES+: 356
Prepared as described for 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-c]pyridin-2-amine (Example 20), to a stirred solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 548 mg, 3.02 mmol) in DME (3 mL) at 0° C. under a flow of N2 was added NaH, 60% dispersion in oil (220 mg, 5.50 mmol) and the resulting suspension allowed to stir for to min. In a separate flask Pd(Ph3P)4 (159 mg, 00.137 mmol) in DME (3 mL) was degassed. The solution in the first flask was added to the solution of Pd(Ph3P)4 in DME. After stirring for a further to min, 2-bromo-N-(4,4-difluorocyclohexyl)pyridin-3-amine (Intermediate 18; 800 mg, 2.75 mmol) was added and the reaction mixture subjected to microwave irradiation at 120° C. for 1.5 h. The crude product was purified by column chromatography (basic silica, 0-50% DCM/EtOAc). The resulting solid was triturated with hot ethanol to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-1.93 (m, 2H) 1.95-2.38 (m, 6H) 4.50-4.66 (m, 1H) 6.89-6.97 (m, 1H) 7.17 (s, 2H) 7.47-7.60 (m, 4H) 8.04-8.09 (m, 2H) 8.11-8.15 (m, 1H)
MS ES+: 392
Prepared as described for 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-c]pyridin-2-amine (Example 20), to a stirred solution of 2-((4-methoxyphenyl)sulfonyl)acetonitrile (CAS 132276-87-o; 638 mg, 3.02 mmol) in DME (4 mL) at 0° C. under a flow of N2 was added NaH, 60% dispersion in oil (2200 mg, 5.50 mmol) and the resulting suspension allowed to stir for 10 minutes. In a different flask Pd(Ph3P)4 (159 mg, 0.137 mmol) in DME (4 mL) was degassed. The solution in the first flask was added to the solution of Pd(Ph3P)4 in DME. After stirring for a further to minutes 2-bromo-N-(4,4-difluorocyclohexyl)pyridin-3-amine (Intermediate 18; 800 mg, 2.75 mmol) was added and the reaction mixture subjected to microwave irradiation at 120° C. for 1.5 h. The crude product was purified by column chromatography (basic silica, 0-100% DCM/EtOAc). The resulting solid was triturated with hot ethanol to afford the title compound.
1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.88-2.12 (m, 4H), 2.27-2.39 (m, 2H), 2.44-2.59 (m, 2H), 3.85 (s, 3H), 4.09-4.28 (m, 1H), 5.93 (s, 2H), 6.89-7.05 (m, 3H), 7.50-7.54 (m, 1H), 8.07-8.20 (m, 2H), 8.30-8.34 (m, 1H)
MS ES+: 422
Prepared as described for 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-c]pyridin-2-amine (Example 20), to a stirred degassed solution Pd(Ph3P)4 (73 mg, 0.063 mmol) in anhydrous DME (3 mL) under an atmosphere of nitrogen was added a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 252 mg, 1.39 mmol) and NaH, 60% dispersion in oil (106 mg, 2.65 mmol) in anhydrous DME (4 mL). The resulting mixture was stirred at room temperature for 10 min followed by addition of a solution of 3-bromo-N-cyclohexylpyridin-4-amine (Intermediate 19; 322 mg, 1.262 mmol) in anhydrous DME (1 mL). The reaction mixture was heated at 120° C. for 1.5 h. Purification was carried out by column chromatography (silica, 0-100% EtOAc/petroleum ether). Further purification was performed by column chromatography (preparative HPLC, 20-600% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19-1.55 (m, 3H) 1.76-2.29 (m, 7H) 3.82-4.19 (m, 1H) 5.75 (br. s, 2H) 7.20 (d, J=6 Hz, 1H) 7.38-7.62 (m, 3H) 7.88-8.09 (m, 2H) 8.23 (d, J=6 Hz, 1H) 8.92 (s, 1H)
MS ES+: 356
To a stirred solution of methyl N-[7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-6-yl]-N-(methoxycarbonyl)carbamate (Intermediate 20; 0.214 g, 0.453 mmol) in MeOH (7 mL) was added sodium methanolate (16 mg, 0.3 mmol) and the resulting mixture stirred at room temperature for 3 h. A further portion of sodium methoxide (10 mg, 0.19 mmol) was added and the reaction was stirred at room temperature for a further 2 h. The solvent was removed under reduced pressure. The residue was partitioned between DCM and water, passed through a phase separator and concentrated in vacuo. Purification was performed by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (4000 MHz, CHLOROFORM-d) δ ppm 1.27-1.46 (m, 3H) 1.66-2.05 (m, 5H) 2.47-2.73 (m, 2H) 3.89 (s, 3H) 4.09-4.28 (m, 1H) 7.37-7.64 (m, 3H) 8.05-8.21 (m, 2H) 8.27 (d, J=3 Hz, 2H) 8.52 (d, J=3 Hz, 1H)
MS ES+: 415
To a stirred solution 2-amino-1-(4,4-difluorocyclohexyl)-6-methyl-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (Intermediate 22; 65 mg, 0.154 mmol) in chloroform (2 mL) under an atmosphere of nitrogen was added trichlorophosphine (0.1 mL, 1.15 mmol). The resulting mixture was heated at reflux for 1 h. The mixture was partitioned between DCM and saturated NaHCO3. The phases were separated and the aqueous extracted with DCM. The combined organics were washed with saturated NaHCO3, dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (preparative HPLC, 40-80% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.76-2.19 (m, 4H) 2.22-2.41 (m, 2H) 2.52 (s, 3H) 2.58-2.81 (m, 2H) 4.58-4.87 (m, 1H) 5.57 (br. s, 2H) 6.91 (d, J=8 Hz, 1H) 7.36-7.60 (m, 3H) 7.76 (d, J=8 Hz, 1H) 7.86-8.07 (m, 2H)
MS ES+: 406
Prepared as described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a stirred degassed solution of Pd(Ph3P)4 (14 mg, 0.013 mmol) and Pd(amphos)2Cl2 (9 mg, 0.013 mmol) in anhydrous DME (1 mL) under an atmosphere of nitrogen was added a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 100 mg, 0.550 mmol) and NaH, 60% dispersion in oil (44.0 mg, 1.100 mmol) in anhydrous DME (1 mL). The resulting mixture was stirred at room temperature for 10 min followed by addition of a solution of 4-chloro-N-cyclohexyl-6-methoxypyrimidin-5-amine (Intermediate 23; 121 mg, 0.5 mmol) in anhydrous DME (1 mL). The reaction mixture was heated at 120° C. for 1.5 h. The crude product was purified by column chromatography (preparative HPLC, 30-70% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13-1.53 (m, 4H) 1.65-2.51 (m, 7H) 4.09 (s, 3H) 5.86 (br. s., 2H) 7.42-7.60 (m, 3H) 8.14-8.30 (m, 2H) 8.51 (s, 1H)
MS ES+: 387
Prepared as described for 3-(benzenesulfonyl)-1-cyclohexyl-1H-pyrrolo[2,3-c]pyridin-2-amine (Example 20), to a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 34 mg, 0.189 mmol) in DME (3 mL) at 0° C. was added NaH, 60% dispersion in oil (14 mg, 0.344 mmol). After 10 minutes the resulting suspension was added to a degassed solution of Pd(Ph3P)4 (10 mg, 8.60 μmol) in DME (2 mL). The resulting suspension was allowed to stir at room temperature for 20 minutes. 4-bromo-6-chloro-N-cyclohexylpyridazin-3-amine (Intermediate 24; 50 mg, 0.172 mmol) was then added and the reaction mixture subjected to microwave irradiation at 120° C. for 2 h. Purification was carried out by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.49 (m, 3H), 1.62-1.7 (m, 3H), 1.77-1.86 (m, 2H), 2.42-2.49 (m, 2H), 4.43 (br. s., 1H), 7.47 (s, 1H), 7.55-7.70 (m, 3H), 7.96 (br. s., 2H), 8.00-8.08 (m, 2H)
MS ES+: 391
A solution of 5-(benzenesulfonyl)-3-chloro-7-cyclohexyl-7H-pyrrolo[2,3-c]pyridazin-6-amine (Example 27; 31 mg, 0.079 mmol) in THF (2 mL) was passed through an H-Cube using a 10% Palladium on carbon cat-cart at 40° C. at ‘full H2’. The reactant was cycled through the H-Cube for 2 h at 1 mL/min. The product solution was then concentrated in vacuo. Purification was carried out by column chromatography (silica, 0-50% EtOAc/petroleum ether) followed by column chromatography (silica, 0-10% MeOH/DCM) and finally by trituration with diethyl ether to afford the title compound.
1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.25-1.44 (m, 3H), 1.62-1.71 (m, 1H), 1.75-1.98 (m, 4H), 2.34-2.48 (m, 2H), 4.32 (br. s., 1H), 6.13 (br. s, 2H), 7.31-7.55 (m, 4H), 7.78-7.89 (m, 2H), 8.57-8.67 (m, 1H)
MS ES+: 357
As described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 373 mg, 2.06 mmol) in DME (3 mL) at 0° C. was added NaH, 60% dispersion in oil (165 mg, 4.11 mmol). After 10 min the resulting suspension was added to a degassed solution of Pd(Ph3P)4 (59 mg, 0.051 mmol) and Pd(amphos)2C2 (36 mg, 0.051 mmol) in DME (2 mL). The resulting suspension was allowed to stir at room temperature for 20 minutes. 4-chloro-N-(4,4-difluorocyclohexyl)-6-ethoxypyrimidin-5-amine (Intermediate 25; 6 mg, 2.06 mmol) was then added and the reaction mixture subjected to microwave irradiation at 120° C. for 2 b. Purification was carried out by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.41 (m, 3H), 1.71-1.80 (m, 2H), 1.92-2.21 (m, 4H), 2.44-2.61 (m, 2H), 4.43-4.45 (m, 3H), 7.34 (br. s, 2H), 7.52-7.64 (m, 3H), 8.00-8.10 (nm, 2H), 8.30 (s, 1H)
MS ES+: 437
As described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 512 mg, 2.83 mmol) in DME (3 mL) at 0° C. was added NaH, 60% dispersion in oil (226 mg, 5.65 mmol). After to min the resulting suspension was added to a degassed solution of Pd(Ph3P)4 (0.082 g, 0.071 mmol) and Pd(amphos)2Cl2 (0.050 g 0.071 mmol) in DME (2 mL). The resulting suspension was allowed to stir at room temperature for 20 minutes. 4-(benzyloxy)-6-chloro-N-(4,4-difluorocyclohexyl)pyrimidin-5-amine (Intermediate 27; 1 g, 2.83 mmol) was then added and the reaction mixture subjected to microwave irradiation at 120° C. for 2 h. Purification was carried out by column chromatography (silica, 0-30% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.78 (m, 2H), 0.83-2.11 (m, 4H), 2.40-2.58 (m, 2H), 4.44-4.57 (m, 1H), 5.55 (s, 2H), 7.26-7.39 (m, 5H), 7.42-7.48 (m, 2H), 7.51-7.66 (m, 3H), 8.02-8.10 (m, 2H), 8.32 (s, 1H)
MS ES+: 499
A solution of 7-(benzenesulfonyl)-4-(benzyloxy)-5-(4,4-difluorocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 30; 420 mg, 0.842 mmol) in methanol (17 mL) was passed through an H-Cube using a palladium on carbon (10%) cat-cart at ‘full H2’ at room temperature at 1 mL/min. The product solution was concentrated and triturated with ethyl acetate to afford the title compound.
1H NMR (4 MHz, DMSO-d6) δ ppm 1.61-1.71 (m, 2H), 1.85-2.18 (m, 4H), 2.68-2.83 (m, 2H), 4.32-4.52 (m, 1H), 6.94 (s, 2H), 7.51-7.68 (m, 3H), 7.86 (s, 1H), 7.94-8.12 (m, 2H), 12.04 (br. s., 1H)
MS ES+: 409
To a stirred suspension of 6-amino-7-(benzenesulfonyl)-5-(4,4-difluorocyclohexyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (Example 31; 75 mg, 0.184 mmol) in POCl3 (1 mL, 10.7 mmol) was heated at 80° C. overnight. The reaction was quenched slowly into warm water. The resulting solution was basified to pH12 with 2M NaOH. The resulting aqueous mixture was extracted with DCM. The organics were separated and concentrated. Trituration with diethyl ether afforded the title compound.
1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.86-2.23 (m, 4H), 2.27-2.68 (m, 4H), 5.41-5.73 (m, 1H), 6.28 (br. s., 2H), 7.35-7.73 (m, 3H), 8.05-8.32 (m, 2H), 8.56 (br. s., 1H)
MS ES+: 427
A solution of 7-(benzenesulfonyl)-4-chloro-5-(4,4-difluorocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 32; 40 mg, 0.094 mmol) and methanamine, 2M in THF (0.234 mL, 0.469 mmol) in THF (1 mL) was subjected to microwave irradiation at 120-160° C. for a total of 7 h. The reaction mixture was concentrated in vacuo. To the crude product was added methanamine 2M in THF (2 ml). The solution was subjected to microwave irradiation for a further 2 h at 160° C. The reaction mixture was poured into sat. NaHCO3 and extracted with DCM. The organics were separated and concentrated to afford the title compound.
1H NMR (4 MHz, DMSO-d6) δ ppm 1.95-2.04 (m, 2H), 2.06-2.30 (m, 4H), 2.33-2.48 (m, 2H), 2.95 (d, J=5 Hz, 3H), 4.45-4.58 (m, 1H), 5.84-5.91 (m, 1H), 6.82 (s, 2H), 7.51-7.73 (m, 3H), 8.04-8.15 (m, 2H), 8.23 (s, 1H)
MS ES+: 422
As described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a stirred degassed solution of Pd(Ph3P)4 (28 mg, 0.024 mmol) and Pd(amphos)2Cl2 (17 mg, 0.024 mmol) in anhydrous DME (3 mL) under an atmosphere of nitrogen was added a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 261 mg, 1.44 mmol) and NaH, 60% dispersion in oil (115 mg, 2.89 mmol) in anhydrous DME (3 mL). The resulting mixture was stirred at room temperature for to min followed by addition of a solution of 6-chloro-5-N-cyclohexyl-4-N,4-N-dimethylpyrimidine-4,5-diamine (Intermediate 28; 245 mg, 0.962 mmol) in anhydrous DME (3 mL). The reaction mixture was heated at 125° C. for 20 h. The crude product was purified by column chromatography (preparative HPLC, 40-80% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.03-2.10 (m, 10H) 2.89 (s, 6H) 4.67-4.92 (m, 1H) 6.01 (br. s., 2H) 7.39-7.63 (m, 3H) 8.11-8.32 (m, 2H) 8.53 (s, 1H)
MS ES+: 400
As described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a stirred degassed solution of Pd(Ph3P)4 (32 mg, 0.027 mmol) and Pd(amphos)2Cl2 (19 mg, 0.027 mmol) in anhydrous DME (2 mL) under an atmosphere of nitrogen was added a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 298 mg, 1.65 mmol) and NaH, 60% dispersion in oil (132 mg, 3.29 mmol) in anhydrous DME (2 mL). The resulting mixture was stirred at room temperature for to min followed by addition of a solution of 4-chloro-N-cyclopentyl-6-methoxypyrimidin-5-amine (Intermediate 29; 250 mg, 1.10 mmol) in anhydrous DME (2 mL). The reaction mixture was heated at 120° C. for 16 h. The crude product was purified by recrystallisation from DMSO/MeOH (1:1) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.73 (m, 2H) 1.80-2.05 (m, 6H) 3.98 (s, 3H) 4.70-5.01 (m, 1H) 7.25 (br. s, 2H) 7.42-7.72 (m, 3H) 7.94-8.13 (m, 2H) 8.33 (s, 1H)
MS ES+: 373
As described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a stirred degassed solution of Pd(Ph3P)4 (23.64 mg, 0.0020 mmol) and Pd(amphos)2Cl2 (19 mg, 0.027 mmol) in anhydrous DME (2 mL) under an atmosphere of nitrogen was added a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 148 mg, 0.818 mmol) and NaH, 60% dispersion in oil (65.5 mg, 1.637 mmol) in anhydrous DME (3 mL). The resulting mixture was stirred at room temperature for to min followed by addition of a solution of 4-chloro-N-cyclohexyl-2-methoxypyridin-3-amine (Intermediate 30; 197 mg, 0.818 mmol) in anhydrous DME (1 mL). The reaction mixture was subjected to microwave irradiation at 120° C. for 2 h. Purification was carried out by column chromatography (C18-silica 5-95% methanol/water+0.1% ammonia) to afford the title compound.
1H NMR (4 MHz, DICHLOROMETHANE-d2) δ ppm 1.06-1.44 (m, 4H), 1.59-2.10 (m, 6H), 2.14-2.58 (m, 1H), 3.91 (s, 3H), 5.58 (br. s., 2H), 7.10 (d, J=5 Hz, 1H), 7.32-7.46 (m, 3H), 7.63 (d, J=5 Hz, 1H), 7.79-7.87 (m, 2H)
MS ES+: 386
A stirred suspension of dicyanozinc (CAS 557-21-1; 18 mg, 0.153 mmol), Pd(Ph3P)4 (30 mg, 0.026 mmol) and 7-(benzenesulfonyl)-4-chloro-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 34; 100 mg, 0.256 mmol) in N,N-dimethylformamide (1 mL) was subjected to microwave irradiation at 150° C. for 30 minutes. The reaction mixture was poured into sat. NaHCO3 solution and extracted with ethyl acetate. The organics were washed with brine, dried over MgSO4 and concentrated to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.37-1.50 (m, 3H) 1.55-1.72 (m, 1H) 1.80-2.00 (m, 4H) 2.24-2.41 (m, 2H) 4.55-4.82 (m, 1H) 7.52-7.69 (m, 3H) 7.97 (br.s., 2H) 8.05-8.11 (m, 2H) 8.67 (s, 1H).
MS ES+: 382
As described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a solution of 2-(2-fluorobenzenesufonyl)acetonitrile (CAS 59849-52-4; 195 mg, 0.978 mmol) in DME (1 mL) was added NaH, 60% dispersion in oil (86 mg, 2.15 mmol). In a separate flask Pd(Ph3P)4 (28 mg, 0.024 mmol), Pd(amphos)2Cl2 (17 mg, 0.024 mmol) and 4-chloro-N-cyclohexyl-6-methoxy-2-methylpyrimidin-5-amine (Intermediate 35; 250 mg, 0.978 mmol) were stirred in DME (2 mL) and degassed. To the catalyst/substrate mixture was added the preformed sodium salt of 2-(2-fluorobenzenesulfonyl)acetonitrile and the reaction subjected to microwave irradiation at 130° C. for 2 h. Purification was carried out by column chromatography (silica, 0-10% MeOH/DCM) followed by trituration with ethyl acetate to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.31 (m, 1H) 1.36-1.49 (m, 2H) 1.63-1.70 (m, 3H) 1.79-1.88 (m, 2H) 2.12-2.24 (m, 2H) 2.35 (s, 3H) 3.97 (s, 3H) 4.28-4.48 (m, 1H) 7.17 (br. s., 2H) 7.27-7.34 (m, 1H) 7.36-7.42 (m, 1H) 7.60-7.70 (m, 1H) 8.01-8.07 (m, 1H)
MS ES+: 419
As described for 7-(benzenesulfonyl)-5-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19), to a solution of 2-(3-fluorobenzenesulfonyl)acetonitrile (CAS 61081-29-6; 300 mg, 1.51 mmol) in dioxane (3 mL) was added NaH, 60% dispersion in oil (133 mg, 3.31 mmol). In a separate flask Pd(Ph3P)4 (70 mg, 0.060 mmol), Pd(amphos)2Cl2 (43 mg, 0.060 mmol) and 4-chloro-N-cyclohexyl-6-methoxy-2-methylpyrimidin-5-amine (Intermediate 35; 385 mg, 0.978 mmol) were stirred in dioxane (2 mL) and degassed. To the catalyst/substrate mixture was added the preformed sodium salt of 2-(3-fluorobenzenesulfonyl)acetonitrile and the reaction heated at reflux for 3 h. Purification was carried out by column chromatography (C18-silica 5-95% methanol/water+0.1% ammonia).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.30 (m, 1H) 1.33-1.47 (m, 2H) 1.58-1.70 (m, 3H) 1.77-1.84 (m, 2H) 2.08-2.21 (m, 2H) 2.49 (s, 3H) 3.99 (s, 3H) 4.25-4.46 (m, 1H) 7.19 (br. s., 2H) 7.42-7.51 (m, 1H) 7.57-7.65 (m, 1H) 7.83-8.00 (m, 2H)
MS ES+: 419
A stirred solution of 4-chloro-6-methoxy-N-(oxan-4-yl)pyrimidin-5-amine (249 mg, 1.02 mmol), 2-(benzenesulfonyl)acetonitrile (CAS 7605-28-9; 204 mg, 1.12 mmol), Pd(Ph3P)4 (59 mg, 0.051 mmol) and Pd(amphos)2Cl2 (36 mg, 0.051 mmol) in Dioxane (5 mL) was degassed for 5 minutes. NaHMDS solution (2M in THF, 1.53 mL, 3.07 mmol) was added and the mixture was heated to reflux for 1.5 h. The mixture was partitioned between ethyl acetate and sat. aq. NaHCO3 then the organic phase was washed with brine and dried over MgSO4 and then concentrated in vacuo. Purification was carried out by column chromatography (silica, 0-100% EtOAc/Petrol then 0-10% MeOH/DCM). Further purification was carried out by column chromatography (preparative HPLC, 20-60% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.57-1.66 (m, 2H) 2.34-2.47 (m, 2H) 3.45 (t, J=11 Hz, 2H) 3.94-4.03 (m, 5H) 4.56-4.67 (m, 1H) 7.32 (br. s, 2H) 7.51-7.62 (m, 3H) 8.02-8.08 (m, 2H) 8.32 (s, 1H)
MS ES+: 389
To a solution of 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-phenyl-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide (Intermediate 43; 46 mg, 0.092 mmol) in EtOH (1 mL) was added hydrazine monohydrate (13 μL, 0.275 mmol) and the reaction mixture stirred at reflux overnight. The reaction mixture was filtered and the resulting solid washed with methanol. The combined filtrates were concentrated in vacuo. Purification was carried out by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.21-1.49 (m, 4H) 1.67-1.82 (m, 2H) 1.84-1.97 (m, 2H) 2.23-2.39 (m, 2H) 4.04-4.18 (m, 1H) 5.77 (br. s., 2H) 6.97-7.07 (m, 3H) 7.10-7.20 (m, 2H) 7.32 (br. s., 1H) 7.90-7.97 (m, 1H) 8.14-8.22 (m, 1H)
MS ES+: 372
To a solution of 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-(pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonamide (Intermediate 43; 20 mg, 0.040 mmol) in EtOH (1 mL) was added hydrazine monohydrate (6 μL, 0.119 mmol) and the reaction mixture stirred at reflux overnight. The reaction mixture was filtered and the resulting solid washed with methanol. The combined filtrates were concentrated in vacuo. Purification was carried out by column chromatography (silica, 0-50% EtOAc/petroleum ether) to afford the title compound. 1H NMR (4 MHz, DMSO-d6) δ ppm 1.20-129 (m, 1H) 1.33-1.50 (m, 2H) 0.61-1.73 (m, 3H) 1.75-1.88 (m, 2H) 2.35-2.48 (m, 2H) 4.30-4.43 (m, 1H) 7.12-7.22 (m, 1H) 7.36-7.47 (m, 3H) 7.84-7.93 (m, 1H) 8.02-8.13 (m, 2H) 8.21-8.8 (m, 1H) 10.42 (s, 1H)
MS ES+: 373
Examples 43 to 56 (see Table 2 following) were prepared according to one of the procedures 1, 2 or 3 described below.
A solution of 2-(benzenesulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 1; 100 mg, 0.34 mmol) in NMP (0.5 mL) was treated with a primary amine (0.68 mmol) and heated in the microwave at 170° C. for 1 h. Where the amine was used as a hydrochloride salt, triethylamine (0.095 mL, 0.68 mmol, 2 eq.) was included in the reaction. A further portion of each amine (1.14 mmol, 3 eq) was added and heating was repeated as before. The reaction mixtures were purified directly by preparative HPLC using one of the methods listed below.
A solution of 2-(benzenesulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 1; 110 mg, 0.326 mmol) in DMSO (1 mL) was treated with a primary amine (1.96 mmol, 6 eq.) and triethylamine (0.045 mL, 0.326 mmol) and heated to 180° C. for 3 h. The reaction mixtures were diluted with DMSO (2 mL), filtered and purified by preparative HPLC using one of the methods listed below.
A solution of 2-(benzenesulfonyl)-2-(3-chloropyrazin-2-yl)acetonitrile (Intermediate 1; 70 mg, 0.238 mmol) in NMP (1.0 mL) was treated with a primary amine (1.43 mmol) and triethylamine (0.033 mL, 0.238 mmol) and heated in the microwave at 180° C. for 2.5 h. Where the amine used was a hydrochloride salt, triethylamine (0.196 mmol, 1.43 mmol) was included in the reaction. Samples were typically diluted with DMSO, filtered and purified by preparative HPLC using one of the methods listed below. If an aqueous workup was necessary, the reaction mixture was diluted with water and extracted with EtOAc). The combined extracts were washed with citric acid solution, water, sodium bicarbonate solution, water and brine then dried (H-frit) and evaporated, with the crude product then being purified by preparative HPLC using one of the methods listed below.
1H NMR data
Note 1Followed by flash chromatography (12 g silica, 25-60% EtOAc/petrol)
Note 2Aqueous workup
Examples 57 to 107 (see Table 3 following) were prepared according to one of the procedures 4 or 5 as described below.
To a solution of 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonyl chloride (Intermediate 41; 50 mg, 0.112 mmol) in THF (1 mL) was added triethylamine (0.089 mL, 0.635 mmol) and a primary or secondary amine (0.175 mmol). The reaction was stirred at rt for 3 hours and then ethanol (1 mL) and hydrazine monohydrate (0.635 mmol) were added. The reaction mixture was warmed to 80° C. and maintained at this temperature overnight. The reaction mixtures were filtered and concentrated. The residue was taken up in DCM and washed with water, then the organic phase was separated and concentrated and the resulting crude product was purified via prep HPLC using one of the methods listed below or column chromatography on silica.
To a solution of 5-cyclohexyl-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-sulfonyl chloride (Intermediate 41; 55 mg, 0.124 mmol) in THF (1 mL) was added triethylamine (0.052 mL, 0.371 mmol) and a primary or secondary amine (00.247 mmol). After 2 h at room temperature the mixture was diluted with water and extracted with DCM. The organic phase was concentrated, then ethanol (1 mL) and hydrazine monohydrate (0.018 mL, 0.371 mmol) were added and the reaction mixture was warmed to 70° C. for 3 h. The reaction mixture was filtered and concentrated and the residue was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether).
1H NMR data
Examples 108 to 118 (see Table 4 following) were prepared using the general procedure 6 described below.
A solution of 2-(5-cyclohexyl-7-((4-methoxyphenyl)sulfonyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)isoindoline-1,3-dione (Intermediate 44; 56 mg, 0.108 mmol) and hydrazine monohydrate (11 μL, 0.22 mmol) in ethanol (1 mL) was stirred at 70° C. in a sealed tube for 1 h. The mixture was allowed to cool then (except where noted otherwise) diluted with DCM and filtered. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography on silica with the indicated eluent, or by preparative reverse phase HPLC as indicated in the table to afford the title compound.
1H NMR
GPR43 agonist/PAM activity was determined by measuring changes in intracellular calcium levels using a Ca2+ sensitive fluorescent dye. The changes in fluorescent signal were monitored by FLIPR (manufactured by Molecular Devices). GPR43 mediated increases in intracellular Ca2+ concentration were readily detected upon activation with sodium acetate. Prior to the assay (24 hours), CHO-K1 Gα16 cells stably expressing human GPR43 were-seeded in cell culture medium in black, clear-bottom 384-well plates (Corning Inc) and grown overnight at 37° C., 5% CO2. On the day of the assay, cell culture media was removed and cells were loaded with Calcium 5 Dye (Molecular Devices) diluted in HBSS containing 25 mM HEPES, 2.5 mM Probenecid, 0.1% BSA for 1 hour at 37° C., 5% CO2. 10 point half log concentration response curves of sodium acetate from 10 mM were conducted prior to the testing of compounds to calculate the sodium acetate concentration that produces 20% of the maximal response (EC20). Test compounds (at to point half log concentration response curves from 10 μM) were added in the presence of sodium acetate to achieve a final concentration that produces approximately 20% maximal response as calculated from the previous experiment. The changes in fluorescent signal were monitored by FLIPR upon addition of the compound/EC20 sodium acetate mix. The EC50 values were determined from ten point concentration response curves. Curves were generated using the average of two wells for each data point.
The above assay detects both GPR43 receptor agonists and positive allosteric modulators of the GPR43 receptor, without distinguishing between the two. Activity in either regard is useful in the treatment of conditions associated with GPR43 receptor activity.
It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the present invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 1411239.5 | Jun 2014 | GB | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/GB2015/051841 | 6/24/2015 | WO | 00 |
