Patent Grant
10059713
The present invention relates to 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 “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, arylalkyl 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. X5 is N.
In another embodiment of the invention, two of X4, X5, X6 and X7 are N, e.g. X4 and X6 are N, X5 is CR5 and X7 is CR7, or X5 and X6 are N, X4 is CR4 and X7 is CR7.
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 five-membered nitrogen-containing ring through the sulphur atom.
In one embodiment of the invention, Q represents —S—, —SO2—, —SO2NR— or —SO2(CH2)m where m is 1 or 2.
R represents a hydrogen atom or a C1-C6, or C1-C4, or C1-C2 alkyl group. In one embodiment, R represents 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, R3 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), 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 C1-C6, or C1-C4, or C1-C2 alkyl 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 R3 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 cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, phenyl and pyridinyl.
The saturated or unsaturated 3- to 10-membered ring system may be substituted by a saturated or unsaturated 5- to 6-membered heterocyclyl group. This heterocyclyl 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, oxadiazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl and furanyl.
In one embodiment of the invention, R3 represents a saturated 3- or 5- to 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 saturated 3- or 5- 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), 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 another embodiment, R3 represents a saturated 5- to 6-membered ring system which may comprise one or two ring heteroatoms independently selected from nitrogen and oxygen (e.g. cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or piperidinyl), wherein the saturated 5- 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), C1-C6 alkyl, C1-C2 haloalkyl (e.g. trifluoromethyl), C1-C4 alkoxy, C1-C2 haloalkoxy (e.g. difluoromethoxy), 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 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), 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, chlorine, bromine or iodine), C1-C6 alkyl, C1-C2 haloalkyl (e.g. trifluoromethyl), C1-C4 alkoxy, C1-C2 haloalkoxy (e.g. difluoromethoxy), 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, R3 represents phenyl optionally substituted by one or two substituents independently selected from fluorine, chlorine, methyl, trifluoromethyl, difluoromethoxy, C1-C3 alkoxy and methylmorpholinyl.
In yet another embodiment, R3 represents an unsubstituted phenyl group.
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. methylamino or 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 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 alkylthio (e.g. methylthio), methylamino or C3-C8 cycloalkyl (e.g. cyclopropyl or cyclohexyl) group.
In another embodiment of the invention, R5 represents a hydrogen 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 alkylthio (e.g. methylthio) or C3-C8 cycloalkyl (e.g. cyclopropyl or cyclohexyl) group.
In an embodiment of the invention, R6 represents a hydrogen or a halogen atom, or a C1-C6, or C1-C4, or C1-C2 alkyl (e.g. methyl or ethyl) or C5-C8 cycloalkenyl (e.g. cyclohexenyl) group.
Examples of R5 and R6 substituents include hydrogen and chlorine atoms and methyl, ethyl, cyclopropyl, cyclohex-1-en-1-yl and methylthio groups.
In yet another embodiment, R5 and R6 each independently represent a hydrogen atom or a methyl group.
As stated above, R7 represents a hydrogen or a halogen atom, 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, 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 C3-C6 cycloalkyl.
The R7 3- to 11-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), NR9R10, or a C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C5-C6 cycloalkenyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, 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), NR9R10, or a C1-C4 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C5-C6 cycloalkenyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, 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), C1-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 XB 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 R16 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 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-methylpropyl)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, propan-2-yloxy, 1-(cyclopropyl)propoxy, butan-2-yloxy, (2,2-dimethylcyclopropyl)methoxy, 1-cyclopentylethoxy, pentan-3-yloxy, cyclobutylmethoxy, 2,2-dimethylpropoxy, 2-methylpropoxy, cyclobutyloxy, (2,2-dimethyloxan-4-yl)oxy, (4,4-difluorocyclohexyl)oxy, 1-cyclohexylethoxy, 1-cyclobutylethoxy, cyclopentyloxy, (2,2-dimethyloxolan-3-yl)oxy, 3,3-difluorocyclobutyloxy, 2-methylmorpholin-4-yl, 2-fluoromethylmorpholin-4-yl, 1-trifluoromethylethoxy, 2,3-dimethylmorpholin-4-yl, 2,2-dimethylmorpholin-4-yl and 2-trifluoromethylmorpholin-4-yl.
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.
In an embodiment of the invention, the compound of formula (I) is one in which:
In another 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); or
(c) when NR1R2 represents NH2, reducing a compound of formula
in which X4, X5, X6, X7, Q and R3 are as defined in formula (I);
wherein any of compounds (II), (III), (IV), (V) or (VI) 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) (i.e. ammonia) 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(0), 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(0) catalyst may be formed in situ, e.g. from Pd(II) acetate and 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane.
As stated above, a compound of formula (IV) may be protected and thus have a formula
wherein P represents a protecting group such as a benzyl or a 4-methoxybenzyl group and X4, X5, X6, X7 and L2 are as defined in formula (IV). The compound of formula (IVa) may conveniently be reacted with the substituted acetonitrile of formula (V) under the conditions discussed in the preceding paragraph, to arrive at a compound of formula
where X4, X5, X6, X7, Q, R1, R2, R3 and P are as previously defined. The protecting group P may then be cleaved using a suitable method; for example a benzyl protecting group may conveniently be cleaved by hydrogenation over Pd(C) in a suitable solvent such as anhydrous methanol; or a 4-methoxybenzyl protecting group may conveniently be cleaved by treatment with an acid such as trifluoroacetic acid, optionally with heating, e.g. at around 50-100° C.
In process (c) the nitro group of the compound of formula (VI) may conveniently be reduced to an amine with subsequent cyclisation to arrive at a compound of formula (I). The reduction may conveniently be carried out by combining the compound of formula (VI) with a metal catalyst such as iron or zinc, in the presence of an acid such as acetic acid and a solvent such as methanol. Typically the reaction mixture is heated, e.g. to around 30-60° C.
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(0), 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.
Compounds of formula (VI) may be prepared by reacting a compound of formula
wherein L4 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 or sodium carbonate, in a solvent such as tetrahydrofuran or methanol, to arrive at a compound of formula (VI). Typically the reaction mixture is allowed to reach a temperature of around 20-30° C.
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 (Ia) 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. from −78 to 0° C.
In another 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 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 boronic 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(0), 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 600-200° 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), (VII) or (VIII) prior to their reaction with compounds of formula (V). Likewise, they may be applied to the intermediates of formula (II) or (VI) to replace substituents prior to reaction with an amine of formula (III) or prior to the reduction of the nitro group.
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 (III), (IV), (IVa), (V), (VII) and (VIII) 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/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-naphthoate (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 meters (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.
In respect of NMR analysis, compounds of formula (I) frequently exhibit signal broadening due to conformationally restricted motion. These effects are temperature and solvent dependent and can complicate the assignment of signals and coupling constants. Addition of deuterated trifluoroacetic acid to DMSO-d6 NMR solutions sharpen the peaks and allowed assignment of signals.
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.
In the following description “room temperature” denotes a temperature in the range from 20° C. to 25° C.
The abbreviations used in the specific examples have the following meanings:
DCM=dichloromethane
DME=1,2-dimethoxyethane
DMF=N,N-dimethylformamide
DMSO=dimethyl sulfoxide
EtOAc=ethyl acetate
EtOH=ethanol
H-frit=H-frit Biotage Phase Separator (Part #120-1908-F)
MeOH=methanol
MTBE=methyl tert-butyl ether
NMP=N-methylpyrrolidone
TFA=trifluoroacetic acid
THF=tetrahydrofuran
To a stirred and nitrogen degassed solution of tetrakis(triphenylphosphane) palladium (116 mg, 100 μmol) in anhydrous DME (1.5 mL) was added a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-25-9; 399 mg, 2.20 mmol) and sodium hydride (168 mg, 4.20 mmol, 60% dispersion in oil) in anhydrous DME (4 mL). The reaction mixture was stirred at rt for 10 min followed by the addition of 2-chloro-3-iodopyridine (CAS 78607-36-0; 479 mg, 2.00 mmol). The reaction mixture was heated at 120° C. for 1.5 h. The reaction mixture was concentrated in vacuo and the residue diluted with water, neutralised with 2 M aq. HCl solution and extracted with DCM. The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, 10-40% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, CDCl3-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
To a stirred and nitrogen degassed solution of 4,6-dichloropyrimidin-5-amine (CAS 5413-85-4; 515 mg, 3.14 mmol), (cyclohex-1-en-1-yl)boronic acid (CAS 89490-05-1; 415 mg, 3.30 mmol) and potassium carbonate (868 mg, 6.28 mmol) in dioxane (9 mL) and water (1.5 mL) was added bis(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2; 22 mg, 31 μmol). The reaction mixture was heated under microwave irradiation at 120° C. for 1 h. The reaction mixture was filtered through Celite washing with water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water, brine, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (basic silica, 0-10% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, CDCl3) δ ppm 1.65-1.88 (m, 4H) 2.16-2.32 (m, 2H) 2.32-2.51 (m, 2H) 4.29 (br. s., 2H) 6.16-6.38 (m, 1H) 8.37 (s, 1H)
MS ES+: 210
To a stirred and nitrogen degassed solution of 4,6-dichloropyrimidin-5-amine (CAS 5413-85-4; 1.00 g, 6.10 mmol), tetrakis(triphenylphosphane) palladium (176 mg, 152 μmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium (108 mg, 452 μmol) in anhydrous DME (12 mL) was added a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-25-9; 1.22 g, 6.71 mmol) and sodium hydride (488 mg, 12.20 mmol, 60% dispersion in oil) in anhydrous DME (12 mL). The reaction mixture was heated under microwave irradiation at 110° C. for 45 min. The reaction mixture was partitioned between EtOAc and sat. aq. NH4Cl solution and extracted further with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 7.14 (s, 2H) 7.45-7.72 (m, 3H) 7.94-8.16 (m, 2H) 8.43 (s, 1H) 11.95 (br. s., 1H)
MS ES+: 309
To a solution of cyanomethanesulfonyl chloride (CAS 27869-04-1; 700 mg, 5.02 mmol) in anhydrous DCM (20 mL) at 0° C. was added 4-methoxy-N-methylaniline (CAS 5961-59-1; 1.03 g, 7.52 mmol) and triethylamine (699 μL, 5.02 mmol). The reaction mixture stirred at rt for 72 h. The reaction mixture was poured into water and extracted with DCM. The combined organics were concentrated in vacuo. 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 3.24-3.34 (m, 3H) 3.77 (s, 3H) 4.92 (s, 2H) 6.94-7.05 (m, 2H) 7.28-7.44 (m, 2H)
MS ES+: 241
To a stirred and nitrogen degassed solution of 3,5-dibromopyridin-4-amine (CAS 84539-34-4; 2.00 g, 7.94 mmol), potassium carbonate (2.20 g, 15.88 mmol) and (cyclohex-1-en-1-yl)boronic acid (CAS 89490-05-1; 1.10 g, 8.73 mmol) in dioxane (26 mL) and water (1.6 mL) was added bis(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2; 557 mg, 794 μmol). The reaction mixture was heated under microwave irradiation at 130° C. for 1.5 h. The reaction mixture was poured into water and extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. 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 1.58-1.69 (m, 2H) 1.69-1.78 (m, 2H) 2.15 (br. s., 4H) 5.62-5.75 (m, 3H) 7.78 (s, 1H) 8.16 (s, 1H)
MS ES+: 255
To a stirred solution of 2,4-dichloropyridin-3-amine (CAS 173772-63-9; 750 mg, 4.60 mmol), potassium carbonate (3.18 g, 23.01 mmol) and (cyclohex-1-en-1-yl)boronic acid (CAS 89490-05-1; 869 mg, 6.90 mmol) in dioxane (8 mL) and water (2 mL) was tetrakis(triphenylphosphane) palladium (532 mg, 460 μmol). The reaction mixture was heated under microwave irradiation at 140° C. for 30 min. The reaction mixture was filtered (Celite) and then poured into water and extracted with EtOAc. The combined organics were dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, METHANOL-d4) δ ppm 1.70-1.81 (m, 2H) 1.81-1.90 (m, 2H) 2.20-2.29 (m, 2H) 2.29-2.39 (m, 2H) 5.91-6.09 (m, 1H) 7.19 (d, J=5 Hz, 1H) 7.72 (d, J=5 Hz, 1H)
MS ES+: 209
Prepared as described for 4-chloro-2-(cyclohex-1-en-1-yl)pyridin-3-amine (Intermediate 6) from 4,6-dichloro-2-methylpyrimidin-5-amine (CAS 39906-04-2; 1.00 g, 5.62 mmol) in dioxane (to mL) and water (4 mL). The reaction mixture was heated under microwave irradiation at 120° C. for 1.5 h and the crude product was purified by column chromatography (silica, 0-30% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.59-1.74 (m, 4H) 2.14-2.21 (m, 2H) 2.25-2.32 (m, 2H) 2.38 (s, 3H) 5.13 (br. s, 2H) 6.12 (br. s., 1H)
MS ES+: 224
A stirred solution of 4-(difluoromethoxy)benzene-1-sulfonyl chloride (CAS 351003-34-4; 243 mg, 1.00 mmol), disodium sulfite (134 mg, 1.60 mmol) and sodium hydrogen carbonate (202 mg, 1.60 mmol) in water (2 mL) and propan-2-ol (0.5 mL) was heated under microwave irradiation at 120° C. for 30 min. 2-chloroacetonitrile (CAS 107-14-2; 190 μL, 3.00 mmol) was added and the reaction mixture was heated under microwave irradiation at 120° C. for 20 min. The reaction mixture was acidified with sat. aq. NH4Cl solution, extracted with EtOAc, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% EtOAc/petroleum ether) to afford the title compound which was used without further purification.
MS ES+: 248
To a stirred solution of 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 300 mg, 1.43 mmol) and benzaldehyde (CAS 100-52-7; 456 mg, 4.29 mmol) in anhydrous DCM (7 mL) at 0° C. and under a atmosphere of nitrogen was added tetrachlorotitanium [1 M in DCM] (1.57 mL, 1.57 mmol) and stirred at rt for 2 h. Sodium bis(acetyloxy)boranuidyl acetate (910 mg, 4.29 mmol) was added and the reaction mixture stirred at rt for 16 h. The reaction mixture was poured into water and extracted with DCM. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-30% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, CDCl3) δ ppm 1.65-1.88 (m, 4H) 2.14-2.40 (m, 4H) 4.36 (s, 2H) 6.10-6.22 (m, 1H) 7.20-7.27 (m, 2H) 7.29-7.39 (m, 3H) 8.45 (s, 1H)
MS ES+: 300
Prepared as described for 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3) from N-benzyl-4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 9; 245 mg, 962 μmol) in anhydrous DME (6 mL). The reaction mixture was heated at 120° C. for 16 h, concentrated in vacuo, diluted with water, neutralised with 2 M aq. HCl solution and extracted with DCM. The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (C18-silica, 5-60% acetonitrile/water (with 0.1% formic acid)). Further purification by column chromatography (preparative HPLC, 30-70% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (400 MHz, CDCl3) δ ppm 1.49-1.58 (m, 2H) 1.61-1.70 (m, 2H) 1.76-1.91 (m, 2H) 2.14-2.30 (m, 2H) 5.33 (s, 2H) 5.61 (br. s., 1H) 5.89 (br. s., 2H) 7.01 (d, J=7 Hz, 2H) 7.29-7.43 (m, 3H) 7.45-7.63 (m, 3H) 8.16-8.36 (m, 2H) 8.85 (s, 1H).
MS ES+: 445
To a stirred solution of 7-(benzenesulfonyl)-5-benzyl-4-(cyclohex-1-en-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 10; 200 mg, 450 μmol) in anhydrous THE (5 mL) at −78° C. and under an atmosphere of nitrogen was added butyllithium [1.6 M in hexanes] (225 μL, 360 μmol) and stirred at 0° C. for 1 h. Iodomethane (CAS 74-88-4; 34 μL, 540 μmol) was added and the reaction stirred at rt for 18 h. The reaction mixture was poured into water and extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 459
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 3-fluorobenzene-1-sulfonyl chloride (CAS 701-27-9; 195 mg, 1.00 mmol) to give the title compound which was used without further purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 5.34 (s, 2H) 7.72-7.93 (m, 4H)
MS ES+: 200
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 2-fluorobenzene-1-sulfonyl chloride (CAS 2905-27-7; 195 mg, 1.00 mmol) to give the title compound which was used without further purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 5.34 (s, 2H) 7.56 (t, J=8 Hz, 1H) 7.63 (m, 1H) 7.87-8.03 (m, 2H)
MS ES+: 200
Prepared as described for 4-chloro-2-(cyclohex-1-en-1-yl)pyridin-3-amine (Intermediate 6) from 4,6-dichloro-2-ethylpyrimidin-5-amine (CAS 6237-96-3; 243 mg, 1.27 mmol) in dioxane (10 mL) and water (2.5 mL). The reaction mixture was heated under microwave irradiation at 100° C. for 40 min. The crude product was purified by column chromatography (silica, 0-30% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=8 Hz, 3H) 1.59-1.75 (m, 4H) 2.14-2.22 (m, 2H) 2.27-2.34 (m, 2H) 2.61-2.70 (m, 2H) 5.14 (s, 2H) 6.14 (br. s., 1H)
MS ES+: 238
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 6-methoxypyridine-3-sulfonyl chloride (CAS 312300-42-8; 270 mg, 1.30 mmol) to give the title compound which was used without further purification.
MS ES+: 213
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 3,4-difluorobenzene-1-sulfonyl chloride (CAS 145758-05-0; 276 mg, 1.30 mmol) with the exception that additional 2-chloroacetonitrile (CAS 107-14-2; 100 μL, 1.58 mmol) was added after 20 min and the reaction mixture was further heated under microwave irradiation at 120° C. for 15 min to give the title compound which was used without further purification.
MS ES+: 218
To a stirred solution of disodium sulfite (1.38 mg, 10.95 mmol) and sodium hydrogen carbonate (0.92 g, 10.95 mmol) in water (1.25 mL) and THF (12.5 mL) was added cyclohexanesulfonyl chloride (CAS 4837-38-1; 1.00 g, 10.95 mmol) at 0° C. The reaction mixture was stirred at rt for 16 h. 2-chloroacetonitrile (CAS 107-14-2; 549 μL, 8.65 mmol) was added and the reaction mixture was heated under microwave irradiation at 100° C. for 1.5 h. The reaction mixture was poured into water and extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 20-50% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, CDCl3) δ ppm 1.19-1.48 (m, 3H) 1.58-1.73 (m, 2H) 1.74-1.87 (m, 1H) 1.91-2.09 (m, 2H) 2.14-2.34 (m, 2H) 3.18-3.40 (m, 1H) 3.94 (s, 2H)
MS ES−: 186
Prepared as described for 2-(cyclohexanesulfonyl)acetonitrile (Intermediate 17) from oxane-4-sulfonyl chloride (CAS 338453-21-7; 1.00 g, 5.42 mmol) in water (1.25 mL) and THF (12.5 mL) and the reaction mixture was heated under microwave irradiation at 100° C. for 30 min. The crude product was purified by column chromatography (silica, 20-80% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, acetonitrile-d) δ ppm 1.67-1.85 (m, 2H) 1.93-2.04 (m, 2H) 3.30-3.43 (m, 2H) 3.44-3.58 (m, 1H) 3.77-4.09 (m, 2H) 4.21 (s, 2H)
MS ES+: 190
To a stirred and nitrogen degassed solution of 4,6-dichloropyrimidin-5-amine (CAS 5413-85-4; 1.20 g, 7.32 mmol), 2-(4-methoxybenzenesulfonyl)acetonitrile (CAS 132276-87-0, 2.00 g, 9.51 mmol), tetrakis(triphenylphosphane) palladium (338 mg, 293 μmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (207 mg, 293 μmol) in anhydrous dioxane (75 mL) was added sodiobis(trimethylsilyl)amine [1 M in THF] (16.83 mL, 16.83 mmol) slowly over 1 h. The mixture was heated at 110° C. for 45 min. The reaction mixture was concentrated in vacuo, partitioned between MTBE and 0.2 M aq. NaOH solution. The organic phase was extracted with 0.2 M aq. NaOH solution. The combined aqueous phases were washed with MTBE and acidified with sat. citric acid solution. The organics were extracted with EtOAc/2-methyltetrahydrofuran (2:1), washed with water/brine (1:1), dried (H frit) and concentrated in vacuo to give the title compound which was used without further purification.
MS ES+: 339
To a stirred and nitrogen degassed solution of 4-chloro-7-(4-methoxybenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 19; 140 mg, 413 μmol), (cyclopent-1-en-1-yl)boronic acid (CAS 850036-28-1; 93 mg, 827 μmol) and caesium carbonate (404 mg, 1.24 mmol) in dioxane (4 mL) and water (1 mL) was added di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium (29 mg, 41 μmol) and the reaction mixture was heated under microwave irradiation at 100° C. for 2 h. The reaction mixture was concentrated in vacuo, partitioned between MTBE and 0.2 M aq. NaOH solution. The organic phase was extracted with 0.2 M aq. NaOH solution. The combined aqueous phases were washed with MTBE and acidified with sat, citric acid solution. The organics were extracted with EtOAc/2-methyltetrahydrofuran (2:1), washed with water/brine (1:1), dried (H frit) and concentrated in vacuo to afford the title compound which was used without further purification.
MS ES+: 371
Prepared as described for 4-chloro-7-(4-methoxybenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 19) from 2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 13; 567 mg, 2.85 mmol). The reaction mixture was heated at reflux for 18 h. The crude product was purified by column chromatography (basic silica, 30-70% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 327
Prepared as described for 2-(cyclohexanesulfonyl)acetonitrile (Intermediate 17) from oxolane-3-sulfonyl chloride (CAS 1207346-29-9; 1.00 g, 5.86 mmol) in water (1.25 mL) and THF (12.5 mL) and the reaction mixture was heated under microwave irradiation at 100° C. for 30 min. The crude product was purified by column chromatography (silica, 20-80% EtOAc/petroleum ether) to afford the title compound.
1H NMR (300 MHz, CDCl3) δ ppm 2.20-2.75 (m, 2H) 3.77-4.19 (m, 6H) 4.25-4.42 (m, 1H)
MS ES+: 176
To a stirred and nitrogen degassed solution of 4-chloro-7-(4-methoxybenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 19; 90 mg, 275 μmol), (cyclopent-1-en-1-yl)boronic acid (CAS 850036-28-1; 62 mg, 551 μmol) and caesium carbonate (269 mg, 826 μmol) in dioxane (4 mL) and water (1 mL) was added di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium (20 mg, 28 μmol) and the reaction mixture was heated under microwave irradiation at 110° C. for 2 h. The reaction mixture was concentrated in vacuo, partitioned between MTBE and 0.2 M aq. NaOH solution. The organic phase was extracted with 0.2 M aq. NaOH solution. The combined aqueous phases were washed with MTBE and acidified with sat. citric acid solution. The organics were extracted with EtOAc/2-methyltetrahydrofuran (2:1), washed with water/brine (1:1), dried (H frit) and concentrated in vacuo to afford the title compound which was used without further purification.
MS ES+: 359
To a stirred and nitrogen degassed solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-25-9; 7.64 g, 42.20 mmol) in anhydrous DME (100 mL) was added sodium hydride (3.83 g, 96 mmol, 60% dispersion in oil) at 0° C. The mixture was stirred at 0° C. for 5 min and then at rt for 15 min. This mixture was added to a previously nitrogen degassed solution of 3,5-dibromo-4-chloropyridine (CAS 13626-17-0; 10.40 g, 38.30 mmol), tetrakis(triphenylphosphane) palladium (1.11 g, 958 μmol) in anhydrous DME (100 mL). The reaction mixture was heated at reflux for 16 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (C18-silica, 0-80% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 7.37-7.58 (m, 3H) 7.67-7.83 (m, 3H) 8.13-8.29 (m, 1H) 8.31-8.44 (m, 1H)
MS ES+: 372
To a stirred solution of 2-(benzenesulfonyl)-2-(5-bromo-4-chloropyridin-3-yl)acetonitrile (Intermediate 24; 6.60 g, 17.76 mmol) in anhydrous NMP (50 mL) was added ethylbis(propan-2-yl)amine (9.31 mL, 53.30 mmol) and (4-methoxyphenyl)methanamine (CAS 2393-23-9; 3.65 g, 26.60 mmol). The mixture was heated at 140° C. for 20 h. The reaction mixture was partitioned between EtOAc and water. The biphasic solution was filtered to obtain some crude product. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo to obtain further crude product. This crude product was combined and purified by column chromatography (silica, 0-80% EtOAc/water and then 0-50% MeOH/DCM). This product was combined with the previously filtered product and triturated with hot EtOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 3.70 (s, 3H) 5.66 (s, 2H) 6.79-6.91 (m, 4H) 7.32 (s, 2H) 7.54-7.66 (m, 3H) 7.96-8.04 (m, 2H) 8.15 (s, 1H) 8.68 (s, 1H)
MS ES+: 472
Prepared as described for 4-chloro-2-(cyclohex-1-en-1-yl)pyridin-3-amine (Intermediate 6) from 3-(benzenesulfonyl)-7-bromo-1-[(4-methoxyphenyl)methyl]-1H-pyrrolo[3,2-c]pyridin-2-amine (Intermediate 25; 100 mg, 212 μmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (CAS 126726-62-3; 60 μL, 318 μmol) in dioxane (1 mL) and water (0.1 mL). The reaction mixture was heated under microwave irradiation at 130° C. for 1.5 h and the crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 434
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from oxan-4-ylmethanesulfonyl chloride (CAS 264608-29-9; 1.00 g, 5.03 mmol) in water (10 mL) and THF (1 mL) and the reaction mixture was heated under microwave irradiation at 100° C. for 1.5 h. The crude product was purified by column chromatography (silica, 20-50% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, CDCl3) δ ppm 1.39-1.69 (m, 1H) 1.79-1.97 (m, 2H) 2.26-2.58 (m, 2H) 3.14-3.31 (m, 2H) 3.39-3.59 (m, 2H) 3.87-4.08 (m, 4H)
MS ES+: 204
Prepared as described for 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3) from 4,6-dichloro-2-methylpyrimidin-5-amine (CAS 39906-04-2; 5.00 g, 28.10 mmol) in anhydrous dioxane (114 mL). The reaction mixture was heated at reflux for 3 h. The crude product was purified by column chromatography (C18-silica, 5-50% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.52 (3H, s) 7.07 (2H, br. s) 7.44-7.73 (3H, m) 7.86-8.20 (2H, m) 11.78 (1H, br. s)
MS ES+: 323
To a stirred solution of 4,6-dichloropyrimidin-5-amine (CAS 5413-85-4; 10 g, 61 mmol) and triethylamine (17 mL, 122 mmol) in anhydrous THF (90 mL) was added 2-methylmorpholine (CAS 27550-90-9; 6.48 g, 64.00 mmol). The mixture was heated at reflux for 20 h. 2-methylmorpholine (CAS 27550-90-9; 1.54 g, 15.21 mmol) was then added and the mixture was heated at reflux for 24 h. The reaction mixture was filtered, poured into EtOAc and washed with 0.1 M aq. HC solution and water/brine (1:1), dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 10-30% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (d, J=6 Hz, 3H), 2.45-2.55 (m, 1H), 2.75-2.85 (m, 1H) 3.57-3.78 (m, 4H) 3.79-3.87 (m, 1H) 5.09 (s, 2H) 7.98 (s, 1H)
MS ES+: 229
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 2-methylbenzene-1-sulfonyl chloride (CAS 133-59-5; 210 mg, 1.10 mmol) to give the title compound which was used without further purification.
MS ES+: 196
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 3-methylbenzene-1-sulfonyl chloride (CAS 1899-93-0; 210 mg, 1.10 mmol) to give the title compound which was used without further purification.
MS ES+: 196
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from pyridine-3-sulfonyl chloride hydrochloride (CAS 42899-76-3; 235 mg, 1.10 mmol) to give the title compound which was used without further purification.
MS ES+: 183
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 3-chloro-4-methoxybenzene-1-sulfonyl chloride (CAS 22952-43-8; 300 mg, 1.24 mmol) with the exception the residue was triturated with diethyl ether to give the title compound which was used without further purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 4.02 (s, 3H) 5.26 (s, 2H) 7.42-7.52 (m, 1H) 7.89-7.97 (m, 1H) 7.97-8.03 (m, 1H)
MS ES+: 246
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 3-fluoro-4-methoxybenzene-1-sulfonyl chloride (CAS 67475-55-2; 280 mg, 1.24 mmol) with the exception the residue was triturated with diethyl ether to give the title compound which was used without further purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 3.99 (s, 3H) 5.23 (s, 2H) 7.46-7.56 (m, 1H) 7.76-7.90 (m, 2H)
MS ES+: 230
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from phenylmethanesulfonyl chloride (CAS 1939-99-7; 300 mg, 1.57 mmol) with the exception the residue was triturated with diethyl ether to give the title compound which was used without further purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 4.74 (s, 2H) 4.92 (s, 2H) 7.39-7.49 (m, 5H)
MS ES+: 196
To a stirred solution of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (CAS 375-95-74-7; 20.00 g, 56.00 mmol) and 4,4-difluorocyclohexan-1-one (CAS 22515-18-0; 5.00 g, 37.00 mmol) in anhydrous THF (125 mL) was added lithiobis(trimethylsilyl)amine [1 M in THF] (52 mL, 52 mmol) at −78° C. The mixture was stirred at rt for 16 h. The reaction mixture was partitioned between EtOAc and water and extracted with EtOAc. The combined organics phases were washed with brine, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% DCM/petroleum ether) to afford the title compound which was used without further purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.17-2.31 (m, 2H) 2.53-2.61 (m, 2H) 2.71-2.84 (m, 2H) 5.84-5.92 (m, 1H)
To a stirred solution of 4,4-difluorocyclohex-1-en-1-yl trifluoromethanesulfonate (Intermediate 36; 7.70 g, 28.90 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (CAS 73183-34-3; 8.81 g, 34.70 mmol), potassium acetate (7.67 g, 78.00 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (CAS 95464-05-4; 1.65 g, 2.03 mmol) in anhydrous dioxane (100 mL) was heated at 130° C. for 16 h. The reaction mixture was filtered (Celite) and partitioned between EtOAc and water. The organic phase was washed with brine, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-25% DCM/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 12H) 1.87-2.01 (m, 2H) 2.22-2.31 (m, 2H) 2.53-2.66 (m, 2H) 6.23-6.33 (m, 1H)
To a stirred solution of cyclopropanecarboximidamide hydrochloride (CAS 57297-29-7; 608 mg, 5.04 mmol) and ethyl 3-cyclohexyl-3-oxopropanoate (CAS 15971-92-3; 1.00 g, 5.04 mmol) in anhydrous MeOH (20 mL), was added sodium methanolate (3 mL, 16.16 mmol, 30% solution in MeOH) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo. The crude product was partitioned between EtOAc and to % aq. citric acid solution. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-5% MeOH/DCM) to afford the title compound.
MS ES+: 219
To sulfonylideneoxidane (CAS 7446-11-9; 2 mL, 49.20 mmol, 20% in c. H2SO4) was added nitric acid (CAS 7697-37-2; 2 mL, 44.8 mmol) at 0° C. 6-cyclohexyl-2-cyclopropylpyrimidin-4-ol (Intermediate 38; 462 mg, 2.12 mmol) was then added and the reaction was stirred at rt for 4 days. The reaction mixture was poured onto ice and extracted with DCM, and then with EtOAc. The organic phases were washed with brine, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-5% MeOH/DCM) to afford the title compound.
MS ES+: 264
To a nitrogen degassed flask containing 6-cyclohexyl-2-cyclopropyl-5-nitropyrimidin-4-ol (Intermediate 39; 212 mg, 805 μmol) was added phosphoroyl trichloride (2 mL, 21.46 mmol) and anhydrous DMF (20 μL, 258 μmol) and the reaction was stirred at rt for 20 h and then at 50° C. for 2 h. The reaction mixture was poured onto ice and extracted with DCM. The organic phase was washed with brine, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-5% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.15 (m, 2H) 1.15-1.37 (m, 5H) 1.51-1.82 (m, 7H) 2.25-2.34 (m, 1H) 2.58-2.68 (m, 1H).
MS ES+: 282
To a stirred and nitrogen degassed solution of 4-chloro-6-cyclohexyl-2-cyclopropyl-5-nitropyrimidine (Intermediate 40; 62 mg, 220 μmol) in acetic acid (2 mL) was added iron (CAS 7439-89-6; 196 mg, 3.51 mmol) and the reaction mixture heated at 70° C. for 1 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-30% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.77-0.82 (m, 2H) 0.83-0.90 (m, 2H) 1.12-1.29 (m, 1H) 1.32-1.51 (m, 4H) 1.61-1.82 (m, 5H) 1.91-2.02 (m, 1H) 2.81-2.97 (m, 1H) 5.23 (s, 2H)
MS ES+: 252
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 4-chloro-3-fluorobenzene-1-sulfonyl chloride (CAS 942035-77-0; 284 mg, 1.24 mmol) with the exception the residue was triturated with petroleum ether to give the title compound which was used without further purification.
1H NMR (300 MHz, DMSO-d6) δ ppm 5.36 (s, 2H) 7.79-7.92 (m, 1H) 7.96-8.09 (m, 2H)
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 2-fluoro-4-methylbenzene-1-sulfonyl chloride (CAS 518070-29-6; 250 mg, 1.20 mmol) with the exception the residue was triturated with petroleum ether to give the title compound which was used without further purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.46 (s, 3H) 5.28 (s, 2H) 7.33-7.39 (m, 1H) 7.44-7.51 (m, 1H) 7.76-7.87 (m, 1H)
MS ES+: 214
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 3,5-difluorobenzene-1-sulfonyl chloride (CAS 210532-25-5; 255 mg, 1.20 mmol) with the exception the residue was triturated with petroleum ether to give the title compound which was used without further purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 5.40 (s, 2H) 7.68-7.81 (m, 2H) 7.84-7.96 (m, 1H)
MS ES+: 216
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 2-methoxybenzene-1-sulfonyl chloride (CAS 10130-87-7; 248 mg, 1.2 mmol) to give the title compound which was used without further purification.
1H NMR (300 MHz, DMSO-d6) δ ppm 3.98 (s, 3H) 5.15 (s, 2H) 7.23 (t, J=8 Hz, 1H) 7.38 (d, J=8 Hz, 1H) 7.75-7.91 (m, 2H)
MS ES+: 212
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 2-phenylethane-1-sulfonyl chloride (CAS 4025-71-2; 246 mg, 1.2 mmol) to give the title compound which was used without further purification.
1H NMR (300 MHz, DMSO-d6) δ ppm 3.01-3.15 (m, 2H) 3.60-3.74 (m, 2H) 4.99 (s, 2H) 7.18-7.41 (m, 5H)
MS ES+: 210
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 3-methoxybenzene-1-sulfonyl chloride (CAS 10130-74-2; 248 mg, 1.2 mmol) to give the title compound which was used without further purification.
MS ES+: 212
To a stirred and nitrogen degassed solution of 4,6-dichloro-2-methylpyrimidin-5-amine (CAS 39906-04-2; 5 g, 28.1 mmol), 2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 13; 6.71 g, 33.70 mmol), di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (497 mg, 702 μmol) and tetrakis(triphenylphosphane) palladium (811 mg, 702 μmol) in anhydrous dioxane (115 mL) was added sodiobis(trimethylsilyl)amine [1 M in THF] (64.6 mL, 64.6 mmol). The reaction mixture was heated at reflux for 3 h. Further portions of di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (497 mg, 702 μmol) and tetrakis(triphenylphosphane) palladium (811 mg, 702 μmol) in anhydrous dioxane (115 mL) were added and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated in vacuo. The reaction mixture was diluted with water and extracted with DCM. The separated aqueous phase was neutralised with 0.5 M aq. HCl solution, extracted with EtOAc. The combined organic phases were concentrated in vacuo. The crude product was purified by column chromatography (C18-silica, 5-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (s, 3H) 7.06 (br. s, 2H) 7.27-7.48 (m, 2H) 7.59-7.73 (m, 1H) 7.94-8.15 (m, 1H) 11.83 (br. s, 1H)
MS ES+: 341
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 4-fluoro-2-methylbenzene-1-sulfonyl chloride (CAS 7079-48-3; 250 mg, 1.20 μmol) to give the title compound which was used without further purification.
MS ES+: 214
To a stirred and nitrogen degassed solution of 2-(3-fluorobenzenesulfonyl)acetonitrile (Intermediate 12; 7.00 g, 35.10 mmol) in anhydrous dioxane (75 mL) was added sodium hydride (3.09 g, 77 mmol, 60% dispersion in oil) at 0° C. The mixture was stirred at 0° C. for 5 min and then at rt for 5 min. This mixture was added to a previously nitrogen degassed solution of 4,6-dichloro-2-methylpyrimidin-5-amine (CAS 39906-04-2; 6.26 g, 35.10 mmol), tetrakis(triphenylphosphane) palladium (1.62 g, 1.40 mmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (995 mg, 1.41 mmol) in anhydrous DME (75 mL). The reaction mixture was heated at reflux for 5 h. The reaction mixture was poured into water and extracted with EtOAc. The biphasic mixture was filtered and then separated. The aqueous phase was extracted again with EtOAc. The combined organic phases were dried (MgSO4) and concentrated in vacuo. 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 2.53 (s, 3H) 7.09 (s, 2H) 7.45-7.52 (m, 1H) 7.60-7.70 (m, 1H) 7.85-7.93 (m, 2H) 11.67-11.95 (m, 1H)
MS ES+: 341
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 2,3-difluorobenzene-1-sulfonyl chloride (CAS 210532-24-4, 213 mg, 1.20 mmol) with the exception that the residue was triturated with petroleum ether to give the title compound which was used without further purification.
MS ES−: 216
A stirred mixture of 4,6-dichloro-2-methyl-5-nitropyrimidine (CAS 13162-43-1; 0.745 g, 3.58 mmol) and 2-methylmorpholine (CAS 27550-90-9; 0.380 g, 3.76 mmol), sodium carbonate (0.418 g, 3.94 mmol) and MeOH (10 mL) was allowed to stir at room temperature for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was separated, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-15% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 273
A stirred mixture of 4-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-methylmorpholine (Intermediate 77; 161 mg, 0.590 mmol) and 2-(2,3-difluorobenzenesulfonyl)acetonitrile (Intermediate 76; 141 mg, 0.649 mmol), sodium carbonate (125 mg, 1.180 mmol) and MeOH (2 mL) was allowed to stir at room temperature for 20 h. The reaction mixture was concentrated in vacuo and the resulting residue partitioned between water and EtOAc. The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to give the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (d, J=6 Hz, 3H) 2.08 (br. s., 3H) 2.69-2.84 (m, 1H) 3.00-3.14 (m, 1H) 3.23-3.90 (m, 6H) 7.30-7.38 (m, 1H) 7.55-7.67 (m, 1H) 7.67-7.75 (m, 1H)
MS ES+: 454
To a stirred and nitrogen degassed solution of 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 250 mg, 775 μmol), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 37; 378 mg, 1.55 mmol) and tripotassium phosphate (493 mg, 2.32 mmol) in dioxane (4 mL) and water (1 mL) was added di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (27 mg, 39 μmol) and the reaction mixture was heated under microwave irradiation at 140° C. for 1.5 h. The reaction mixture was partitioned between water and EtOAc. The aqueous phase was neutralised with 2 M aq. HC solution and extracted with EtOAc. The combined organic phases were washed with brine, dried (H frit) and concentrated in vacuo. 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 1.99 (s, 3H) 2.10-2.24 (m, 2H) 2.70-2.97 (m, 4H) 6.25 (br. s., 1H) 6.77 (s, 2H) 7.51-7.62 (m, 3H) 8.03-8.09 (m, 2H) 10.87 (s, 1H)
MS ES+: 405
To a stirred and nitrogen degassed solution of 4,6-dichloro-2-methylpyrimidin-5-amine (CAS 39906-04-2; 4.5 g, 25.3 mmol), 2-(4-methoxybenzenesulfonyl)acetonitrile (CAS 132276-87-0; 8.01 g, 37.9 mmol), tetrakis(triphenylphosphane) palladium (730 mg, 632 μmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (447 mg, 632 μmol) in anhydrous dioxane (100 mL) was added sodiobis(trimethylsilyl)amine [1 M in THF] (50.6 mL, 50.6 mmol). The mixture was heated at 110° C. for 3 h. Further portions of tetrakis(triphenylphosphane) palladium (730 mg, 632 μmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (447 mg, 632 μmol) were added and the reaction mixture was heated at 110° C. for 3 h. The reaction mixture was concentrated in vacuo, partitioned between EtOAc and 0.2 M aq. NaOH solution. The organic phase was extracted with 0.2 M aq. NaOH solution. The aqueous phase was acidified with 2 M aq. HCl solution. The organic phase was extracted with EtOAc, washed with water/brine (1:1), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% MeOH/DCM). Further purification by column chromatography (C18-silica, 5-55% acetonitrile/water (with 0.1% formic acid)) afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 3.32 (br. s., 3H) 3.80 (s, 3H) 7.00 (s, 2H) 7.04-7.14 (m, 2H) 7.92-8.02 (m, 2H) 11.52-12.00 (m, 1H)
MS ES+: 353
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from benzyl 4-(chlorosulfonyl)piperidine-1-carboxylate (CAS 287953-54-2; 501 mg, 1.58 mmol). 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 1.49-1.64 (m, 2H) 2.04-2.16 (m, 2H) 2.93 (br. s., 2H) 3.60-3.71 (m, 1H) 4.09-4.19 (m, 2H) 5.01 (s, 2H) 5.10 (s, 2H) 7.28-7.44 (m, 5H)
MS ES+: 323
To a stirred and nitrogen degassed solution of 4-chloro-7-(3-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 52; 200 mg, 587 μmol), (cyclopent-1-en-1-yl)boronic acid (CAS 850036-28-1; 131 mg, 1.17 mmol) and tripotassium phosphate (374 mg, 1.76 mmol) in dioxane (3 mL) and water (0.6 mL) was added di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium (21 mg, 29 μmol) and the reaction mixture was heated under microwave irradiation at 120° C. for 1.5 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.86-2.03 (m, 2H) 2.53 (s, 3H) 2.55-2.65 (m, 2H) 2.73-2.86 (m, 2H) 6.59 (br. s., 1H) 6.81 (s, 2H) 7.36-7.51 (m, 1H) 7.55-7.66 (m, 1H) 7.82-7.96 (m, 2H) 10.75 (br. s., 1H)
MS ES+: 373
To a stirred solution of 4,4-difluoropiperidine hydrochloride (CAS 144260-52-4; 990 mg, 6.32 mmol) and ethylbis(propan-2-yl)amine (2.22 g, 17.24 mmol) in acetonitrile (9 mL) was added 4-chloro-3-nitro-1,2-dihydropyridin-2-one (CAS 165547-79-5; 1.00 g, 5.75 mmol) in acetonitrile (1 mL) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was filtered and the resulting solid washed with acetonitrile to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.02-2.12 (m, 4H) 3.29-3.32 (m, 4H) 6.19-6.21 (d, J=8 Hz, 1H) 7.38-7.40 (d, J=8 Hz, 1H) 11.63 (s, 1H)
MS ES+: 260
To a stirred solution of 4-(4,4-difluoropiperidin-1-yl)-3-nitro-1,2-dihydropyridin-2-one (Intermediate 60; 500 mg, 1.93 mmol) in acetonitrile (5 mL) was added phosphoroyl trichloride (1.47 g, 9.65 mmol) and tetraethylazanium bromide (318 mg, 1.93 mmol) and the reaction mixture was heated at 85° C. for 16 h. The reaction mixture was poured into water, basified with NaHCO3 and extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.03-2.13 (m, 4H) 3.34-3.37 (m, 4H) 7.33 (d, J=8 Hz, 1H) 8.24 (d, J=8 Hz, 1H)
MS ES+: 278
A mixture of 2-chloro-4-(4,4-difluoropiperidin-1-yl)-3-nitropyridine (Intermediate 61; 520 mg, 1.88 mmol) and dioxoplatinum (200 mg, 880 μmol) in anhydrous MeOH (20 mL) was placed under an atmosphere of hydrogen and stirred at rt for 4 h under 50 psi pressure. The reaction mixture was filtered (Celite) and concentrated in vacuo to give the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.06-2.24 (m, 4H) 2.98-3.01 (m, 4H) 5.04 (br. s., 2H) 6.95 (d, J=8 Hz, 1H) 7.59 (d, J=8 Hz, 1H)
MS ES+: 248
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from benzyl 4-fluoro-2-methoxybenzene-1-sulfonyl chloride (CAS 1214377-19-1; 8.8 g, 39.20 mmol) in water (50 mL) and propan-2-ol (50 mL). The crude product was purified by column chromatography (silica, 0-30% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 3.99 (s, 3H) 5.15 (s, 2H) 7.02-7.12 (m, 1H) 7.30-7.39 (m, 1H) 7.88-7.96 (m, 1H)
MS ES+: 230
To a stirred solution of sat. ammonia methanol (40 mL) was added 3,4,5-trichloropyridazine (CAS 1780-27-4; 3.00 g, 6.32 mmol) at −10° C. The reaction mixture was heated at 125° C. for 5 h. The reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-30% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 7.16 (s, 2H) 8.76 (s, 1H)
MS ES+: 164
To a stirred mixture of 3,5-dichloropyridazine-4-amine (200 mg, 1.22 mmol) and cyclohex-1-en-1-yl-boronic acid pinacole ester (250 mg, 1.22 mmol) in dioxane:water (8 mL, 5:1) under an atmosphere of nitrogen was added K3PO4 (0.65 g, 3.06 mmol). The reaction mixture was degassed with nitrogen for 10 min. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (CAS 95464-05-4; 0.044 g, 0.061 mmol) was added and the reaction mixture was heated at 100° C. for 4 h. After completion, reaction mixture was poured into water and extracted with EtOAc. Combined organic layer was washed with brine, dried over sodium sulphate and concentrated in vacuo. The crude compound was purified by column chromatography (silica, 0-30% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.76 (m, 4H) 2.17-2.20 (m, 2H) 2.28-2.30 (m, 2H) 5.96-5.98 (m, 1H) 6.32 (br. s, 2H) 8.60 (s, 1H)
MS ES+: 210
Prepared as described for 2-(2,3-difluorobenzenesulfonyl)acetonitrile (Intermediate 53) from 2,5-difluorobenzene-1-sulfonyl chloride (CAS 26120-86-5; 213 mg, 1.00 mmol).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.73 (m, 4H), 2.13-2.14 (m, 4H), 4.72 (s, 2H), 5.66 (d, J=2 Hz, 1H), 6.49 (t, J=8 Hz, 1H), 6.85-6.87 (m, 1H), 7.25-7.27 (m, 1H)
MS ES+: 252
A suspension of 4-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-methylmorpholine (Intermediate 54; 156 mg, 0.573 mmol), 2-(2,5-difluorobenzenesulfonyl)acetonitrile (Intermediate 66; 137 mg, 0.631 mmol) and SODIUM CARBONATE (122 mg, 1.147 mmol) in MeOH (2.00 mL) was stirred at RT for 20 h. Dichloromethane (2.00 mL) was added and the reaction mixture was stirred at RT for 24 h. The reaction mixture was concentrated in vacuo and resulting residue partitioned between EtOAc and water. The layers were separated and the aqueous was extracted with EtOAc. The combined organics were dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petroleum ether to afford the title compound.
MS ES+: 454
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 2-fluoro-4-methoxybenzene-1-sulfonyl chloride (CAS 1016516-68-9; 8.80 g, 39.20 mmol) in water (50 mL) and propan-2-ol (50 mL). The crude product was purified by column chromatography (silica, 0-30% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 3.92 (s, 3H) 5.23 (s, 2H) 7.05-7.11 (m, 1H) 7.20-7.27 (m, 1H) 7.83 (t, J=9 Hz, 1H).
MS ES+: 230
To a stirred and nitrogen degassed solution of 4,6-dichloro-2-methylpyrimidin-5-amine (CAS 39906-04-2; 800 mg, 25.3 mmol), 2-(2-fluoro-4-methoxybenzenesulfonyl)acetonitrile (Intermediate 68; 1.30 g, 5.67 mmol), tetrakis(triphenylphosphane) palladium (80 mg, 112 μmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (140 mg, 121 μmol) in anhydrous dioxane (18 mL) was added sodiobis(trimethylsilyl)amine [1 M in THF] (10.00 mL, 10.00 mmol). The mixture was heated under microwave irradiation at 120° C. for 3 h. The reaction mixture was partitioned between MTBE/diethyl ether (2:1) and 0.2 M aq. NaOH solution. The organic phase was extracted with 0.2 M aq. NaOH solution. The aqueous phase was washed with diethyl ether then acidified with sat. aq. citric acid solution. The organic phase was extracted with EtOAc/THF (2:1), dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 30-70% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 371
To a stirred solution of 3,4,5-trichloropyridazine (CAS 14161-11-6; 2.00 g, 10.9 mmol) and triethylamine (1.10 g, 10.9 mmol) in anhydrous THF (30 mL) was added (4-methoxyphenyl)methanamine (CAS 2393-23-9; 1.50 g, 10.9 mmol). The reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was concentrated in vacuo and resulting residue dissolved in DCM, washed with sat. aq. NaHCO3 and concentrated in vacuo. 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 3.72 (s, 3H) 4.76-4.84 (m, 2H) 6.83-6.94 (m, 2H) 7.16-7.24 (m, 2H) 7.27-7.33 (m, 1H) 8.69 (s, 1H)
MS ES+: 284
To a stirred solution of 3,5-dichloro-N-(4-methoxybenzyl)pyridazin-4-amine (650 mg, 2.288 mmol) in DMSO (8 mL) was added ethylbis(propan-2-yl)amine (0.799 mL, 4.58 mmol) and 2,2-dimethylmorpholine (CAS 147688-58-2; 790 mg, 6.86 mmol). The reaction mixture was heated under microwave irradiation at 180° C. for 2 h. The reaction mixture was poured into water and extracted with EtOAc. The combined organics were dried (MgSO4) and concentrated in vacuo. 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 1.20-1.28 (m, 6H) 2.85-3.03 (m, 4H) 3.70 (s, 3H) 3.80-3.90 (m, 2H) 4.63-4.77 (m, 2H) 6.12-6.21 (m, 1H) 6.79-6.89 (m, 2H) 7.12-7.23 (m, 2H) 8.52 (s, 1H)
MS ES+: 363
To a stirred and nitrogen degassed suspension of 5-chloro-3-(2,2-dimethylmorpholino)-N-(4-methoxybenzyl)pyridazin-4-amine (Intermediate 71; 375 mg, 1.033 mmol), tetrakis(triphenylphosphane) palladium (29.9 mg, 0.026 mmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium (18.29 mg, 0.026 mmol) in anhydrous dioxane (5 mL) was added a solution of 2-((2-fluorophenyl)sulfonyl)acetonitrile (Intermediate 13; 309 mg, 1.550 mmol and sodium hydride (91 mg, 2.274 mmol, 60% dispersion in oil) in anhydrous dioxane (5 mL). The reaction mixture was heated at 100° C. for 4 h in a sealed tube. A second portion of tetrakis(triphenylphosphane) palladium (29.9 mg, 0.026 mmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium (18.29 mg, 0.026 mmol) was added and the reaction mixture was heated under microwave irradiation at 140° C. for 1.5 h. A further portion of tetrakis(triphenylphosphane) palladium (29.9 mg, 0.026 mmol), di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium (18.29 mg, 0.026 mmol) and a solution of 2-((2-fluorophenyl)sulfonyl)acetonitrile (Intermediate 13; 309 mg, 1.550 mmol and sodium hydride (91 mg, 2.274 mmol, 60% dispersion in oil) in anhydrous dioxane (5 mL) was added and the reaction mixture was heated under microwave irradiation at 140° C. for 1.5 h. The reaction mixture was partitioned between EtOAc and water and extracted further with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) to afford the title compound.
MS ES+: 526
To a stirred solution of disodium sulfite (528 mg, 4.19 mmol) and sodium hydrogen carbonate (352 mg, 4.19 mmol) in water (5 mL) and THF (0.833 mL) was added 4-chloro-2-fluorobenzene-1-sulfonyl chloride (CAS 141337-26-0; 600 mg, 2.62 mmol) at 0° C. The reaction mixture was stirred at rt for 16 h. 2-chloroacetonitrile (CAS 107-14-2; 0.499 mL, 7.86 mmol) was added and the reaction mixture was heated under microwave irradiation at 100° C. for 4 h. The reaction mixture was poured in water and extracted with DCM concentrated in vacuo. The resulting residue was triturated with petroleum ether and the resulting solid was filtered and dried to give the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 5.37 (s, 2H) 7.67 (m, 1H) 7.88-8.01 (m, 2H)
MS ES−: 232
To a solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (CAS 13162-43-1; 1.00 g, 4.81 mmol) and triethylamine (1.34 mL, 9.62 mmol) in DCM (20 mL) was added (S)-2-methylmorpholine (CAS 74572-13-7; 0.486 g, 4.81 mmol) and the reaction mixture allowed to stir at room temperature for 16 h. The reaction mixture was diluted with water allowed to stir for 20 minutes. The organic phase was separated and concentrated in vacuo. 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 1.10 (d, J=1 Hz, 3H) 2.46 (s, 3H) 2.82-2.92 (m, 1H) 3.10-3.22 (m, 1H) 3.46-3.53 (m, 1H) 3.53-3.60 (m, 1H) 3.66-3.76 (m, 1H) 3.85-3.93 (m, 2H)
MS ES+: 273
To a stirred solution of (S)-4-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-methylmorpholine (Intermediate 74; 350 mg, 1.284 mmol) in THF (4 mL) at 0° C. was added sodium hydride (103 mg, 2.57 mmol, 60% dispersion in oil). After 15 minutes 2-((4-chloro-2-fluorophenyl)sulfonyl)acetonitrile (Intermediate 73; 300 mg, 1.284 mmol) in THF (3 mL) was added dropwise and the reaction mixture was allowed to warm to rt and stirred for 5 hours. The reaction mixture was poured into water and extracted with EtOAc. The organics were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) followed by triturated with petroleum ether and the resulting solid was filtered and dried to give the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.12 (m, 3H) 2.25 (br. s., 3H) 2.89-2.99 (m, 1H) 3.19-3.29 (m, 1H) 3.49-3.61 (m, 2H) 3.66-3.76 (m, 1H) 3.85-3.92 (m, 2H) 7.44-7.53 (m, 1H) 7.57-7.68 (m, 1H) 7.85-7.93 (m, 1H)
MS ES+: 470
To a stirred and nitrogen degassed suspension of 4,6-dichloro-2-(methylsulfanyl)pyrimidin-5-amine (CAS 333388-03-7; 240 mg, 1.142 mmol), tetrakis(triphenylphosphane) palladium (33.0 mg, 0.029 mmol), di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium (20.22 mg, 0.029 mmol) and 2-(phenylsulfonyl)acetonitrile (228 mg, 1.257 mmol) in anhydrous dioxane (5 mL) was added a solution of sodiobis(trimethylsilyl)amine (2M solution in THF) (1.714 mL, 3.43 mmol). The reaction mixture was heated at reflux temperature for 5 h. The mixture was allowed to cool and quenched with sat. ammonium chloride solution (2 mL). The mixture was partitioned between 1:1 water/sat. aq. sodium bicarbonate and EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) to afford the title compound.
MS ES+: 355
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 4-bromo-2-fluorobenzene-1-sulfonyl chloride (CAS 216159-03-4; 328 mg, 1.2 mmol) with the exception that the reaction mixture was filtered washing with diethyl ether to afford the title compound which was used without further purification.
MS ES−: 276
Prepared as described for 2-(2,3-difluorobenzenesulfonyl)-2-[2-methyl-6-(2-methylmorpholin-4-yl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 55) from 4,6-dichloro-2-methyl-5-nitropyrimidine (CAS 13162-43-1174 mg, 0.839 mmol) and 2-(4-bromo-2-fluorobenzenesulfonyl)acetonitrile (Intermediate 80; 212 mg, 0.762 mmol). The crude product was purified by column chromatography (silica, 20-80% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 449/451
To a stirred mixture of 2-(4-bromo-2-fluorobenzenesulfonyl)-2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)acetonitrile (Intermediate 78; 0.39 g, 0.867 mmol) and AcOH (6 mL) was added iron (0.145 g, 2.60 mmol) and the reaction mixture was stirred at rt for 20 h. A second portion of iron (0.048 g, 0.867 mmol) was added and the reaction stirred at 50° C. for 1 h, and then stirred at rt for 20 h. The reaction mixture was filtered through Celite washing with EtOAc and concentrated in vacuo. The crude product was purified by column chromatography (silica, 20-70% EtOAc/petroleum ether) to afford the title compound.
MS ES+: 419
To a stirred suspension 3-hydroxyoxolan-2-one (CAS; 1.94 g, 19.0 mmol) and imidazole (2.98 g, 43.7 mmol) in DCM (30 mL) under nitrogen at 0° C. was added tert-butyl(chloro)diphenylsilane (5.86 mL, 22.80 mmol). The reaction was stirred at room temperature for 2 hours. The mixture was partitioned between DCM and water. The organics were dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% ethyl acetate/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (s, 9H) 2.10-2.31 (m, 2H) 3.99-4.11 (m, 1H) 4.22-4.30 (m, 1H) 4.55-4.62 (m, 1H) 7.40-7.50 (m, 6H) 7.63-7.70 (m, 2H) 7.70-7.77 (m, 2H)
To a stirred suspension of 3-[(tert-butyldiphenylsilyl)oxy]oxolan-2-one (Intermediate 80; 2.35 g, 6.90 mmol) in THF (45 mL) under nitrogen at −78° C. was added methylmagnesium bromide [3M in ether] (13.80 mL, 41.4 mmol). The reaction was stirred at −78° C. for 15 minutes, and then stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organics were washed with saturated brine, dried (MgSO4) and concentrated in vacuo to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 0.98 (s, 9H) 1.05-1.13 (m, 6H) 1.42-1.59 (m, 1H) 1.73-1.90 (m, 1H) 2.97-3.10 (m, 1H) 3.11-3.25 (m, 1H) 3.45 (t, J=5 Hz, 1H) 4.23 (t, J=5 Hz, 1H) 4.35 (s, 1H) 7.37-7.49 (m, 6H) 7.59-7.71 (m, 4H)
MS ES−: 371
4-methylbenzene-1-sulfonyl chloride (1.315 g, 6.90 mmol) was added portionwise to a solution of 3-((tert-butyldiphenylsilyl)oxy)-4-methylpentane-1,4-diol (Intermediate 81; 2.57 g, 6.90 mmol) in pyridine (25 mL) under nitrogen at 0° C. The reaction was stirred at room temperature for 2 hours then at reflux temperature for 6 hours. The reaction was poured into water and extracted with DCM. The combined organics were washed with water, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-10% ethyl acetate/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (s, 3H) 1.03 (s, 9H) 1.13 (s, 3H) 1.63-1.77 (m, 1H) 1.82-1.96 (m, 1H) 3.49-3.58 (m, 1H) 3.68-3.78 (m, 1H) 3.91-3.99 (m, 1H) 7.38-7.51 (m, 6H) 7.61 (d, J=7 Hz, 4H)
To a solution of tert-butyl((2,2-dimethyltetrahydrofuran-3-yl)oxy)diphenylsilane (Intermediate 82; 2.16 g, 6.09 mmol) in THF (20 mL) under nitrogen was added TBAF [1M in THF] (12.18 mL, 12.18 mmol). The reaction was stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and sat. aq. NaHCO3 solution. The phases were separated and the aqueous extracted with ethyl acetate. The combined organics were dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-50% ethyl acetate/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 6H) 1.67-1.76 (m, 1H) 2.07-2.18 (m, 1H) 3.59-3.66 (m, 1H) 3.69-3.77 (m, 2H) 4.78 (d, J=5 Hz, 1H)
To a stirred solution of 2-(phenylsulfonyl)acetonitrile (8.71 g, 48.1 mmol) in anhydrous THF (300 mL) at 0° C. was added and sodium hydride (3.85 g, 96 mmol, 60% dispersion in oil). The reaction was stirred at 0° C. for 30 min followed by addition of 4,6-dichloro-2-methyl-5-nitropyrimidine (CAS 13162-43-1; 10 g, 48.1 mmol) and the reaction mixture was stirred at 0° C. for 1 h. The reaction was quenched with sat. aq. NH4Cl solution and extracted with EtOAc. The combined organics were washed with brine, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% methanol/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H) 7.46-7.59 (m, 3H) 7.86-7.96 (m, 2H)
MS ES+: 353
Sodium hydride (39 mg, 0.971 mmol, 60% dispersion in oil) was added to a solution of 3,3-difluorocyclobutanol (0.1 g, 0.925 mmol) in THF (3 mL) under nitrogen. The reaction was stirred at room temperature for 20 minutes. 2-(benzenesulfonyl)-2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)acetonitrile (Intermediate 84; 0.326 g, 0.925 mmol) was added and the reaction stirred at room temperature for 16 h. A further portion of sodium hydride (39 mg, 0.971 mmol, 60% dispersion in oil) was added and the reaction stirred at room temperature for 1 hour. The mixture was quenched with sat. aq. NH4Cl solution and extracted with ethyl acetate. The combined organics were washed with saturated brine, dried (H-frit) and concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H) 2.55-2.71 (m, 2H) 2.95-3.13 (m, 2H) 4.97-5.17 (m, 1H) 7.40-7.56 (m, 3H) 7.84-7.96 (m, 2H)
MS ES+: 425
Prepared as described for 2-(benzenesulfonyl)-2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)acetonitrile (Intermediate 84) from 4,6-dichloro-2-methyl-5-nitropyrimidine (CAS 13162-43-1; 0.5 g, 2.404 mmol) and 2-((2-fluorophenyl)sulfonyl)acetonitrile (0.479 g, 2.404 mmol) The crude product was purified by column chromatography (silica, 0-10% methanol/DCM) to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 2.12 (s, 3H) 7.21-7.40 (m, 2H) 7.51-7.64 (m, 1H) 7.93-8.03 (m, 1H)
MS ES+: 371
Prepared as described for 2-(benzenesulfonyl)-2-[6-(3,3-difluorocyclobutoxy)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 85) from cyclobutanol (CAS 2919-23-5; 0.210 mL, 2.70 mmol) and 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 86; 1 g, 2.70 mmol). The crude product was used without further purification.
MS ES+: 407
To a stirred solution of 2-chloroacetonitrile (0.522 g, 6.91 mmol) and 2-chlorobenzenethiol (CAS 18527-20-3; 1 g, 6.91 mmol) in acetone (30 mL) was added sodium bicarbonate (1.046 g, 12.45 mmol) and the reaction stirred at room temperature for 4 days. The reaction mixture was concentrated in vacuo and the residue partitioned between waster and DCM. The organic layer was separated and the aqueous layer extracted with DCM and the combined organics concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-50% ethyl acetate/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 4.36 (s, 2H) 7.28-7.36 (m, 1H) 7.40-7.51 (m, 1H) 7.53-7.60 (m, 2H)
MS ES−: 182
To a stirred solution of 2-[(2-chlorophenyl)sulfanyl]acetonitrile (Intermediate 88; 500 mg, 2.72 mmol) in DCM (10 mL) at 0° C. was added mCPBA (940 mg, 5.44 mmol) portionwise. The reaction was allowed to stir at room temperature for 16 h. A second portion of mCPBA (940 mg, 5.44 mmol) was added and the reaction was allowed to stir for a further 3 hours. A third portion of mCPBA (940 mg, 5.44 mmol) was added and the reaction was allowed to stir at room temperature for 16 h. The reaction was poured into sat. aq. NaHCO3 solution and extracted with DCM. The organics were concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-50% ethyl acetate/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 5.37 (s, 2H) 7.68-7.78 (m, 1H) 7.81-7.93 (m, 2H) 8.08-8.18 (m, 1H)
MS ES−: 214
Prepared as described for 2-(4-chloro-2-fluorobenzenesulfonyl)-2-{2-methyl-6-[(2S)-2-methylmorpholin-4-yl]-5-nitropyrimidin-4-yl}acetonitrile (Intermediate 75) from (2S)-4-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-methylmorpholine (Intermediate 74; 474 mg, 1.739 mmol) and 2-(2-chlorobenzenesulfonyl)acetonitrile (Intermediate 89; 375 mg, 1.739 mmol). The reaction mixture poured into water and extracted with ethyl acetate. The aqueous phase was basified to pH 14 with 2M NaOH and then re-extracted with ethyl acetate. The organics were dried (MgSO4) and concentrated. The crude product was purified by column chromatography (silica, 0-100% methanol/DCM to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.07 (m, 3H) 1.90 (s, 3H) 2.62-2.73 (m, 1H) 2.92-3.05 (m, 1H) 3.40-3.58 (m, 3H) 3.63-3.71 (m, 1H) 3.75-3.82 (m, 1H) 7.41-7.51 (m, 3H) 8.11-8.18 (m, 1H)
MS ES+: 452/454
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 2,4-difluorobenzene-1-sulfonyl chloride (CAS 1153970-85-4; 213 mg, 1.20 mmol). The crude product was purified by column chromatography (silica, 0-35% ethyl acetate/petroleum ether) to afford the title compound.
MS ES−: 217
Prepared as described for 2-(2,3-difluorobenzenesulfonyl)-2-[2-methyl-6-(2-methylmorpholin-4-yl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 55) from 2-(2,4-difluorobenzenesulfonyl)acetonitrile (Intermediate 91; 141 mg, 0.649 mmol) and 4-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-methylmorpholine (Intermediate 54; 161 mg, 0.590 mmol). The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petroleum ether) to afford the title compound.
MS ES+: 454
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 2,6-difluorobenzene-1-sulfonyl chloride (CAS 1326942-29-3; 213 mg, 1.20 mmol). The crude product was purified by column chromatography (silica, 0-35% ethyl acetate/petroleum ether) to afford the title compound.
MS ES−: 216
Prepared as described for 2-(2,3-difluorobenzenesulfonyl)-2-[2-methyl-6-(2-methylmorpholin-4-yl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 55) from 2-(2,6-difluorobenzenesulfonyl)acetonitrile (Intermediate 93; 42 mg, 0.193 mmol) and 4-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-methylmorpholine (Intermediate 54; 52.7 mg, 0.193 mmol). The crude product was purified by column chromatography (silica, 0-80% ethyl acetate/petroleum ether) to afford the title compound.
MS ES+: 454
A mixture of 4,6-dichloro-2-(methylsulfanyl)-5-nitropyrimidine (CAS 1979-96-0; 111 mg, 0.462 mmol), 2-(3-fluorobenzenesulfonyl)acetonitrile (Intermediate 12; 92 mg, 0.462 mmol) and sodium hydride (37.0 mg, 0.925 mmol, 60% dispersion in oil) in anhydrous THF (5 mL) under an atmosphere of nitrogen was stirred at room temperature for 1 h. 2-methylmorpholine (CAS 27550-90-9; 154 mg, 1.523 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with sat. aq. NaHCO3 solution and extracted with DCM. The organic layer was dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 100% ethyl acetate) to afford the title compound.
MS ES−: 466
Prepared as described for 2-(3-fluorobenzenesulfonyl)-2-[6-(2-methylmorpholin-4-yl)-2-(methylsulfanyl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 95) from 4,6-dichloro-5-nitro-2-(trifluoromethyl)pyrimidine (CAS 715-46-8; 103 mg, 0.393 mmol), 2-(3-fluorobenzenesulfonyl)acetonitrile (Intermediate 12; 78 mg, 0.393 mmol) and 2-methylmorpholine (CAS 27550-90-9; 112 mg, 1.107 mmol). The crude product was used without further purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6 Hz, 3H) 2.76-2.85 (m, 1H) 3.04-3.15 (m, 1H) 3.44-3.57 (m, 2H) 3.62 (d, J=15 Hz, 1H) 3.70 (d, J=13 Hz, 1H) 3.79-3.86 (m, 1H) 7.35-7.41 (m, 1H) 7.50-7.57 (m, 1H) 7.63-7.70 (m, 2H)
MS ES+: 490
Prepared as described for 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8) from 2-fluoro-5-methoxybenzene-1-sulfonyl chloride (CAS 1214334-01-6; 250 mg, 1.11 mmol). The crude product was purified by column chromatography (silica, 0-50% ethyl acetate/petroleum ether) to afford the title compound.
MS ES−: 228
Prepared as described for 2-(4-chloro-2-fluorobenzenesulfonyl)-2-{2-methyl-6-[(2S)-2-methylmorpholin-4-yl]-5-nitropyrimidin-4-yl}acetonitrile (Intermediate 75) from 2-(2-fluoro-5-methoxybenzenesulfonyl)acetonitrile (Intermediate 97; 173 mg, 0.755 mmol) and 4-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-methylmorpholine (Intermediate 54; 187 mg, 0.686 mmol). The crude product was purified by column chromatography (silica, 20-75% ethyl acetate/petroleum ether) to afford the title compound.
MS ES+: 466
A mixture of 4 4,6-dichloro-5-nitro-2-(trifluoromethyl)pyrimidine (CAS 715-46-8; 132 mg, 0.502 mmol), 2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 13; 100 mg, 0.502 mmol) and potassium carbonate (208 mg, 1.506 mmol) in THF (5 mL) was stirred at room temperature for 16 h. 2-methylmorpholine (CAS 27550-90-9; 67 mg, 0.662 mmol) was added and the reaction was stirred 16 h. The reaction mixture was partitioned between water and ethyl acetate and separated. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-15% methanol/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6 Hz, 3H) 2.76-2.83 (m, 1H) 3.04-3.13 (m, 1H) 3.44-3.58 (m, 2H) 3.62 (d, J=13 Hz, 1H) 3.70 (d, J=13 Hz, 1H) 3.82 (d, J=12 Hz, 1H) 7.22-7.30 (m, 2H) 7.51-7.58 (m, 1H) 7.89 (t, J=7 Hz, 1H)
MS ES+: 490
To a stir mixture of 4,6-dichloro-2-(methylsulfanyl)-5-nitropyrimidine (CAS 1979-96-0; 1.4 g, 5.83 mmol) and 2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 13; 1.162 g, 5.83 mmol) in THF (20 mL) under an atmosphere of nitrogen was added potassium carbonate (2.418 g, 17.50 mmol) and the reaction was stirred at room temperature for 72 h. The mixture was concentrated in vacuo, partitioned between water and ethyl acetate and separated. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-10% methanol/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.18 (s, 3H) 7.28-7.36 (m, 2H) 7.56-7.64 (m, 1H) 7.83-7.90 (m, 1H)
MS ES+: 403
To a stirred mixture of 2-[6-chloro-2-(methylsulfanyl)-5-nitropyrimidin-4-yl]-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 100; 50 mg, 0.124 mmol) and 2-methylmorpholine (CAS 27550-90-9; 19 mg, 0.188 mmol) in THF (2 mL) under an atmosphere of nitrogen was added potassium carbonate (51.5 mg, 0.372 mmol). The reaction mixture was purified directly by column chromatography (silica, 0-15% methanol/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (d, J=6 Hz, 3H) 2.18 (s, 3H) 2.74-2.84 (m, 1H) 3.04-3.14 (m, 1H) 3.44-3.59 (m, 2H) 3.60-3.76 (m, 2H) 3.83 (d, J=11 Hz, 1H) 6.0 (br. s., 2H) 7.23-7.35 (m, 2H) 7.56 (br. s., 1H) 7.79-7.87 (m, 1H)
MS ES+: 468
To a stirred solution of 2-(2-fluorobenzenesulfonyl)-2-[6-(2-methylmorpholin-4-yl)-2-(methylsulfanyl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 101; 54 mg, 0.116 mmol) in THF (2 mL) under nitrogen was added dimethylamine (2M in THF) (1 mL, 2.00 mmol). The reaction mixture was stirred at room temperature for 36 h. A further portion of dimethylamine (2M in THF) (1 mL, 2.00 mmol) was added and the reaction mixture was heated under microwave irradiation at 100° C. for 2 h. The mixture was concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.008 (d, J=6 Hz, 3H) 2.71-2.98 (m, 7H) 3.00-3.09 (m, 1H) 3.44-3.63 (m, 3H) 3.72-3.85 (m, 3H) 7.20-7.30 (m, 2H) 7.48-7.55 (m, 1H) 7.86 (t, J=7 Hz, 1H)
MS ES+:465
A stirred solution of 2-(2-fluorobenzenesulfonyl)-2-[6-(2-methylmorpholin-4-yl)-2-(methylsulfanyl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 101; 54 mg, 0.116 mmol) in methanol (2 mL) under an atmosphere of nitrogen was added triethylamine (0.1 mL, 0.717 mmol) and the reaction mixture was heated under microwave irradiation at 120° C. for 12 hours. 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL, 1.327 mmol) was added and the mixture was heated under microwave irradiation at 140° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and 10% citric acid. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound.
MS ES+: 452
Prepared as described for 2-(benzenesulfonyl)-2-[6-(3,3-difluorocyclobutoxy)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 85) from 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 86; 1.5 g, 4.05 mmol) and propan-2-ol (CAS 67-63-0; 0.371 mL, 4.86 mmol). The crude product was purified by column chromatography on (silica, 0-100% ethyl acetate/petroleum ether) to afford the title compound.
MS ES+: 395
Prepared as described for 2-(benzenesulfonyl)-2-[6-(3,3-difluorocyclobutoxy)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 85) from 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 86; 2.40 g, 6.47 mmol) and 2,2-dimethyloxan-4-ol (CAS 24945-13-9; 1.01 g, 7.76 mmol). The crude material was taken up in 0.5 M aq. NaOH solution and extracted with ethyl acetate. The combined organics were dried (H-frit) and concentrated in vacuo to afford the title compound which was used without further purification.
MS ES+: 465
Prepared as described for 2-(benzenesulfonyl)-2-[6-(3,3-difluorocyclobutoxy)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 85) from 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 86; 230 mg, 0.620 mmol) and 1,1,1-trifluoropropan-2-ol (CAS 374-01-6; 92 mg, 0.806 mmol). The crude product was purified by column chromatography (silica, 0-60% (ethyl acetate+1% AcOH)/petroleum ether) to afford the title compound.
MS ES+: 449
To a stirred solution of 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 86; 2 g, 5.39 mmol) and triethylamine (2.256 mL, 16.18 mmol) in DCM (20 mL) was added a solution of (RS,SR)-2,3-dimethylmorpholine, HCl (CAS 475111-28-5; 0.818 g, 5.39 mmol) in DCM (6.67 mL). The reaction mixture was heated under microwave irradiation at 110° C. for 3 hours. The reaction mixture was concentrated in vacuo and the resulting residue partitioned between ethyl acetate and water. The organic layer was separated washed with water, brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography on (silica, 0-100% ethyl acetate/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.09 (m, 3H) 1.14-1.22 (m, 3H) 2.20-2.39 (m, 3H) 3.04-3.14 (m, 1H) 3.46-3.59 (m, 2H) 3.64-3.75 (m, 2H) 3.84-3.90 (m, 1H) 7.35-7.43 (m, 2H) 7.64-7.71 (m, 1H) 7.86-7.93 (m, 1H)
MS ES+: 450
Prepared as described for 2-{6-[(RS,SR)-2,3-dimethylmorpholin-4-yl]-2-methyl-5-nitropyrimidin-4-yl}-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 107) from 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 86; 2.2 g, 5.93 mmol) and (RR,SS)-2,3-dimethylmorpholine, HCl (CAS 316806-96-9; 0.990 g, 6.53 mmol). The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petroleum ether) followed by column chromatography (C18 silica, 5-95% methanol/water (0.1% formic acid)) to give the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (d, J=6 Hz, 3H) 1.12 (d, J=6 Hz, 3H) 2.05 (s, 3H) 2.80-2.92 (m, 1H) 3.01-3.12 (m, 1H) 3.36-3.51 (m, 3H) 3.69-3.80 (m, 1H) 7.20-7.26 (m, 1H) 7.27-7.35 (m, 1H) 7.49-7.57 (m, 1H) 7.90-8.00 (m, 1H)
MS ES+: 450
Prepared as described for 4-(4,4-difluoropiperidin-1-yl)-3-nitro-1,2-dihydropyridin-2-one (Intermediate 60) from 4-chloro-3-nitro-1,2-dihydropyridin-2-one (CAS 165547-79-5; 2.50 g, 14.3 mmol) and 2,2-dimethylmorpholine (CAS 147688-58-2; 1.82 g, 15.8 mmol). The precipitate was filtered to afford the title compound which was used without further purification.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.16 (s, 6H) 2.97-3.24 (m, 4H) 3.54-3.78 (m, 2H) 6.14 (d, J=7 Hz, 1H) 7.35 (d, J=7 Hz, 1H) 11.50 (br. s., 1H)
MS ES+: 254
Prepared as described for 2-chloro-4-(4,4-difluoropiperidin-1-yl)-3-nitropyridine (Intermediate 61) from 4-(2,2-dimethylmorpholin-4-yl)-3-nitro-1,2-dihydropyridin-2-one (Intermediate 109; 2.10 g, 8.29 mmol). The crude product was used without further purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (s, 1H) 3.03-3.21 (m, 1H) 3.59-3.80 (m, 1H) 7.25 (d, J=6 Hz, 1H) 8.22 (d, J=6 Hz, 1H)
MS ES+: 272
Prepared as described for 2-chloro-4-(4,4-difluoropiperidin-1-yl)pyridin-3-amine (Intermediate 62) from 4-(2-chloro-3-nitropyridin-4-yl)-2,2-dimethylmorpholine (Intermediate 110; 2.00 g, 7.36 mmol). The crude product was purified by column chromatography (silica, 0-50% ethyl acetate/petroleum ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 7H) 2.71 (s, 2H) 2.77-2.87 (m, 2H) 3.74-3.90 (m, 2H) 4.83 (s, 2H) 6.88 (d, J=5 Hz, 1H) 7.62 (d, J=5 Hz, 1H)
MS ES+: 242
To a stirred solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (CAS 13162-43-1; 10 g, 48.1 mmol) and triethylamine (7.37 mL, 52.9 mmol) in DCM (go mL) at 0° C. was added a solution of 2,2-dimethylmorpholine (CAS 147688-58-2; 5.54 g, 48.1 mmol) in DCM (30 mL). The reaction mixture was allowed to warm to rt and stirred for 2 h. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and washed with water, 10% aq. citric acid solution, sat. aq. NaHCO3 solution and brine. The organics were separated, dried (MgSO4) and concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (s, 6H) 2.46 (s, 3H) 3.27-3.34 (m, 2H) 3.51 (s, 2H) 3.68-3.72 (m, 2H)
MS ES+: 287
To a solution of 2-(2,4-difluorobenzenesulfonyl)acetonitrile (Intermediate 91; 2.1 g, 9.67 mmol) in THF (20 mL) at 0° C. and under an atmosphere of nitrogen was added sodium hydride (770 mg, 19.3 mmol, 60% dispersion in oil). The resulting suspension was allowed to stir at 0° C. for 20 minutes. A solution of 4-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2,2-dimethylmorpholine (Intermediate 112; 2.77 g, 9.67 mmol) in THF (10 mL) was then added dropwise. The resulting solution was allowed to warm to rt and stirred for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organics were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-10% methanol/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (s, 6H) 2.35 (br. s., 3H) 3.41-3.50 (m, 2H) 3.54-3.62 (m, 2H) 3.62-3.80 (m, 3H) 7.26-7.35 (m, 1H) 7.45-7.56 (m, 1H) 7.90-8.01 (m, 1H)
MS ES+: 468
Prepared as described for 2-(2,4-difluorobenzenesulfonyl)-2-[6-(2,2-dimethylmorpholin-4-yl)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 113) from 2-(4-chloro-2-fluorobenzenesulfonyl)acetonitrile (Intermediate 73; 2.04 g, 8.72 mmol) and 4-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2,2-dimethylmorpholine (Intermediate 112; 2.50 g, 8.72 mmol). The crude product was purified by column chromatography (silica, 0-10% methanol/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (s, 6H) 2.33 (s, 3H) 3.36-3.61 (m, 4H) 3.70-3.80 (m, 2H) 7.47-7.54 (m, 1H) 7.4-0.72 (m, 1H) 7.85-7.92 (m, 1H)
MS ES+: 484
Prepared as described for 2-(2,4-difluorobenzenesulfonyl)-2-[6-(2,2-dimethylmorpholin-4-yl)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 113) from 2-((2,3-difluorophenyl)sulfonyl)acetonitrile (Intermediate 53; 1.92 g, 8.83 mmol) 4-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2,2-dimethylmorpholine (Intermediate 112; 2.11 g, 7.36 mmol). The crude product was purified by column chromatography (silica, 20-60% ethyl acetate (+1% AcOH)/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (s, 6H) 2.30 (br. s., 3H) 3.38-3.78 (m, 7H) 7.35-7.45 (m, 1H) 7.66-7.76 (m, 2H)
MS ES+: 468
To a solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (CAS 13162-43-1; 6.14 g, 29.5 mmol) in THF (100 mL) was added a suspension of (S)-2-(trifluoromethyl)morpholine hydrochloride (CAS 1394909-69-3; 5.66 g, 29.5 mmol), triethylamine (12.34 mL, 89 mmol), THF (40 mL) and DMF (20 mL) dropwise over 2 h. The reaction was then stirred at room temperature for a further 2 h. The reaction was diluted with ethyl acetate and washed with water, dilute citric acid, sat. aq. NaHCO3 solution and brine. The organics were dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% ethyl acetate/petroleum ether (with 1% AcOH)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 3.28-3.41 (m, 2H) 3.58-3.67 (m, 1H) 3.67-3.77 (m, 1H) 3.97-4.09 (m, 1H) 4.16-4.27 (m, 1H) 4.34-4.47 m, 1H) 3H obscured by solvent peak.
MS ES+: 327
Prepared as described for 2-(2,4-difluorobenzenesulfonyl)-2-[6-(2,2-dimethylmorpholin-4-yl)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 113) from (S)-4-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(trifluoromethyl)morpholine (Intermediate 116; 1.67 g, 5.11 mmol) and 2-((2-fluoro-4-methoxyphenyl)sulfonyl)acetonitrile (Intermediate 68; 1.406 g, 6.13 mmol). The crude product was purified by column chromatography (silica, 10-50% (EtOAc+1% AcOH)/petroleum ether) to afford the title compound.
MS ES+: 520
Prepared as described for 2-(2,4-difluorobenzenesulfonyl)-2-[6-(2,2-dimethylmorpholin-4-yl)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 113) from 2-(2,4-difluorobenzenesulfonyl)acetonitrile (Intermediate 91; 1.93 g, 8.88 mmol) and (2S)-4-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(trifluoromethyl)morpholine (Intermediate 116; 2.9 g, 8.88 mmol). The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 3H) 3.24-3.36 (m, 2H) 3.65-3.75 (m, 2H) 3.96-4.08 (m, 2H) 4.29-4.42 (m, 1H) 7.22-7.31 (m, 1H) 7.37-7.46 (m, 1H) 7.93-8.00 (m, 1H)
MS ES+: 508
Prepared as described for 2-(2,4-difluorobenzenesulfonyl)-2-[6-(2,2-dimethylmorpholin-4-yl)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 113) from 2-(4-chloro-2-fluorobenzenesulfonyl)acetonitrile (Intermediate 73; 2.07 g, 8.88 mmol) and (2S)-4-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(trifluoromethyl)morpholine (Intermediate 116; 2.90 g, 8.88 mmol). The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.15 (s, 3H) 3.15-3.30 (m, 2H) 3.53-3.72 (m, 3H) 3.94-4.01 (m, 1H) 4.23-4.38 (m, 1H) 7.44-7.50 (m, 1H) 7.54-7.60 (m, 1H) 7.86-7.96 (m, 1H)
MS ES+: 524
Prepared as described for 2-(2,4-difluorobenzenesulfonyl)-2-[6-(2,2-dimethylmorpholin-4-yl)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 113) from (S)-4-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(trifluoromethyl)morpholine (Intermediate 116, 1.72 g, 5.27 mmol) and 2-((2,3-difluorophenyl)sulfonyl)acetonitrile (Intermediate 53; 1.372 g, 6.32 mmol). The crude product was purified by column chromatography (silica, 10-50% (EtOAc+1% AcOH)/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.22 (s, 3H) 3.22-3.38 (m, 2H) 3.62-3.76 (m, 2H) 3.97-4.09 (m, 2H) 4.30-4.42 (m, 1H) 7.33-7.43 (m, 1H) 7.61-7.75 (m, 2H)
MS ES+: 478
Prepared as described for 2-[6-chloro-2-(methylsulfanyl)-5-nitropyrimidin-4-yl]-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 100) from 2-((2,3-difluorophenyl)sulfonyl)acetonitrile (Intermediate 53; 1.41 g, 6.49 mmol) and 4,6-dichloro-2-methyl-5-nitropyrimidine (1.350 g, 6.49 mmol). The crude product was purified by column chromatography (silica, 10-50% (EtOAc+1% HCO2H)/petroleum ether) to afford the title compound.
MS ES+: 389
Prepared as described for 2-(2-fluorobenzenesulfonyl)-2-[6-(2-methylmorpholin-4-yl)-2-(methylsulfanyl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 101) from 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-((2,3-difluorophenyl)sulfonyl)acetonitrile (Intermediate 121; 1.35 g, 3.47 mmol) and (R)-2-(trifluoromethyl)morpholine hydrochloride (CAS 1394909-70-6; 0.699 g, 3.65 mmol). The crude product was used without purification
MS ES+: 508
To a solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (1.735 g, 8.34 mmol) and 2-((2,6-difluorophenyl)sulfonyl)acetonitrile (Intermediate 93; 1.812 g, 8.34 mmol) in anhydrous THF (30 mL) under an atmosphere of nitrogen was added K2CO3 (2.306 g, 16.69 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between sat. aq. NH4Cl solution and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (H-frit) and concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.16 (s, 3H) 7.10-7.19 (m, 2H) 7.52-7.63 (m, 1H)
MS ES+: 389
A stirred solution of 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-((2,6-difluorophenyl)sulfonyl)acetonitrile (Intermediate 123; 861 mg, 1.861 mmol), 2,2-dimethylmorpholine (257 mg, 2.233 mmol) and K2CO3 (771 mg, 5.58 mmol) in THF (20 mL) under an atmosphere of nitrogen was heated to 60° C. for 72 h. The reaction mixture was concentrated in vacuo and the residue partitioned between sat. aq. NH4Cl solution and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with brine, dried (H-frit) and concentrated in vacuo to afford the title compound.
MS ES+: 468
Prepared as described for 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(2,6-difluorobenzenesulfonyl)acetonitrile (Intermediate 123) from 4,6-dichloro-2-methyl-5-nitropyrimidine (1.966 g, 9.45 mmol) and 2-(2,5-difluorobenzenesulfonyl)acetonitrile (CAS 1153970-94-5; 2.053 g, 9.45 mmol). The crude product was used without purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.16 (s, 3H) 7.31-7.40 (m, 1H) 7.43-7.51 (m, 1H) 7.67-7.75 (m, 1H)
MS ES+: 389
Prepared as described for 2-(2,6-difluorobenzenesulfonyl)-2-[6-(2,2-dimethylmorpholin-4-yl)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 124) from 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-((2,5-difluorophenyl)sulfonyl)acetonitrile (Intermediate 125; 861 mg, 1.816 mmol) and 2,2-dimethylmorpholine (251 mg, 2.179 mmol). The crude product was used without purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (s, 6H) 2.01 (s, 3H) 3.15-3.26 (m, 4H) 3.60-3.69 (m, 2H) 7.25-7.35 (m, 1H) 7.36-7.45 (m, 1H) 7.61-7.68 (m, 1H)
MS ES+: 468
Prepared as described for 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(2,6-difluorobenzenesulfonyl)acetonitrile (Intermediate 123) from 4,6-dichloro-2-methyl-5-nitropyrimidine (1.966 g, 9.45 mmol) and 2-((2,4-difluorophenyl)sulfonyl)acetonitrile (Intermediate 91; 2.052 g, 9.45 mmol). The crude product was used without purification.
MS ES+: 389
Prepared as described for 2-(2,6-difluorobenzenesulfonyl)-2-[6-(2,2-dimethylmorpholin-4-yl)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 124) from 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(2,4-difluorobenzenesulfonyl)acetonitrile (Intermediate 126; 1.00 g, 2.57 mmol) and (R)-2-(trifluoromethyl)morpholine hydrochloride (CAS 1394909-70-6; 479 mg, 3.009 mmol). The crude product was used without further purification.
MS ES+: 508
Prepared as described for 2-(2,6-difluorobenzenesulfonyl)-2-[6-(2,2-dimethylmorpholin-4-yl)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 124) from 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(2,5-difluorobenzenesulfonyl)acetonitrile (Intermediate 125, 1.435 g, 3.69 mmol) and (R)-2-(trifluoromethyl)morpholine hydrochloride (CAS 1394909-70; 0.778 g, 4.06 mmol). The crude product was used without further purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.04 (s, 3H) 3.03-3.17 (m, 2H) 3.46-3.54 (m, 1H) 3.58-3.67 (m, 1H) 3.88-4.00 (m, 2H) 4.21-4.32 (m, 1H) 7.27-7.36 (m, 1H) 7.37-7.46 (m, 1H) 7.62-7.70 (m, 1H)
Prepared as described for 2-(2,6-difluorobenzenesulfonyl)-2-[6-(2,2-dimethylmorpholin-4-yl)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 124) from 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(2,5-difluorobenzenesulfonyl)acetonitrile (Intermediate 125, 1.435 g, 3.69 mmol) and, (S)-2-(trifluoromethyl)morpholine hydrochloride (CAS 1394909-69-3; 0.778 g, 4.06 mmol) The crude product was used without further purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.04 (s, 3H) 3.03-3.17 (m, 2H) 3.46-3.54 (m, 1H) 3.57-3.67 (m, 1H) 3.87-4.00 (m, 2H) 4.21-4.31 (m, 1H) 7.28-7.35 (m, 1H) 7.37-7.45 (m, 1H) 7.62-7.70 (m, 1H)
MS ES+: 508
A stirred mixture of 4,6-dichloro-2-methyl-5-nitropyrimidine (1.203 g, 5.78 mmol), 2-((2-fluoro-4-methoxyphenyl)sulfonyl)acetonitrile (Intermediate 68; 1.326 g, 5.78 mmol) and potassium carbonate (2.80 g, 20.24 mmol) in dry THF (30 mL) was stirred at room temperature under nitrogen for 72 h. (R)-2-(trifluoromethyl)morpholine hydrochloride (CAS 1394909-70; 1.108 g, 5.78 mmol) was added and the reaction mixture was heated at 60° C. for 5 h. The reaction was acidified with sat. aq. NH4Cl solution, extracted with EtOAc, dried (H-frit) and concentrated in vacuo. The crude product was purified column chromatography (silica, 10-60% (EtOAc+1% AcOH)/petroleum ether) to afford the title compound.
MS ES+: 520
Prepared as described for 2-(2,6-difluorobenzenesulfonyl)-2-[6-(2,2-dimethylmorpholin-4-yl)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 124) from 2-(6-Chloro-2-methyl-5-nitropyrimidin-4-yl)-2-((2,6-difluorophenyl)sulfonyl)acetonitrile (Intermediate 123, 1.24 g, 3.20 mmol) and (S)-2-(trifluoromethyl)morpholine hydrochloride (CAS 1394909-69-3; 0.674 g, 3.52 mmol). The crude product was used without further purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (s, 3H) 2.99-3.20 (m, 2H) 3.44-3.70 (m, 2H) 3.86-4.00 (m, 2H) 4.18-4.33 (m, 1H) 7.03-7.17 (m, 2H) 7.45-7.59 (m, 1H)
MS ES+: 508
Prepared as described for 2-(2,6-difluorobenzenesulfonyl)-2-[6-(2,2-dimethylmorpholin-4-yl)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 124) from 2-(6-Chloro-2-methyl-5-nitropyrimidin-4-yl)-2-((2,6-difluorophenyl)sulfonyl)acetonitrile (Intermediate 123, 1.24 g, 3.20 mmol) and (R)-2-(trifluoromethyl)morpholine hydrochloride (CAS 1394909-70; 0.674 g, 3.52 mmol). The crude product was used without further purification.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (s, 3H) 3.03-3.16 (m, 2H) 3.46-3.54 (m, 1H) 3.58-3.67 (m, 1H) 3.88-4.00 (m, 2H) 4.20-4.32 (m, 1H) 7.05-7.15 (m, 2H) 7.47-7.57 (m, 1H)
MS ES+: 508
Prepared as described for 2-(benzenesulfonyl)-2-[6-(3,3-difluorocyclobutoxy)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 85) from 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 86; 299 mg, 0.807 mmol) and 2,2-dimethyloxan-3-ol (CAS 107536-56-1; 200 mg, 0.968 mmol). The crude product was used without further purification.
MS ES−: 463
Prepared as described for 2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-2-(2,6-difluorobenzenesulfonyl)acetonitrile (Intermediate 123) from 4,6-dichloro-2-methyl-5-nitropyrimidine (1.97 g, 9.45 mmol) and 2-(4-chloro-2-fluorobenzenesulfonyl)acetonitrile (Intermediate 73; 2.21 g, 9.45 mmol). The crude product was used without further purification.
MS ES+: 404
Prepared as described for 2-(2,6-difluorobenzenesulfonyl)-2-[6-(2,2-dimethylmorpholin-4-yl)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 124) from 2-((4-chloro-2-fluorophenyl)sulfonyl)-2-(6-chloro-2-methyl-5-nitropyrimidin-4-yl)acetonitrile (Intermediate 135; 2.10 g, 5.18 mmol) and (R)-2-(trifluoromethyl)morpholine hydrochloride (CAS 1394909-70; 1.1 g, 5.74 mmol). The crude product was used without further purification.
MS ES+: 524
2-(2-fluorobenzenesulfonyl)-2-[6-(2-methylmorpholin-4-yl)-2-(methylsulfanyl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 101; 102 mg, 0.228 mmol) was treated with methylamine (33% in EtOH) (3 mL, 24.1 mmol). The mixture was allowed to stand at room temperature for three days then allowed to evaporate. The crude product was purified by column chromatography (silica, 0-15% methanol/DCM) to afford the title compound.
MS ES+: 451
To a stirred mixture of (R)-4-benzyl-2-(fluoromethyl)morpholine (CAS 1359658-47-1; 2.5 g, 11.96 mmol) and 10% dry Palladium on carbon) (2.5 g) in EtOH (90 mL) was added 4N HC in dioxane (0.5 mL) at room temperature. The reaction mixture was stirred under hydrogen atmosphere at room temperature for 15 h. After completion, reaction mixture was filtered through celite washing with methanol. The filtrate was acidified by 4N HCl in dioxane (10 mL) and concentration in vacuo. The crude material was triturated with diethyl ether and decanted to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.83-2.85 (m, 1H) 2.97-3.19 (m, 1H) 3.19-3.27 (m, 2H) 3.71-3.83 (m, 1H) 3.89-4.04 (m, 2H) 4.41-4.51 (m, 1H) 4.53-4.63 (m, 1H) 9.49-9.67 (m, 2H)
MS ES+: 120
To a stirred suspension of 2-[6-chloro-2-(methylsulfanyl)-5-nitropyrimidin-4-yl]-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 100; 801 mg, 1.99 mmol) and 2-(trifluoromethyl)morpholine hydrochloride (CAS 1196152-51-8; 381 mg, 1.99 mmol) in anhydrous THF (18 mL) was added K2CO3 (824 mg, 5.97 mmol). The reaction was heated to 50° C. for 3 days, under an atmosphere of nitrogen. The reaction mixture was evaporated and the residue partitioned between aq. NH4Cl solution and EtOAc. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were then washed with brine, dried (H-frit) and evaporated to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.19 (s, 3H) 3.10-3.26 (m, 2H) 3.58-3.72 (m, 2H) 3.91-4.01 (m, 2H) 4.26-4.37 (m, 1H) 7.24-7.35 (m, 2H) 7.52-7.61 (m, 1H) 7.80-7.89 (m, 1H)
MS ES+: 522
A stirred solution of 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol (0.14 g, 0.99 mmol), benzaldehyde (0.10 mL, 0.99 mmol) and Hunig's Base (0.21 mL, 1.19 mmol) in anhydrous MeOH (20 mL) was heated under microwave irradiation at 110° C. for 4 h. After this time a second portion of 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol (142 mg, 0.99 mmol) was added and the reaction heated under microwave irradiation at 110° C. for 4 h. The reaction was cooled to 0° C. and sodium borohydride (56 mg, 1.49 mmol) was added. The reaction was stirred at room temperature for 72 h, quenched with acetic acid and concentrated under reduced pressure. The crude mixture was loaded onto a cation exchange cartridge, washed with MeOH and eluted with 7 M ammonia/MeOH solution then concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
MS ES+: 234
A solution/suspension of 3-(benzylamino)-1,1,1-trifluoro-2-methylpropan-2-ol (Intermediate 140; 2.07 g, 8.88 mmol) in anhydrous toluene (20 mL) cooled to 0° C. and under an atmosphere of nitrogen was treated with 2-chloroacetyl chloride (0.73 mL, 9.23 mmol). A solution of triethylamine (1.86 mL, 13.3 mmol) in dry toluene (4 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 1 h under nitrogen. A solution of sodium methoxide, 30% wt in MeOH (5.28 mL, 28.4 mmol) in dry Methanol (5.40 mL) was added dropwise and the reaction mixture was stirred at room temperature under nitrogen for 16 h. The reaction mixture was concentrated to about ¼ of the volume and partitioned between 5% aq. citric acid solution and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed sequentially with water, sat. aq. NaHCO3 solution and brine, dried (MgSO4) and evaporated to afford the title compound.
1H NMR (400 MHz, CDCl3) δ ppm 1.37 (s, 3H) 3.16 (d, J=13 Hz, 1H) 3.58 (d, J=13 Hz, 1H) 4.26-4.45 (m, 2H) 4.50 (d, J=14 Hz, 1H) 4.82 (d, J=14 Hz, 1H) 7.20-7.50 (m, 5H).
MS ES+: 274
To a stirred solution of 4-benzyl-6-methyl-6-(trifluoromethyl)morpholin-3-one (Intermediate 141; 2.30 g, 8.42 mmol) in anhydrous THF (30 mL) under an atmosphere of nitrogen and at 0° C. was added sodium borohydride (0.96 g, 25.3 mmol). The reaction was stirred at 0° C. for 30 min followed by the dropwise addition of boron trifluoride etherate (3.20 mL, 25.3 mmol). The reaction mixture was heated at reflux temperature for 1 h. The reaction was cooled to 0° C. and quenched by dropwise addition of methanol (15 mL) and concentrated under reduced pressure. The residue was taken into 2M hydrochloric acid (75 mL, 150 mmol) and heated at 80° C. for 16 h. The reaction mixture was cooled to room temperature, adjusted to pH 3 with 2 M aq. NaOH solution, extracted with DCM, dried (MgSO4) and concentration in vacuo. The crude product was purified by column chromatography (silica, 0-10% ethyl acetate/petrol) to afford the title compound.
1H NMR (400 MHz, CDCl3) δ ppm 1.52 (s, 3H) 2.27-2.38 (m, 1H) 2.38-2.46 (m, 1H) 2.48-2.57 (m, 1H) 2.58-2.67 (m, 1H) 3.43-3.63 (m, 2H) 3.77-4.00 (m, 2H) 7.29-7.41 (m, 5H).
MS ES+: 260
A mixture of 4-benzyl-2-methyl-2-(trifluoromethyl)morpholine (Intermediate 142; 1.90 g, 7.33 mmol) and 10% palladium on carbon (0.78 g, 0.73 mmol) in ethanol (50 mL) was treated with HCl, 4M in dioxane (2.02 mL, 8.06 mmol) and placed under an atmosphere of hydrogen. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 3 h. The reaction mixture was filtered through Celite, washing with EtOH and evaporated to dryness. 4M HCl in dioxane (20 mL) was added and the reaction mixture re-evaporated. The residue was treated with a mixture of diethyl ether/acetone (1:1, 20 mL) and the resulting white solid filtered and dried in vacuo to give the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (s, 3H) 2.97-3.09 (m, 1H) 3.11-3.22 (m, 2H) 3.35-3.46 (m, 1H) 3.86-4.04 (m, 2H) 9.92 (br. s., 2H).
As will be appreciated, although exemplified herein as precursor compounds, intermediates 3, 19, 20, 21, 23, 28, 50, 52, 56, 57, 59, 69, 76 and 79 also represent compounds of the invention in their own right. Accordingly, these intermediates may also find use as active pharmaceutical ingredients in the pharmaceutical compositions and medical uses discussed above.
To a stirred solution of 2-(benzenesulfonyl)-2-(2-chloropyridin-3-yl)acetonitrile (Intermediate 1; 239 mg, 816 μmol) in anhydrous NMP (1 mL) was added a solution of 4,4-4,4-difluorocyclohexan-1-amine (CAS 458566-84-2; 662 mg, 4.90 mmol) and triethylamine (797 μL, 5.71 mmol) in NMP (2 mL) and the reaction mixture heated under microwave irradiation at 170° C. for 5 h. The reaction mixture was partitioned between EtOAc and water. The phases were separated and the aqueous phases extracted with EtOAc. The combined organics were washed with 5% citric acid, water, sat. aq. NaHCO3 solution and brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-40% EtOAc/petroleum ether). Further purification by column chromatography (preparative HPLC, 30-70% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 1.69-1.85 (m, 2H) 1.98-2.21 (m, 6H) 3.58-3.76 (m, 1H) 6.59 (d, J=9 Hz, 1H) 6.92-7.10 (m, 1H) 7.40-7.62 (m, 3H) 7.65-7.80 (m, 1H) 7.84-8.03 (m, 3H) 9.43-10.05 (m, 1H).
MS ES+: 392
To a stirred and nitrogen degassed solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-25-9; 380 mg, 2.10 mmol) in anhydrous DME (5 mL) was added sodium hydride (153 mg, 3.82 mmol, 60% dispersion in oil) at 0° C. The mixture was stirred at 0° C. for 5 min and then at rt for 5 min. This mixture was added to a previously nitrogen degassed solution of 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 400 mg, 1.91 mmol), tetrakis(triphenylphosphane) palladium (21 mg, 18 μmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (34 mg, 48 μmol) in anhydrous DME (5 mL). The reaction mixture was heated under microwave irradiation at 110° C. for 2 h. The reaction mixture was diluted with 0.2 M aq. NaOH solution and washed with MTBE. The separated aqueous phase was neutralised with 10% aq. citric acid solution and the resulting precipitate filtered to give the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.79 (m, 4H) 2.21-2.31 (m, 2H) 2.42-2.48 (m, 2H) 6.43 (br. s., 1H) 6.79 (s, 2H) 7.51-7.64 (m, 3H) 8.05 (d, J=7 Hz, 2H) 8.54 (s, 1H) 10.88 (s, 1H).
MS ES+: 355
A mixture of 7-(benzenesulfonyl)-4-(cyclohex-1-en-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 2; 84 mg, 237 μmol) and palladium on carbon (25 mg, 237 μmol) in anhydrous MeOH (20 mL) was placed under an atmosphere of hydrogen and stirred at rt for 1 h. The reaction mixture was filtered (Celite) and concentrated in vacuo to give the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.44 (m, 3H) 1.53-1.86 (m, 7H) 2.89-3.00 (m, 1H) 6.94 (s, 2H) 7.51-7.62 (m, 3H) 8.02-8.09 (m, 2H) 8.52 (s, 1H) 11.49 (hr. s., 1H).
MS ES+: 357
To a stirred and nitrogen degassed solution of 2-(4-methoxybenzenesulfonyl)acetonitrile (CAS 132276-87-0, 500 mg, 2.37 mmol), 4-chloro-6-(cyclohex-1-en-1-yl) pyrimidin-5-amine (Intermediate 2; 451 mg, 2.15 mmol), tetrakis(triphenylphosphane) palladium (62 mg, 54 μmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium (38 mg, 54 μmol) in anhydrous dioxane (10 mL) was added sodium hydride (189 mg, 4.73 mmol, 60% dispersion in oil) at 0° C. The reaction mixture was heated at reflux temperature for 48 h. A further portion of tetrakis(triphenylphosphane) palladium and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium was added and the reaction mixture heated at reflux temperature for 4 h. The reaction mixture was diluted with 0.2 M aq. NaOH solution and extracted with EtOAc. The organic phase was extracted with 0.2 M aq. HCl solution and washed with EtOAc. The separated aqueous phase was neutralised with solid NaHCO3 and the resulting precipitate filtered to give the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.55-1.80 (m, 4H) 2.15-2.33 (m, 2H) 2.36-2.45 (m, 2H) 3.79 (s, 3H) 6.44 (br. s., 1H) 6.73 (s, 2H) 7.07 (d, J=9 Hz, 2H) 7.98 (d, J=9 Hz, 2H) 8.52 (s, 1H) 10.86 (br. s., 1H).
MS ES+: 385
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 7-[(4-methoxybenzene)sulfonyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 4; 1.06 g, 2.76 mmol) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.45 (m, 3H) 1.53-1.85 (m, 7H) 2.89-3.00 (m, 1H) 3.79 (s, 3H) 6.83 (s, 2H) 7.06 (d, J=9 Hz, 2H) 7.98 (d, J=9 Hz, 2H) 8.49 (s, 1H) 11.39 (br. s., 1H).
MS ES+: 387
A solution of 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 150 mg, 486 μmol), morpholine (CAS 110-91-8; 169 μL, 1.94 mmol) and triethylamine (135 μL, 972 μmol) in anhydrous DMF (2 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 1 h. The reaction mixture was partitioned between EtOAc and water and extracted further with EtOAc. The combined organic layers were washed with water/brine (1:1), dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (basic silica, 0-100% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 3.39-3.80 (m, 8H) 6.50 (br. s, 2H) 7.44-7.67 (m, 3H) 8.02 (m, 2H) 8.20 (s, 1H) 10.84 (s, 1H).
MS ES+: 360
A solution of 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and piperidine (CAS 110-89-4; 257 μL, 2.59 mmol) in anhydrous DMF (2.5 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 1 h. The reaction mixture was partitioned between EtOAc and water and extracted with EtOAc. The combined organic layers were washed with water/brine (1:1), dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (basic silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.68 (m, 6H) 3.44-3.79 (m, 4H) 6.36 (br. s., 2H) 7.49-7.61 (m, 3H) 8.02 (d, J=7 Hz, 2H) 8.12 (s, 1H) 10.72 (br. s., 1H).
MS ES+: 358
A solution of 4-chloro-7-((2-fluorophenyl)sulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 750 mg, 2.201 mmol), 2,2,3-trimethylmorpholine (CAS 1314925-76-2; 490 mg, 3.79 mmol) and triethylamine (614 μL, 4.40 mmol) in EtOH (12 mL) was heated under at 180° C. for 3 days. The reaction mixture was concentrated under reduced pressure and the resulting residue partitioned between ethyl acetate (20 mL) and water (20 mL). The organic phase was separated and concentrated in vacuo. The crude material was purified by column chromatography (C18 silica, 5-60% acetonitrile/water (with 0.05% ammonia)) followed by further column chromatography (silica, 0-100% ethyl acetate/petroleum ether). The resulting material was recrystallised from EtOH/pentane to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.14 (s, 3H) 1.23 (s, 3H) 1.26 (d, J=7 Hz, 3H) 2.60 (s, 3H) 3.37-3.57 (m, 1H) 3.61-3.76 (m, 1H) 3.77-3.92 (m, 1H) 3.96-4.66 (m, 2H) 7.35-7.53 (m, 2H) 7.64-7.85 (m, 1H) 8.03-8.26 (m, 1H)
MS ES+: 434
To a stirred and nitrogen degassed solution of 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 100 mg, 324 μmol), phenylboronic acid (CAS 98-80-6; 79 mg, 648 μmol) and potassium carbonate (134 mg, 972 μmol) in dioxane (2 mL) and water (0.5 mL) was added tetrakis(triphenylphosphane) palladium (9 mg, 8 μmol) and the reaction mixture was irradiated in the microwave at 140° C. for 1 h. The solution was filtered (Celite) washed with EtOAc. The filtrate was washed with water, brine, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM). Further purification by column chromatography (preparative HPLC, 5-40% acetonitrile/water (with 0.1% formic acid)) afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 6.86 (s, 2H) 7.48-7.64 (m, 6H) 7.92 (d, J=7 Hz, 2H) 8.04-8.11 (m, 2H) 8.67 (s, 1H) 11.29 (br. s., 1H).
MS ES+: 351
To a stirred and nitrogen degassed solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-25-9; 480 mg, 2.65 mmol) in anhydrous DME (5 mL) was added sodium hydride (193 mg, 4.82 mmol, 60% dispersion in oil) at 0° C. The mixture was stirred at 0° C. for 5 min and at rt for 5 min. This mixture was added to a previously nitrogen degassed solution of 2-bromo-5-chloropyridin-3-amine (CAS 90902-83-3; 500 mg, 2.41 mmol), tetrakis(triphenylphosphane) palladium (279 mg, 241 μmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium (171 mg, 241 μmol) in anhydrous DME (5 mL). The reaction mixture was heated under microwave irradiation at 110° C. for 2 h. The reaction mixture was diluted with 0.2 M aq. NaOH solution and washed with MTBE. The separated aqueous phase was neutralised with 10% aq. citric acid solution, extracted with EtOAc. The organic phase was dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% MeOH/DCM) to give the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 7.10-7.41 (m, 2H) 7.50-7.65 (m, 4H) 8.04 (d, J=7 Hz, 2H) 8.10 (d, J=2 Hz, 1H) 11.16 (br. s, 1H).
MS ES+: 308
To a stirred and nitrogen degassed solution of 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol), 2-[(E)-2-cyclopropylethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS 849061-99-0; 151 mg, 777 μmol) and potassium phosphate (413 mg, 1.94 mmol) in dioxane (4 mL) and water (1 mL) was added di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (14 mg, 19 μmol) and the reaction mixture was irradiated in the microwave at 140° C. for 1.5 h. The solution was filtered through Celite washing with EtOAc. The filtrate was washed with water, brine, dried (H-frit) and concentrated in vacuo. The aqueous phase was neutralised 2 M aq. HCl solution and extracted with DCM. The organic layers were dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether). Further purification by column chromatography (C18 silica, 5-40% acetonitrile/water (with 0.1% ammonia)). Further purification by column chromatography (preparative HPLC, 5-40% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.60-0.67 (m, 2H) 0.88-0.95 (m, 2H) 1.61-1.72 (m, 1H) 6.51-6.62 (m, 1H) 6.83 (d, J=15 Hz, 1H) 7.06 (s, 2H) 7.51-7.62 (m, 3H) 8.01-8.08 (m, 2H) 8.43 (s, 1H) 11.56 (br. s, 1H).
MS ES+: 341
A suspension of 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (CAS 126726-62-3; 163 mg, 972 μmol), di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (17 mg, 24 μmol) and potassium phosphate (520 mg, 2.43 mmol) in dioxane (4 mL) and water (1 mL) which had been degassed with nitrogen for 5 min was irradiated in the microwave at 140° C. for 1 h. After this time additional portions of 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium were added and the reaction irradiated in the microwave at 140° C. for a further 2 h. The suspension was filtered through Celite washing with EtOAc and the phases were separated. The aqueous phase was neutralised with 2M aq. HCl solution and extracted with ethyl acetate. The combined organics were washed with water, brine, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether). Further purification by column chromatography (preparative HPLC, 5-40% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.16 (s, 3H) 5.55-5.75 (m, 2H) 6.82 (s, 2H) 7.48-7.63 (m, 3H) 8.00-8.09 (m, 2H) 8.57 (s, 1H) 10.99 (br. s., 1H).
MS ES+: 315
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 7-(benzenesulfonyl)-4-[(E)-2-cyclopropylethenyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 11; 55 mg, 162 mol) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm −0.02-0.05 (m, 2H) 0.32-0.38 (m, 2H) 0.64-0.75 (m, 1H) 1.50-1.60 (m, 2H) 2.79-2.88 (m, 2H) 6.93 (s, 2H) 7.50-7.61 (m, 3H) 7.99-8.07 (m, 2H) 8.48 (s, 1H).
MS ES+: 343
Prepared as described for 7-(benzenesulfonyl)-4-(cyclohex-1-en-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 2) from 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 47 mg, 227 μmol) and 1-cyano-N-(4-methoxyphenyl)-N-methylmethanesulfonamide (Intermediate 4; 60 mg, 250 μmol) in anhydrous DME (2 mL) with the exception that tetrakis(triphenylphosphane) palladium is the sole catalyst and the reaction mixture was heated under microwave irradiation at 120° C. for 2 h. The resulting solid was triturated with hot EtOAc, filtered, washed with petroleum ether and dried to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.80 (m, 4H), 2.25-2.32 (m, 2H), 3.71 (s, 3H), 6.18 (s, 2H), 6.47 (br. s., 1H), 6.82 (d, J=9 Hz, 2H), 7.09 (d, J=9 Hz, 2H), 8.57 (s, 1H), 10.78 (br. s., 1H).
MS ES+: 314
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 7-(benzenesulfonyl)-4-(prop-1-en-2-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 12; 110 mg, 350 μmol) in anhydrous MeOH (4 mL). The crude product was purified by column chromatography (C18 silica, 5-40% acetonitrile/water (with 0.05% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (d, J=7 Hz, 6H) 3.22-3.29 (m, 1H) 6.93 (s, 2H) 7.50-7.62 (m, 3H) 8.00-8.10 (m, 2H) 8.53 (s, 1H) 11.46 (br. s, 1H).
MS ES+: 317
Prepared as described for 7-(benzenesulfonyl)-4-(cyclohex-1-en-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 2) from 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 5; 266 mg, 1.05 mmol) in anhydrous DME (5 mL). The reaction mixture was heated under microwave irradiation at 120° C. for 2 h. The reaction mixture was poured into water and extracted with EtOAc. The organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether, and then with 0-10% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.82 (m, 4H) 2.14-2.28 (m, 2H) 2.31-2.44 (m, 2H) 5.85-6.07 (m, 1H) 6.45 (br. s., 2H) 7.44-7.63 (m, 3H) 7.83-7.99 (m, 3H) 8.46 (br. s, 1H) 10.75 (br. s, 1H).
MS ES+: 354
To a stirred solution of 4-(cyclohex-1-en-1-yl)-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 2; 100 mg, 282 μmol) in anhydrous DCM (4 mL) was added chloro(methoxy)methanone (CAS 79-22-1; 26 μL, 339 μmol) followed by ethylbis(propan-2-yl)amine (148 μL, 846 μmol) and the reaction mixture was stirred at rt for 96 h. A second portion of chloro(methoxy)methanone (CAS 79-22-1; 26 μL, 339 μmol) and ethylbis(propan-2-yl)amine (148 μL, 846 μmol) was added and the reaction heated at 40° C. for 4 h. The mixture was partitioned between DCM and water. The phases were separated and the aqueous extracted with DCM. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (preparative HPLC, 5-40% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, CDCl3) δ ppm 1.68-1.91 (m, 4H) 2.35 (m, 2H) 2.60 (m, 2H) 3.96 (s, 3H) 6.62 (t, J=4 Hz, 1H) 7.44-7.67 (m, 3H) 8.08-8.36 (m, 2H) 8.96 (s, 1H) 9.72 (br. s., 1H) 10.86 (br. s., 1H).
MS ES+: 413
To a stirred and nitrogen degassed solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-25-9; 391 mg, 2.16 mmol) in anhydrous DME (5 mL) was added sodium hydride (172 mg, 4.31 mmol, 60% dispersion in oil) at 0° C. The mixture was stirred at 0° C. for 5 min and then at rt for 5 min. This mixture was added to a previously nitrogen degassed solution 4-chloro-2-(cyclohex-1-en-1-yl)pyridin-3-amine (Intermediate 6; 300 mg, 1.44 mmol), (acetyloxy)palladio acetate (16 mg, 72 μmol) and 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (51 μL, 144 mol) in anhydrous DME (5 mL). The reaction mixture was heated under microwave irradiation at 130° C. for 2 h. The reaction mixture was diluted with 0.2 M aq. NaOH solution and washed with MTBE. The separated aqueous phase was neutralised with 10% aq. citric acid solution and extracted with EtOAc. The organic phase was concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether, and then with 0-100% MeOH/DCM) to afford the title compound.
1H NMR (300 MHz, METHANOL-d4) δ ppm 1.60-1.78 (m, 4H) 2.11-2.24 (m, 2H) 2.32-2.41 (m, 2H) 6.00-6.15 (m, 1H) 7.31 (d, J=6 Hz, 1H) 7.37-7.49 (m, 3H) 7.78-7.96 (m, 3H).
MS ES+: 354
Prepared as described for 7-(benzenesulfonyl)-4-(cyclohex-1-en-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 2) from 4-chloro-6-(cyclohex-1-en-1-yl)-2-methylpyrimidin-5-amine (Intermediate 7; 980 mg, 3.50 mmol) in anhydrous dioxane (20 mL) with the exception that the reaction mixture was heated at 110° C. for 3 h. After aqueous workup (Example 2) the crude mixture was loaded onto a cation exchange cartridge, washed with MeOH and eluted with 2 M ammonia/MeOH solution then concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) and recrystallised from hot EtOH to afford the title compound.
1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 1.65-1.79 (m, 4H) 2.22-2.29 (m, 2H) 2.42-2.49 (m, 2H) 2.53 (s, 3H) 6.18 (br. s., 2H) 6.35 (br. s., 1H) 7.48-7.60 (m, 3H) 8.10 (d, J=7 Hz, 2H) 9.25 (br. s., 1H).
MS ES+: 369
Prepared as described for 7-(benzenesulfonyl)-4-(cyclohex-1-en-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 2) from 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 155 mg, 739 μmol) and 2-(pyridin-2-ylsulfonyl)acetonitrile (CAS170449-34-0; 148 mg, 813 μmol) in anhydrous 2-methyloxolane (4 mL). The reaction mixture was heated at 110° C. for 2 h. 2-tert-butyl-1,1,3,3-tetramethylguanidine (253 mg, 1.48 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (CAS 95464-05-4; 20 mg, 27 μmol) was added and the reaction mixture was heated under microwave irradiation at 130° C. for 1 h then heated at 130° C. for 22 h. The crude mixture was loaded onto a cation exchange cartridge, washed with MeOH and eluted with 2 M ammonia/MeOH solution then concentrated in vacuo. The crude product was purified by column chromatography (C-18 silica, 5-30% acetonitrile/water (with 0.1% formic acid) to afford the title compound.
1H NMR (400 MHz, Methanol-d4) δ ppm 1.71-1.87 (m, 4H) 2.27-2.36 (nm, 2H) 2.46-2.53 (m, 2H) 6.37-6.43 (m, 1H) 7.53-7.59 (m, 1H) 8.1-8.08 (m, 1H) 8.27-8.34 (m, 1H) 8.42 (s, 1H) 8.57-8.61 (m, 1H).
MS ES+: 356
To a stirred and nitrogen degassed solution of 2-(4-chlorobenzenesulfonyl)acetonitrile (CAS 1851-09-8; 123 mg, 572 μmol) in anhydrous dioxane (0.5 mL) was added sodiobis(trimethylsilyl)amine [1 M in THF] (668 μL, 668 μmol) at 0° C. The mixture was stirred at 0° C. for 20 min and then at rt for 5 min. This mixture was added to a previously nitrogen degassed solution 4-4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 100 mg, 477 μmol), (acetyloxy)palladio acetate (4.28 mg, 19 μmol) and 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (14 μL, 38 μmol) in anhydrous dioxane (0.5 mL). The reaction mixture was heated under microwave irradiation at 130° C. for 5 h. The reaction mixture was diluted with 0.2 M aq. NaOH solution and washed with MTBE. The separated aqueous phase was neutralised with 10% aq. citric acid solution, extracted with EtOAc:2-methyloxolane (2:1) and dried (H-frit). The organic phase was concentrated in vacuo. The crude product was purified by column chromatography (basic silica, 50-100% EtOAc/petroleum ether, and then with 0-10% MeOH (with 0.1% formic acid)/EtOAc). The residue was triturated with MTBE and then purified 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 1.59-1.78 (m, 4H) 2.21-2.32 (m, 2H) 2.41-2.52 (m, 2H) 6.44 (hr. s., 1H) 6.82 (s, 2H) 7.64 (d, J=8 Hz, 2H) 8.05 (d, J=8 Hz, 2H) 8.54 (s, 1H) 10.91 (br. s., 1H).
MS ES+: 389
Prepared as described for 7-(benzenesulfonyl)-4-[(E)-2-cyclopropylethenyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 11) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and (cyclopent-1-en-1-yl)boronic acid (CAS 850036-28-1; 181 mg, 1.62 mmol) in dioxane (4 mL) and water (1 mL) and the reaction mixture was heated under microwave irradiation at 140° C. for 1 h. The crude product was purified by column chromatography (silica, 0-10% EtOAc/petroleum ether). Further purification by column chromatography (C18-silica, 5-40% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.86-2.03 (m, 2H) 2.55-2.67 (m, 2H) 2.77-2.88 (m, 2H) 6.63 (br. s., 1H) 6.82 (br. s., 2H) 7.49-7.63 (m, 3H) 7.98-8.10 (m, 2H) 8.54 (s, 1H) 10.87 (br. s., 1H).
MS ES+: 341
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 7-(benzenesulfonyl)-4-(cyclopent-1-en-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 22; 100 mg, 294 μmol) in anhydrous MeOH (4 mL). The crude product was purified by column chromatography (C18-silica, 5-40% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.56-1.99 (m, 8H) 3.34-3.45 (m, 1H) 6.82 (br. s., 2H) 7.50-7.59 (m, 3H) 8.06 (d, J=7 Hz, 2H) 8.51 (s, 1H) 10.83-11.28 (m, 1H).
MS ES+: 343
Prepared as described for 7-(benzenesulfonyl)-4-(piperidin-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 7) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 225 mg, 729 μmol) and 4,4-difluoropiperidine hydrochloride (CAS 144260-52-4; 459 mg, 2.92 mmol). The reaction mixture was heated at 120° C. for 2.5 h additional portions of 4,4-difluoropiperidine hydrochloride (CAS 144260-52-4; 459 mg, 2.92 mmol) and triethylamine (203 μL, 1.46 mmol) were added and the reaction mixture was heated at 120° C. for 16 h. The crude product was purified by column chromatography (C18-silica, 5-40% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.95-2.12 (m, 4H) 3.58-3.88 (m, 4H) 6.46 (br. s, 2H) 7.50-7.59 (m, 3H) 8.03 (d, J=6 Hz, 2H) 8.18 (s, 1H) 10.88-11.12 (m, 1H).
MS ES+: 394
Prepared as described for 7-(benzenesulfonyl)-4-[(E)-2-cyclopropylethenyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 11) from 3-(benzenesulfonyl)-6-chloro-1H-pyrrolo[3,2-b]pyridin-2-amine (Example 10; 350 mg, 1.137 mmol) and (cyclohex-1-en-1-yl)boronic acid (CAS 850036-28-1; 287 mg, 2.28 mmol) in dioxane (4 mL) and water (1 mL). The reaction mixture was heated under microwave irradiation at 140° C. for 1 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, METHANOL-d4) δ ppm 1.64-1.75 (m, 2H) 1.78-1.89 (m, 2H) 2.19-2.27 (m, 2H) 2.38-2.47 (m, 2H) 6.05-6.13 (m, 1H) 7.41-7.46 (m, 1H) 7.46-7.57 (m, 3H) 8.06-8.12 (m, 2H) 8.14 (br. s., 1H).
MS ES+: 354
To a stirred and nitrogen degassed solution of 2-(4-fluorobenzenesulfonyl)acetonitrile (CAS 32083-66-2; 117 mg, 589 μmol) and bis(tri-tert-butylphosphane) palladium (19 mg, 36 μmol) in anhydrous DME (1 mL) was added sodiobis(trimethylsilyl)amine [1 M in THF] (634 μL, 634 μmol) at 0° C. The mixture was stirred at 0° C. for 10 min and then at rt for 5 min. This mixture was added to a previously nitrogen degassed solution 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 100 mg, 477 μmol) in anhydrous DME (1 mL). The reaction mixture was heated under microwave irradiation at 110° C. for 2 h. To the reaction mixture was added sodium hydride (21.75 mg, 544 μmol, 60% dispersion in oil) and heated under microwave irradiation at 130° C. for 40 min. The reaction mixture was diluted with 0.2 M aq. NaOH solution and washed with MTBE. The separated aqueous phase was neutralised with 10% aq. citric acid solution, extracted with EtOAc/2-methyloxolane (2:1) and dried (H-frit). The organic phase was concentrated in vacuo. The crude product was purified by column chromatography (basic silica, 50-100% EtOAc/petroleum ether, and then with 0-10% MeOH (with 0.1% formic acid)/EtOAc). The crude product was then purified by column chromatography (silica, 0-100% EtOAc/petroleum ether). The residue was triturated with hot EtOH and washed with diethyl ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.57-1.83 (m, 4H) 2.15-2.34 (m, 2H) 2.35-2.47 (m, 2H) 6.45 (br. s., 1H) 6.80 (br. s., 2H) 7.40 (m, 2H) 7.95-8.20 (m, 2H) 8.54 (s, 1H) 10.91 (br. s., 1H).
MS ES+: 373
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 4-(cyclohex-1-en-1-yl)-7-[(4-fluorobenzene)sulfonyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 26; 100 mg, 269 μmol) in anhydrous MeOH (3 mL). The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.15-1.47 (m, 3H) 1.50-1.86 (m, 7H) 2.88-3.02 (m, 1H) 6.94 (s, 2H) 7.35-7.46 (m, 2H) 8.06-8.17 (m, 2H) 8.52 (s, 1H) 11.42 (br. s., 1H).
MS ES+: 375
Prepared as described for 7-(benzenesulfonyl)-4-(piperidin-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 7) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 225 mg, 729 μmol) and 4-methoxypiperidine (CAS 4045-24-3; 336 mg, 2.92 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 2.5 h. The crude product was purified by column chromatography (C18-silica, 5-40% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.54 (m, 2H) 1.83-1.96 (m, 2H) 3.21-3.32 (m, 5H) 3.38-3.48 (m, 1H) 3.74-4.12 (m, 2H) 6.40 (br. s., 2H) 7.47-7.60 (m, 3H) 8.02 (d, J=7 Hz, 2H) 8.13 (s, 1H) 10.82 (br. s., 1H).
MS ES+: 388
Prepared as described for 7-(benzenesulfonyl)-4-(piperidin-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 7) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 3,3-difluoropyrrolidine hydrochloride (CAS 163457-23-6; 279 mg, 1.94 mmol) in EtOH (3 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 2 h. Additional portions of 3,3-difluoropyrrolidine hydrochloride (CAS 163457-23-6; 279 mg, 1.94 mmol) and triethylamine (451 μL, 3.24 mmol) were added and the reaction mixture was heated under microwave irradiation at 140° C. for 2 h. The crude product was purified by column chromatography (basic silica, 0-10% MeOH/DCM). Further purification by column chromatography (C18-silica, 5-40% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.52-2.59 (m, 2H) 3.81-3.91 (m, 2H) 3.99-4.12 (m, 2H) 6.40 (br. s., 2H) 7.48-7.60 (m, 3H) 8.01 (d, J=7 Hz, 2H) 8.12 (s, 1H) 10.63 (br. s., 1H).
MS ES+: 380
Prepared as described for 7-(benzenesulfonyl)-4-(piperidin-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 7) from 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and azetidine (CAS 503-29-7; 111 mg, 1.94 mmol) in EtOH (3 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 2 h. The crude product was purified by column chromatography (basic silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 2.27-2.43 (m, 2H) 4.06-4.24 (m, 4H) 6.45 (br. s., 2H) 7.48-7.61 (m, 3H) 7.97-8.14 (m, 3H) 10.33-10.56 (m, 1H).
MS ES+: 330
Prepared as described for 7-(benzenesulfonyl)-4-(piperidin-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 7) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and pyrrolidine (CAS 123-75-1; 161 μL, 1.94 mmol) in EtOH (3 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 2 h. The crude product was purified by column chromatography (basic silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.86-1.96 (m, 4H) 3.55-3.67 (m, 4H) 6.32 (br. s., 2H) 7.48-7.59 (m, 3H) 7.97-8.07 (m, 3H) 10.39-10.57 (m, 1H).
MS ES+: 344
A solution of 4-(cyclohex-1-en-1-yl)-7-[(4-fluorobenzene)sulfonyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 16; 45 mg, 127 μmol) in anhydrous THF (3 mL) was passed through a hydrogen generating flow reactor fitted with a to % palladium on carbon catalyst cartridge at 50° C. and 20 bar of pressure. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, Methanol-d4) δ ppm 1.31-1.44 (m, 1H) 1.44-1.67 (m, 4H) 1.72-2.06 (m, 5H) 2.76-3.05 (m, 1H) 7.42-7.63 (m, 3H) 7.76-8.06 (m, 3H) 8.25-8.60 (m, 1H).
MS ES+: 356
To a stirred and nitrogen degassed solution of 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 129 mg, 615 μmol), 2-[4-(difluoromethoxy)benzenesulfonyl]acetonitrile (Intermediate 8; 228 mg, 922 μmol), tris((1E,4E)-1,5-diphenylpenta-1,4-dien-3-one) dipalladium (45 mg, 49 μmol) and tris(2-methylphenyl)phosphane (30 mg, 98 μmol) in anhydrous DME (3 mL) was added lithiobis(trimethylsilyl)amine [1 M in THF] (1.85 mL, 1.85 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 1.5 h. To the reaction mixture was added sodium hydride (49 mg, 1.23 mmol, 60% dispersion in oil) and the reaction mixture was heated under microwave irradiation at 120° C. for 40 min. The reaction mixture was diluted with 0.2 M aq. NaOH solution and washed with MTBE. The separated aqueous phase was neutralised with 10% aq. citric acid solution, extracted with EtOAc/2-methyloxolane (2:1) and dried (H-frit). The organic phase was concentrated in vacuo. The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.59-1.79 (m, 4H) 2.21-2.32 (m, 2H) 2.44-2.55 (m, 2H) 6.47 (hr. s., 1H) 6.75 (s, 2H) 7.29 (t, J=7 Hz, 1H) 7.33 (d, J=9 Hz, 2H) 8.11 (d, J=9 Hz, 2H) 8.53 (s, 1H).
MS ES+: 421
Prepared as described for 7-(benzenesulfonyl)-4-(piperidin-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 7) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 300 mg, 972 μmol) and 3,3-difluoropiperidine hydrochloride (CAS 496807-97-7; 459 mg, 2.92 mmol) in EtOH (5 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 1.5 h. Additional portions of 3,3-difluoropiperidine hydrochloride (CAS 496807-97-7; 459 mg, 2.92 mmol) and triethylamine (677 μL, 4.86 mmol) were added and the reaction mixture was heated under microwave irradiation at 140° C. for 5.5 h. The crude product was purified by column chromatography (basic silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.73-1.84 (m, 2H) 2.02-2.17 (m, 2H) 3.47-4.05 (m, 4H) 6.50 (br. s., 2H) 7.48-7.61 (m, 3H) 8.02 (d, J=7 Hz, 2H) 8.16 (br. s., 1H) 10.83 (br. s., 1H).
MS ES+: 394
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 7-(benzenesulfonyl)-5-benzyl-4-(cyclohex-1-en-1-yl)-N-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 11; 70 mg, 153 μmol) in anhydrous MeOH (15 mL). The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.32 (m, 1H) 1.33-1.50 (m, 2H) 1.53-1.90 (m, 7H) 3.08 (d, J=5 Hz, 3H) 3.15-3.26 (m, 1H) 7.37 (br. s., 1H) 7.48-7.66 (m, 3H) 7.97-8.12 (m, 2H) 8.50 (s, 1H) 11.05 (br. s., 1H).
MS ES+: 371
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 4-(cyclohex-1-e1-yl)-7-{[4-(difluoromethoxy)benzene]sulfonyl}-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 33; 29 mg, 69 μmol) in anhydrous MeOH (1.5 mL). The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, METHANOL-d4) δ ppm 1.23-1.59 (m, 3H) 1.60-1.85 (m, 5H) 1.85-1.97 (m, 2H) 2.005 (br. s., 1H) 2.89-3.02 (m, 1H) 6.74-7.14 (m, 1H) 7.26 (d, J=9 Hz, 2H) 8.16 (d, J=9 Hz, 2H) 8.52 (s, 1H).
MS ES+: 423
To a stirred and nitrogen degassed solution of 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 115 mg, 548 μmol), 2-(3-fluorobenzenesulfonyl)acetonitrile (Intermediate 12; 142 mg, 713 μmol), di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium (19 mg, 27 μmol), tris((1E,4E)-1,5-diphenylpenta-1,4-dien-3-one) dipalladium (25 mg, 27 μmol) and tris(2-methylphenyl)phosphane (17 mg, 55 μmol) in anhydrous DME (2.2 mL) was added sodiobis(trimethylsilyl)amine [1 M in THF] (1.10 mL, 1.10 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 2 h. To the reaction mixture was added sodium hydride (49 mg, 1.23 mmol, 60% dispersion in oil) and the reaction mixture was heated under microwave irradiation at 120° C. for 40 min. The reaction mixture was diluted with 0.2 M aq. NaOH solution and washed with MTBE. The separated aqueous phase was neutralised with 10% aq. citric acid solution, extracted with EtOAc/2-methyloxolane (2:1) and dried (H-frit). The organic phase was concentrated in vacuo. The residue was triturated with DCM, MTBE and dried (air) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.57-1.79 (m, 4H) 2.19-2.35 (m, 2H) 2.41-2.56 (m, 2H) 6.44 (br. s., 1H) 6.84 (s, 2H) 7.42-7.51 (m, 1H) 7.55-7.68 (m, 1H) 7.81-7.93 (m, 2H) 8.56 (s, 1H) 10.94 (br. s., 1H).
MS ES+: 373
Prepared as described for 4-(cyclohex-1-en-1-yl)-7-[(3-fluorobenzene)sulfonyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 37) from 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 108 mg, 517 μmol) and 2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 13; 134 mg, 673 μmol) in anhydrous DME (2 mL) with the exception that 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine, polymerbound (150 μL, 517 μmol, Aldrich cat. 536490) and another portion of di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (18 mg, 26 μmol) was added and the reaction mixture was heated under microwave irradiation at 120° C. for 1.5 h. The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.59-1.78 (m, 4H) 2.21-2.32 (m, 2H) 2.41-2.50 (m, 2H) 6.48 (br. s., 1H) 6.86 (s, 2H) 7.26-7.37 (m, 1H) 7.37-7.45 (m, 1H) 7.59-7.70 (m, 1H) 8.00-8.10 (m, 1H) 8.42 (s, 1H), 11.01 (br. s., 1H).
MS ES+: 373
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 4-(cyclohex-1-en-1-yl)-7-[(3-fluorobenzene)sulfonyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 37; 213 mg, 572 μmol) in anhydrous MeOH (6 mL) with the exception that after 18 h an additional portion of palladium on carbon was added and the reaction stirred for 5 h. The crude product was purified by column chromatography (silica, 0-70% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.45 (m, 3H) 1.51-1.87 (m, 7H) 2.89-3.02 (m, 1H) 6.98 (s, 2H) 7.41-7.51 (m, 1H) 7.57-7.68 (m, 1H) 7.83-7.95 (m, 2H) 8.55 (s, 1H) 11.46 (br. s., 1H).
MS ES+: 375
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 7-(benzenesulfonyl)-4-(cyclohex-1-en-1-yl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 19; 116 mg, 315 μmol) in anhydrous MeOH (5 mL). The crude product was purified by column chromatography (basic silica, 80-100% EtOAc/petroleum ether) and triturated with diethyl ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.44 (m, 3H) 1.50-1.86 (m, 7H) 2.50 (s, 3H) 2.78-2.97 (m, 1H) 6.83 (br. s., 2H) 7.47-7.65 (m, 3H) 8.07 (d, J=7 Hz, 2H) 11.22 (s, 1H).
MS ES+: 371
To a stirred and nitrogen degassed solution of 4-chloro-6-(cyclohex-1-en-1-yl)-2-ethylpyrimidin-5-amine (Intermediate 14; 260 mg, 1.09 mmol), 2-(benzenesulfonyl)acetonitrile (CAS 7605-25-9; 297 mg, 1.64 mmol), tetrakis(triphenylphosphane) palladium (38 mg, 33 μmol), di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium (23 mg, 33 μmol) in anhydrous dioxane (5 mL) was added sodiobis(trimethylsilyl)amine [1 M in THF] (2.73 mL, 2.73 mmol). The reaction mixture was heated at 80° C. for 3 h. To the reaction mixture was added another portion of tetrakis(triphenylphosphane) palladium (38 mg, 33 μmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (23 mg, 33 μmol). The reaction mixture was absorbed onto Celite and washed with DCM and EtOAc. The combined organic fractions were concentrated in vacuo. The crude product was purified by column chromatography (basic silica, 0-10% MeOH/DCM) and recrystallised from EtOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (t, J=7 Hz, 3H) 1.59-1.75 (m, 4H) 2.20-2.27 (m, 2H) 2.41-2.48 (m, 2H) 2.78 (q, J=7 Hz, 2H) 6.36-6.41 (m, 1H) 6.70 (br. s, 2H) 7.49-7.62 (m, 3H) 8.10 (d, J=7 Hz, 2H) 10.73 (br. s, 1H).
MS ES+: 383
Prepared as described for 4-(cyclohex-1-en-1-yl)-7-[(3-fluorobenzene)sulfonyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 37) from 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 108 mg, 517 μmol) and 2-(4-methylbenzenesulfonyl)acetonitrile (CAS 5697-44-9; 134 mg, 673 μmol) in anhydrous DME (2 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 3 h. The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.57-1.77 (m, 4H) 2.20-2.29 (m, 2H) 2.32 (s, 3H) 2.40-2.49 (m, 2H) 6.43 (br. s., 1H) 6.78 (s, 2H) 7.34 (d, J=8 Hz, 2H) 7.91 (d, J=8 Hz, 2H) 8.51 (s, 1H).
MS ES+: 369
Prepared as described for 4-(cyclohex-1-en-1-yl)-7-[(3-fluorobenzene)sulfonyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 37) from 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 156 mg, 744 μmol) and 2-[(6-methoxypyridin-3-yl)sulfonyl]acetonitrile (Intermediate 15; 221 mg, 1.04 mmol) in anhydrous DME (3 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 3 h. The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.58-1.78 (m, 4H) 2.20-2.31 (m, 2H) 2.40-2.52 (m, 2H) 3.90 (s, 3H) 6.46 (br. s., 1H) 6.83 (s, 2H) 6.96 (d, J=9 Hz, 1H) 8.21-8.30 (m, 1H) 8.54 (s, 1H) 8.82 (d, J=2 Hz, 1H), 10.91 (br. s., 1H).
MS ES+: 386
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 4-(cyclohex-1-en-1-yl)-7-(6-methoxypyridine-3-sulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 43; 133 mg, 345 μmol) in anhydrous MeOH (4 mL) with the exception that after 18 h an additional portion of palladium on carbon was added and the reaction mixture stirred at rt for 5 h. The crude product was purified by column chromatography (silica, 30-70% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.46 (m, 3H) 1.52-1.67 (m, 2H) 1.67-1.76 (m, 3H) 1.76-1.85 (m, 2H) 2.95 (s, 1H) 3.90 (s, 3H) 6.88-7.01 (m, 3H) 8.23-8.30 (m, 1H) 8.53 (s, 1H) 8.83 (d, J=3 Hz, 1H) 11.42 (s, 1H).
MS ES+: 388
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 4-(cyclohex-1-en-1-yl)-7-[(4-methylbenzene)sulfonyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 42; 109 mg, 296 μmol) in anhydrous MeOH (6 mL) and the reaction mixture stirred at rt for 72 h to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.26-1.45 (m, 3H) 1.52-1.66 (m, 2H) 1.66-1.75 (m, 3H) 1.75-1.85 (m, 2H) 2.33 (s, 3H) 2.87-3.00 (m, 1H) 6.89 (s, 2H) 7.34 (d, J=8 Hz, 2H) 7.93 (d, J=8 Hz, 2H) 8.51 (s, 1H) 11.38 (s, 1H).
MS ES+: 371
Prepared as described for 7-(benzenesulfonyl)-4-(piperidin-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 7) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 4-fluoropiperidine hydrochloride (CAS 57395-89-8; 271 mg, 1.94 mmol) in EtOH (3 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 2 h. The crude product was purified by column chromatography (basic silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.81 (m, 2H) 1.86-2.04 (m, 2H) 3.43-3.92 (m, 4H) 4.78-5.00 (m, 1H) 6.41 (br. s., 2H) 7.48-7.62 (m, 3H) 8.02 (d, J=7 Hz, 2H) 8.15 (s, 1H) 10.83 (br. s., 1H).
MS ES+: 376
Prepared as described for 7-(benzenesulfonyl)-4-(piperidin-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 7) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 3,3-dimethylpyrrolidine (CAS 3437-30-7; 193 mg, 1.94 mmol) in EtOH (3 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 2 h. The crude product was purified by column chromatography (basic silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (s, 6H) 1.73 (t, J=7 Hz, 2H) 3.41 (s, 2H) 3.71 (t, J=7 Hz, 2H) 6.27 (br. s., 2H) 7.46-7.59 (m, 3H) 7.94-8.07 (m, 3H) 10.08-10.54 (m, 1H).
MS ES+: 372
Prepared as described for 7-(benzenesulfonyl)-4-(piperidin-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 7) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and azepane (CAS 111-49-9; 193 mg, 1.94 mmol) in EtOH (3 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 2 h. The crude product was purified by column chromatography (basic silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.52 (m, 4H) 1.64-1.80 (m, 4H) 3.65-3.82 (m, 4H) 6.29 (br. s., 2H) 7.49-7.60 (m, 3H) 7.99-8.08 (m, 3H) 10.38 (br. s., 1H).
MS ES+: 372
Prepared as described for 4-(cyclohex-1-en-1-yl)-7-[(3-fluorobenzene)sulfonyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 37) from 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 183 mg, 872 μmol) and 2-(3,4-difluorobenzenesulfonyl)acetonitrile (Intermediate 16; 265 mg, 1.22 mmol) in anhydrous DME (3.5 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 3 h. The crude product was purified by column chromatography (preparative HPLC, 20-60% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.59-1.79 (m, 4H) 2.21-2.31 (m, 2H) 2.42-2.50 (m, 2H) 6.46 (br. s., 1H) 6.83 (s, 2H) 7.61-7.72 (m, 1H) 7.87-7.97 (m, 1H) 8.07-8.16 (m, 1H) 8.56 (s, 1H).
MS ES+: 391
Prepared as described for 7-(benzenesulfonyl)-4-(cyclohex-1-en-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 2) from 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 290 mg, 1.38 mmol) and 2-(cyclohexanesulfonyl)acetonitrile (Intermediate 17; 388 mg, 2.08 mmol) in anhydrous DME (9 mL) and the reaction mixture was heated at 120° C. for 16 h. The resulting solid was triturated with hot DCM/petroleum ether and filtered. The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, Methanol-d4) δ ppm 0.97-1.41 (m, 3H) 1.44-1.63 (m, 2H) 1.64-2.00 (m, 7H) 2.03-2.23 (m, 2H) 2.25-2.44 (m, 2H) 2.46-2.63 (m, 2H) 3.17-3.28 (m, 1H) 6.32-6.55 (m, 1H) 8.54 (s, 1H).
MS ES+: 361
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 4-(cyclohex-1-en-1-yl)-7-(cyclohexanesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 50; 251 mg, 696 μmol) in anhydrous MeOH (20 mL). The crude product was purified by column chromatography (C18-silica, 5-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.97-1.49 (m, 8H) 1.51-2.05 (m, 12H) 2.91-3.07 (m, 1H) 3.11-3.23 (m, 1H) 6.65 (s, 2H) 8.50 (s, 1H) 11.02-11.98 (br s, 1H).
MS ES+: 363
To a stirred solution of 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol), 2-methylmorpholine (CAS 27550-90-9; 262 mg, 2.59 mmol) and triethylamine (181 μL, 1.30 mmol) in anhydrous DMF (8 mL) and the reaction mixture was heated under microwave irradiation at 130° C. for 2 h. The reaction mixture poured into water and extracted with EtOAc. The combined organic fractions were washed with brine and concentrated in vacuo. The crude product was purified by column chromatography (preparative HPLC, 5-40% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.26 (d, J=6 Hz, 3H) 2.85-3.03 (m, 1H) 3.20-3.36 (m, 1H) 3.60-3.76 (m, 2H) 3.93-4.06 (m, 1H) 4.81-4.95 (m, 2H) 7.45-7.57 (m, 2H) 7.57-7.68 (m, 1H) 7.90-8.01 (m, 2H) 8.11 (s, 1H) 8.28 (s, 1H)
MS ES+: 374
A solution of 7-(benzenesulfonyl)-4-(cyclohex-1-en-1-yl)-2-ethyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 41; 36 mg, 94 μmol) in EtOH (30 mL) was passed through a hydrogen generating flow reactor fitted with a to % palladium on carbon catalyst cartridge at ambient temperature and pressure. The reaction mixture was concentrated in vacuo to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.43 (m, 6H) 1.52-1.84 (m, 7H) 2.77 (q, J=8 Hz, 2H) 2.83-2.94 (m, 1H) 6.81 (br. s., 2H) 7.49-7.61 (m, 3H) 8.11 (d, J=7 Hz, 2H) 11.21 (hr. s., 1H).
MS ES+: 385
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 3-methylmorpholine (CAS 42185-06-8; 262 mg, 2.59 mmol) in anhydrous DMF (8 mL) and the reaction mixture was heated under microwave irradiation at 190° C. for 6 h. The crude product was purified by column chromatography (C-18 silica, 5-50% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.21 (m, 3H) 3.34-3.44 (m, 1H) 3.46-3.60 (m, 2H) 3.63-3.74 (m, 2H) 3.83-3.97 (m, 2H) 6.49 (br. s., 2H) 7.47-7.64 (m, 3H) 8.03 (d, J=7 Hz, 2H) 8.15 (s, 1H).
MS ES+: 374
To a solution of cyclopropylmethanol (CAS 2516-33-8; 105 μL, 1.30 mmol) in anhydrous THF (4 mL) was added sodium hydride (54 mg, 1.36 mmol, 60% dispersion in oil) and stirred at rt for 20 min. To the reaction mixture was added 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and the reaction mixture was heated under microwave irradiation at 100° C. for 2 h. The reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography (C18-silica, 5-50% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.29-0.43 (m, 2H) 0.50-0.64 (m, 2H) 1.20-1.37 (m, 1H) 4.26 (d, J=7 Hz, 2H) 6.63 (s, 2H) 7.46-7.65 (m, 3H) 7.98-8.08 (m, 2H) 8.26 (s, 1H) 11.61 (s, 1H).
MS ES+: 345
Prepared as described for 7-(benzenesulfonyl)-4-(piperidin-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 7) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 2,2-dimethylpyrrolidine hydrochloride (CAS 623580-01-8; 264 mg, 1.94 mmol) in EtOH (3 mL). The reaction mixture was heated under microwave irradiation at 120° C. for 2 h. Further portions of 2,2-dimethylpyrrolidine hydrochloride (CAS 623580-01-8; 264 mg, 1.94 mmol) and triethylamine (451 μL, 3.24 mmol) were added and the reaction mixture was heated at 130° C. for 48 h. The crude product was purified by column chromatography (basic silica, 0-100% EtOAc/petroleum ether). The crude product was further purified by column chromatography (C18-silica, 25-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 6H) 1.77-1.85 (m, 2H) 1.89-1.99 (m, 2H) 3.73-3.87 (m, 2H) 6.29 (br. s., 2H) 7.48-7.59 (m, 3H) 7.98-8.05 (m, 3H) 10.23-10.41 (m, 1H).
MS ES+: 372
Prepared as described for 7-(benzenesulfonyl)-4-[(E)-2-cyclopropylethenyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 11) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and (3-methylphenyl)boronic acid (CAS 17933-03-8; 132 mg, 972 μmol) in dioxane (4 mL) and water (1 mL). The reaction mixture was heated under microwave irradiation at 140° C. for 1.25 h. The exception that the aqueous phase was neutralised with 2 M aq. HCl solution and the precipitate was filtered. The residue was recrystallised from hot EtOH and water to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.41 (s, 3H) 6.89 (s, 2H) 7.30-7.37 (m, 1H) 7.42-7.50 (m, 1H) 7.53-7.74 (m, 5H) 8.04-8.11 (m, 2H) 8.67 (s, 1H) 11.20 (br. s., 1H).
MS ES+: 365
Prepared as described for 7-(benzenesulfonyl)-4-(piperidin-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 7) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 3-methylpiperidine (CAS 626-56-2; 193 mg, 1.94 mmol) in EtOH (3 mL). The crude product was purified by column chromatography (basic silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.84-0.92 (m, 3H) 1.08-1.21 (m, 1H) 1.40-1.84 (m, 4H) 2.55-2.65 (m, 1H) 2.87-2.98 (m, 1H) 4.09-4.41 (m, 2H) 6.33 (br. s., 2H) 7.49-7.58 (m, 3H) 7.97-8.05 (m, 2H) 8.11 (s, 1H) 10.73 (br. s., 1H).
MS ES+: 372
Prepared as described for 7-(benzenesulfonyl)-4-(piperidin-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 7) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 4-methylpiperidine (CAS 626-58-4; 193 mg, 1.94 mmol) in EtOH (3 mL). The crude product was purified by column chromatography (basic silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (d, J=6 Hz, 3H) 1.04-1.19 (m, 2H) 1.56-1.73 (m, 3H) 2.87-2.99 (m, 2H) 3.93-4.52 (m, 2H) 6.38 (br. s., 2H) 7.49-7.58 (m, 3H) 7.98-8.05 (m, 2H) 8.11 (s, 1H) 10.43-10.90 (m, 1H)
MS ES+: 372
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 4-(cyclohex-1-en-1-yl)-7-[(3,4-difluorobenzene)sulfonyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 49; 225 mg, 576 μmol) in EtOH (30 mL) and stirred at rt for 40 h. The crude product was purified by column chromatography (basic silica, 10-60% EtOAc/petroleum ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.45 (m, 3H) 1.51-1.67 (m, 2H) 1.67-1.76 (m, 3H) 1.76-1.85 (m, 2H) 2.89-3.01 (m, 1H) 6.99 (s, 2H) 7.59-7.71 (m, 1H) 7.89-7.98 (m, 1H) 8.08-8.18 (m, 1H) 8.55 (s, 1H) 11.46 (s, 1H).
MS ES+: 393
To a stirred and nitrogen degassed solution of 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 110 mg, 525 μmol), 2-(oxane-4-sulfonyl)acetonitrile (Intermediate 18; 149 mg, 787 μmol), tetrakis(triphenylphosphane) palladium (15 mg, 13 μmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (9 mg, 13 μmol) in anhydrous dioxane (3 mL) was added sodiobis(trimethylsilyl)amine [1 M in THF] (1.05 mL, 1.05 mmol) at 0° C. The mixture was heated at 110° C. for 3 h. The reaction mixture was poured in water, neutralised with 0.5 M aq. HCl solution and extracted with DCM. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (C18-silica, 25-50% acetonitrile/water (with 0.1% formic acid)). The residue was triturated with MeOH/diethyl ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.92-1.21 (m, 1H) 1.31-2.03 (m, 6H) 2.14-2.39 (m, 2H) 3.12-3.63 (m, 6H) 3.75-4.07 (m, 2H) 6.10-6.91 (m, 3H) 8.53 (br. s., 1H) 10.60-11.28 (m, 1H).
MS ES+: 363
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and ethyl(furan-2-ylmethyl)amine (CAS 14496-33-4; 324 mg, 2.59 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 180° C. for 3 h. The crude product was purified by column chromatography (C-18 silica, 5-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H-NMR (400 MHz, DMSO-d6) δ ppm 1.06 (t, J=7 Hz, 3H) 3.47-3.65 (m, 2H) 4.79 (s, 2H) 6.29-6.42 (m, 2H) 6.42-6.54 (m, 2H) 7.46-7.67 (m, 4H) 8.04 (d, J=7 Hz, 2H) 8.13 (s, 1H) 10.35 (br. s., 1H)
MS ES+: 398
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and (cyclopropylmethyl)(oxolan-2-ylmethyl)amine (CAS 356539-57-6; 402 mg, 2.59 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 180° C. for 3 h. The crude product was purified by column chromatography (C-18 silica, 5-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.18-0.30 (m, 2H) 0.38-0.50 (m, 2H) 0.97-1.12 (m, 1H) 1.44-1.65 (m, 1H) 1.72-1.99 (m, 3H) 3.39-3.52 (m, 1H) 3.52-3.67 (m, 3H) 3.70-3.84 (m, 2H) 3.94-4.05 (m, 1H) 6.63 (br. s., 2H) 7.44-7.68 (m, 3H) 7.93-8.07 (m, 2H) 8.09 (br. s., 1H) 10.28 (br. s., 1H)
MS ES+: 428
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and ethyl[(1-methyl-1H-pyrazol-4-yl)methyl]amine (CAS 949095-17-4; 361 mg, 2.59 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 180° C. for 3 h. The crude product was purified by column chromatography (C-18 silica, 5-50% acetonitrile/water (with 0.1% ammonia)) to afford Example 64. Further purification by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) afforded Example 65.
1H NMR (300 MHz, DICHLOROMETHANE-d2) δ ppm 1.25 (t, J=7 Hz, 3H) 3.46 (s, 3H) 3.78-3.95 (m, 4H) 4.98 (br. s., 2H) 7.33-7.46 (m, 2H) 7.46-7.66 (m, 3H) 7.94-8.02 (m, 2H) 8.10 (s, 1H).
MS ES+: 412
1H NMR (300 MHz, Methanol-d4) δ ppm 1.28 (t, J=7 Hz, 3H) 3.50 (m, 2H) 7.43-7.61 (m, 3H) 8.01-8.15 (m, 3H).
MS ES+: 318
Prepared as described for 7-(benzenesulfonyl)-4-[(E)-2-cyclopropylethenyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 11) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and (pyridin-4-yl)boronic acid (CAS 1692-15-5; 318 mg, 2.59 mmol) in dioxane (8 mL) and water (2 mL) and the reaction mixture was heated under microwave irradiation at 150° C. for 1.5 h. The crude product was triturated with EtOAc/water and filtered to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 7.03 (s, 2H) 7.54-7.66 (m, 3H) 7.86 (d, J=5 Hz, 2H) 8.09 (d, J=8 Hz, 2H) 8.74 (s, 1H) 8.78 (d, J=6 Hz, 2H) 11.45 (s, 1H).
MS ES+: 352
Prepared as described for 7-(benzenesulfonyl)-4-[(E)-2-cyclopropylethenyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 11) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and (pyridin-3-yl)boronic acid (CAS 1692-25-7; 318 mg, 2.59 mmol) in dioxane (8 mL) and water (2 mL) and the reaction mixture was heated under microwave irradiation at 150° C. for 1.5 h. The crude product was triturated with EtOAc/water and filtered to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 6.96 (br. s., 2H) 7.51-7.66 (m, 4H) 8.09 (d, J=8 Hz, 2H) 8.29 (d, J=7 Hz, 1H) 8.67-8.76 (m, 2H) 9.08 (hr. s., 1H) 11.48 (br. s., 1H)
To a stirred solution of 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 19; 99 mg, 292 μmol), 4,4-difluoropiperidine hydrochloride (CAS 144260-52-4; 273 mg, 1.73 mmol) and triethylamine (244 μL, 1.750 mmol) in anhydrous NMP (0.5 mL) was heated under microwave irradiation at 120° C. for 1.5 h. The reaction mixture poured into 10% aq. citric acid solution and extracted with EtOAc. The combined organic fractions were washed with water/brine (1:1) and concentrated in vacuo. The crude product was purified by column chromatography (basic silica, 10-70% EtOAc/petroleum ether). Further purification by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% formic acid)) afforded the title compound.
1H NMR (400 MHz, Methanol-d4) δ ppm 2.01-2.15 (m, 4H) 3.76-3.89 (m, 7H) 7.02 (d, J=9 Hz, 2H) 8.01 (d, J=9 Hz, 2H) 8.21 (s, 1H).
MS ES+: 424
Prepared as described for 7-(benzenesulfonyl)-4-(piperidin-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 7) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 2-methylpiperidine (GAS 109-05-7; 193 mg, 1.94 mmol) in EtOH (3 mL). The reaction mixture was heated under microwave irradiation at 120° C. for 2 h. Additional portions of 2-methylpiperidine (CAS 109-05-7; 193 mg, 1.94 mmol) and triethylamine (451 μL, 3.24 mmol) were added and the reaction mixture was heated at 140° C. for 24 h. The crude product was purified by column chromatography (preparative HPLC, 100-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=7 Hz, 3H) 1.37-1.76 (m, 6H) 2.99-3.15 (m, 1H) 3.67-4.26 (m, 1H) 4.30-4.77 (m, 1H) 6.40 (br. s., 2H) 7.50-7.60 (m, 3H) 8.01 (d, J=7 Hz, 2H) 8.11 (br. s., 1H) 10.54 (br. s., 1H).
MS ES+: 372
Prepared as described for 7-(benzenesulfonyl)-4-(piperidin-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 7) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and cyclopropylmethanamine (CAS 2516-47-4; 138 mg, 1.94 mmol) in EtOH (3 mL) The reaction mixture was heated under microwave irradiation at 120° C. for 1 h. Additional portions of cyclopropylmethanamine (CAS 2516-47-4; 138 mg, 1.94 mmol) and triethylamine (451 μL, 3.24 mmol) were added and the reaction mixture was heated under microwave irradiation at 140° C. for 1.5 h. The crude product was purified by column chromatography (basic silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 0.16-0.25 (m, 2H) 0.39-0.49 (m, 2H) 0.94-1.10 (m, 1H) 3.21-3.29 (m, 2H) 6.83 (t, J=5 Hz, 1H) 6.94 (s, 2H) 7.47-7.60 (m, 3H) 7.96-8.09 (m, 3H) 10.52 (br. s., 1H).
MS ES+: 344
To a stirred and nitrogen degassed solution of 4-chloro-7-(4-methoxybenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 19; 140 mg, 413 μmol), potassium trifluoro(prop-1-en-2-yl)boranuide (CAS 395083-14-4; 122 mg, 827 μmol) and caesium carbonate (404 mg, 1.24 mmol) in dioxane (4 mL) and water (1 mL) was added di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium (29 mg, 41 μmol) and the reaction mixture was heated under microwave irradiation at 110° C. for 2 h. The reaction mixture was concentrated in vacuo, partitioned between MTBE and 0.2 M aq. NaOH solution. The organic phase was extracted with 0.2 M aq. NaOH solution. The combined aqueous phases were washed with MTBE and acidified with sat. citric acid solution. The organics were extracted with EtOAc/2-methyltetrahydrofuran (2:1), washed with water/brine (1:1), dried (H frit) and concentrated in vacuo. The crude product was purified by column chromatography (basic silica, 10-75% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (s, 3H) 3.80 (s, 3H) 5.60-5.60 (m, 2H) 6.80 (s, 2H) 7.07 (d, J=9 Hz, 2H) 7.98 (d, J=9 Hz, 2H) 8.57 (s, 1H) 10.92 (s, 1H).
MS ES+: 345
To a stirred solution of 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 19; 127 mg, 375 μmol), 6-azaspiro[2.5]octane (CAS 872-64-0; 83 mg, 750 μmol) and triethylamine (105 μL, 750 μmol) in anhydrous NMP (0.5 mL) was heated under microwave irradiation at 120° C. for 3 h. The reaction mixture poured into 10% aq. citric acid solution and extracted with EtOAc. The combined organic fractions were washed with water/brine (1:1) and concentrated in vacuo. The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.35 (s, 4H) 1.32-1.46 (m, 4H) 3.60 (m, 4H) 3.79 (s, 3H) 6.41 (br. s., 2H) 7.06 (d, J=9 Hz, 2H) 7.95 (d, J=9 Hz, 2H) 8.13 (br. s., 1H) 10.64 (br. s, 1H).
MS ES+: 414
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 4-(cyclopent-1-en-1-yl)-7-[(4-methoxybenzene)sulfonyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 20; 120 mg, 324 μmol) in EtOH (10 mL) and stirred at rt for 20 h. The crude product was purified by column chromatography (basic silica, 10-90% EtOAc/petroleum ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.56-1.70 (m, 2H) 1.70-1.86 (m, 4H) 1.86-1.99 (m, 2H) 3.35-3.45 (m, 1H) 3.79 (s, 3H) 6.89 (s, 2H) 7.06 (d, J=9 Hz, 2H) 7.98 (d, J=9 Hz, 2H) 8.51 (s, 1H) 11.36 (br. s., 1H).
MS ES+: 373
Prepared as described for 4-(4,4-difluoropiperidin-1-yl)-7-(4-methoxybenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 68) from 4-chloro-7-(2-fluorobenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 21; 75 mg, 230 μmol) and 4,4-difluoropiperidine hydrochloride (CAS 144260-52-4; 253 mg, 1.61 mmol) in anhydrous NMP (0.5 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 1.5 h. The crude product was purified by column chromatography (silica, 10-100% EtOAc/petroleum ether). The crude product was further purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.96-2.14 (m, 4H) 3.50-4.00 (m, 4H), 6.55 (br. s, 2H), 7.26-7.36 (m, 1H) 7.40 (t, J=8 Hz, 1H) 7.58-7.69 (m, 1H) 7.99-8.07 (m, 1H) 8.08 (s, 1H), 11.02 (br. s, 1H).
MS ES+: 412
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 350 mg, 1.13 mmol) and (2R,6S)-2,6-dimethylmorpholine (CAS 6485-55-8; 522 mg, 4.53 mmol) in EtOH (10 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 1 h. The crude product was triturated with EtOAc/water and filtered to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 6H) 2.55-2.65 (m, 2H) 3.57-3.74 (m, 2H) 3.86-4.29 (m, 2H) 6.46 (br. s., 2H) 7.49-7.61 (m, 3H) 7.96-8.11 (m, 2H) 8.16 (s, 1H).
MS ES+: 388
Prepared as described for 7-(4-methoxybenzenesulfonyl)-4-(prop-1-en-2-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 71) from 4-chloro-7-(4-methoxybenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 19; 180 g, 531 μmol) and phenylboronic acid (CAS 98-80-6; 130 mg, 1.06 mmol) in dioxane (4 mL) and water (1 mL) and the reaction mixture was heated under microwave irradiation at 110° C. for 1 h. The crude product was purified by column chromatography (basic silica, 20-80% EtOAc/petroleum ether). The crude product was further purified by column chromatography (C18-silica, 5-95% MeOH/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 3.80 (s, 3H) 6.84 (s, 2H) 7.05-7.12 (m, 2H) 7.50-7.62 (m, 3H) 7.85-7.92 (m, 2H) 7.99-8.04 (m, 2H) 8.68 (s, 1H) 11.20 (s, 1H).
MS ES+: 381
To a stirred and nitrogen degassed solution of 3,5-dibromopyridin-4-amine (CAS 84539-34-4; 2.5 g, 9.92 mmol), tetrakis(triphenylphosphane) palladium (287 mg, 248 μmol) in anhydrous DME (20 mL) was added a solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-25-9; 1.98 g, 10.92 mmol) and sodium hydride (992 mg, 24.81 mmol, 60% dispersion in oil) in anhydrous DME (12 mL). The reaction mixture was heated under microwave irradiation at 130° C. for 2 h. The reaction mixture was poured into water and extracted with EtOAc. The combined organics were filtered and dried (MgSO4), filtered and concentrated in vacuo. 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 6.65 (br. s., 2H) 7.40-7.64 (m, 3H) 7.91-7.98 (m, 2H) 8.18 (s, 1H) 8.54 (br. s., 1H) 11.57 (s, 1H).
MS ES+: 354
Prepared as described for 4-(cyclohex-1-en-1-yl)-7-(oxane-4-sulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 61) from 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 240 mg, 1.15 mmol) and 2-(oxolane-3-sulfonyl)acetonitrile (Intermediate 22; 201 mg, 1.15 mmol) in dioxane (7 mL) and heated at reflux for 16 h. The crude product was purified by column chromatography (C-18 silica, 5-95% acetonitrile/water (with 0.1% ammonia)). Further purification by column chromatography (silica, 0-10% MeOH/DCM) afforded the title compound.
1H NMR (400 MHz, Methanol-d4) δ ppm 1.65-1.94 (m, 4H) 2.11-2.28 (m, 1H) 2.28-2.61 (m, 5H) 3.60-4.005 (m, 3H) 4.06-4.44 (m, 2H) 6.43 (br. s., 1H) 8.53 (s, 1H).
MS ES+: 348
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 2-ethylmorpholine (CAS 52769-10-5; 298 mg, 2.59 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 1 h. The crude product was triturated with EtOAc/water and filtered to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7 Hz, 3H) 1.40-1.57 (m, 2H) 2.63-2.89 (m, 2H) 2.99-3.18 (m, 1H) 3.33-3.45 (m, 1H) 3.49-3.71 (m, 1H) 3.83-3.99 (m, 1H) 3.99-4.14 (m, 1H) 6.51 (br. s., 2H) 7.48-7.64 (m, 3H) 8.02 (d, J=7 Hz, 2H) 8.17 (br. s., 1H).
MS ES+: 388
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 2-cyclopropylmorpholine (CAS 1063734-79-1; 330 mg, 2.59 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 1 h. The crude product was triturated with EtOAc/water and filtered to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.22-0.38 (m, 2H) 0.40-0.56 (m, 2H) 0.74-0.94 (m, 2H) 2.79-2.94 (m, 2H) 2.98-3.16 (m, 1H) 3.41-3.62 (m, 1H) 3.83-3.97 (m, 1H) 4.07-4.24 (m, 1H) 6.52 (br. s., 2H) 7.46-7.65 (m, 3H) 8.02 (d, J=7 Hz, 2H) 8.17 (br. s., 1H)
MS ES+: 400
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 2-(methoxymethyl)morpholine (CAS 141196-39-6; 340 mg, 2.59 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 1 h. The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.74-2.88 (m, 1H) 3.01-3.14 (m, 1H) 3.28 (s, 3H) 3.34-3.48 (m, 2H) 3.54-3.72 (m, 2H) 3.83-3.96 (m, 2H) 3.98-4.12 (m, 1H) 6.53 (br. s., 2H) 7.46-7.63 (m, 3H) 8.02 (d, J=7 Hz, 2H) 8.18 (br. s., 1H) 10.84 (br. s., 1H)
MS ES+: 404
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 1,4-oxazepane hydrochloride (CAS 178312-62-4; 357 mg, 2.59 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 1 h. The crude product was purified by column chromatography (C18-silica HPLC, 5-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.78-1.97 (m, 2H) 3.54-3.65 (m, 2H) 3.65-3.75 (m, 2H) 3.77-4.03 (m, 4H) 6.37 (br. s., 2H) 7.46-7.66 (m, 3H) 7.97-8.12 (m, 3H) 10.41 (br. s., 1H)
MS ES+: 374
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and (cyclohexylmethyl)(ethyl)amine (CAS 14002-08-5; 460 mg, 2.59 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 1 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 (300 MHz, DMSO-d6) δ ppm 0.81-1.01 (m, 2H) 1.06-1.20 (m, 6H) 1.51-1.80 (m, 6H) 3.39-3.54 (m, 2H) 3.56-3.72 (m, 2H) 6.18-6.51 (m, 2H) 7.45-7.64 (m, 3H) 7.98-8.13 (m, 3H).
MS ES+: 414
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 350 mg, 1.13 mmol) and 2,2-dimethylmorpholine (CAS 147688-58-2; 522 mg, 4.53 mmol) in EtOH (10 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 1 h. The crude product was triturated with EtOAc/water and filtered to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (s, 6H) 3.35-3.47 (m, 2H) 3.47-3.60 (m, 2H) 3.65-3.79 (m, 2H) 6.23-6.79 (m, 2H) 7.45-7.69 (m, 3H) 8.02 (d, J=7 Hz, 2H) 8.15 (hr. s., 1H) 10.66 (br. s., 1H).
MS ES+: 388
Prepared as described 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and 2,5-dimethylmorpholine (CAS 106-56-9; 373 mg, 3.24 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 3 h. The crude product was triturated with EtOAc/water and filtered. The crude product was purified by column chromatography (C18-silica HPLC, 5-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.23 (m, 6H) 2.85-3.02 (m, 1H) 3.26-3.35 (m, 1H) 3.50-3.64 (m, 1H) 3.64-3.78 (m, 2H) 3.83-4.00 (m, 1H) 6.48 (br. s., 2H) 7.48-7.65 (m, 3H) 7.97-8.08 (m, 2H) 8.14 (br. s., 1H) 10.37-10.84 (m, 1H)
MS ES+: 388
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and (2S)-2-methylmorpholine hydrochloride (CAS 1147108-99-3; 446 mg, 3.24 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 3 h. The crude product was triturated with EtOAc/water to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.59-2.77 (m, 1H) 2.95-3.14 (m, 1H) 3.48-3.64 (m, 2H) 3.81-3.95 (m, 2H) 3.95-4.11 (m, 1H) 6.51 (br. s., 2H) 7.47-7.68 (m, 3H) 8.02 (d, J=7 Hz, 2H) 8.17 (br. s., 1H) 10.83 (br. s., 1H).
MS ES+: 374
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and (2R,6R)-2,6-dimethylmorpholine (CAS 171753-74-5; 373 mg, 3.24 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 3 h. The crude product was triturated with EtOAc/water to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (d, J=6 Hz, 6H) 3.24-3.52 (m, 2H) 3.59-3.88 (m, 2H) 3.98-4.13 (m, 2H) 6.40 (br. s., 2H) 7.44-7.64 (m, 3H) 8.03 (d, J=7 Hz, 2H) 8.13 (hr. s., 1H) 10.25-10.81 (m, 1H).
MS ES+: 388
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 4-(cyclopent-1-en-1-yl)-7-(2-fluorobenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 23; 103 mg, 277 μmol) in EtOH (10 mL) and stirred at rt for 30 h. The crude product was purified by column chromatography (basic silica, 0-70% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, METHANOL-d4) δ ppm 1.67-1.82 (m 2H) 1.82-1.98 (m, 4H) 1.98-2.13 (m, 2H) 3.35-3.45 (m, 1H) 7.14-7.24 (m, 1H) 7.33-7.41 (m, 1H) 7.56-7.65 (m, 1H) 8.16-8.26 (m, 1H) 8.43 (s, 1H).
MS ES+: 361
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 4-(cyclohex-1-en-1-yl)-7-[(2-fluorobenzene)sulfonyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 38; 99 mg, 276 μmol) in EtOH (10 mL) and stirred at rt for 30 h. The crude product was purified by column chromatography (basic silica, 0-70% EtOAc/petroleum ether). The residue was triturated with DCM to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.31 (m, 1H) 1.31-1.46 (m, 2H) 1.50-1.66 (m, 2H) 1.66-1.76 (m, 3H) 1.76-1.85 (m, 2H) 2.91-3.02 (m, 1H) 6.95 (s, 2H) 7.26-7.37 (m, 1H) 7.38-7.45 (m, 1H) 7.59-7.71 (m, 1H) 8.02-8.10 (m, 1H) 8.42 (s, 1H) 11.50 (br. s., 1H).
MS ES+: 375
To a stirred mixture of 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 50 mg, 162 μmol) and [(3-chlorophenyl)methyl](methyl)amine (CAS 39191-07-6; 10 mg, 648 μmol) in EtOH (2 mL) was added triethylamine (45 μL, 324 μmol). The reaction was heated under microwave irradiation at 160° C. for 1 h, cooled to room temperature and concentrated in vacuo. The resulting residue was partitioned between DCM and water and extracted with DCM followed by EtOAc. The combined organic layers were dried (H-frit) and concentrated in vacuo. Purification by column chromatography (preparative HPLC, 20-60% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 3.27-3.40 (m, 3H) 4.84 (br. s, 2H) 6.42 (br. s., 2H) 7.13-7.25 (m, 1H) 7.25-7.39 (m, 3H) 7.46-7.63 (m, 3H) 7.98-8.07 (m, 2H) 8.07-8.19 (m, 1H) 10.55 (br. s., 1H)
MS ES+: 428
1H NMR (300 MHz, DMSO-d6) δ ppm 1.08- 1.32 (m, 1 H) 1.32-1.49 (m, 2 H) 1.49-1.65 (m, 2 H) 1.65-1.84 (m, 1 H) 3.28-3.38 (m, 4 H) 3.44- 3.70 (m, 3 H) 3.80-3.98 (m, 1 H) 6.51 (br. s., 2 H) 7.45-7.66 (m, 3 H) 7.95- 8.13 (m, 3 H) 10.36 (br. s., 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 3.20 (br. 8., 3 H) 3.77 (s, 3 H) 4.76 (br. s., 2 H) 6.42 (br. s., 2 H) 6.76-6.90 (m, 1 H) 6.93-7.05 (m, 2 H) 7.14-7.27 (m, 1H) 7.45- 7.66 (m, 3 H) 7.95-8.14 (m, 3 H) 10.51 (br. s., 1H)
1H NMR (300 MHz, DMSO-d6) δ ppm 3.28 (br. s., 3 H) 3.67-3.81 (m, 4 H) 3.87-4.00 (m, 2 H) 4.89-5.10 (m, 1 H) 6.46 (br. s., 2 H) 7.45-7.62 (m, 3 H) 7.96-8.14 (m, 3 H) 10.35-10.57 (m, 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 1.00- 1.23 (m, 6 H) 3.43-3.75 (m, 4 H) 6.41 (br. s., 2 H) 7.42-7.68 (m, 3 H) 7.91- 8.19 (m, 3 H) 10.18 (br. s., 1H)
1H NMR (300 MHz, DMSO-d6) δ ppm 3.25 (br. s., 3 H) 4.86 (br. s., 2 H) 6.56 (br. s., 2 H) 7.17- 7.36 (m, 2 H) 7.48-7.63 (m, 3 H) 7.68-7.81 (m, 1 H) 7.94-8.17 (m, 3 H) 8.55 (br. s., 1 H) 11.07 (br. s., 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 3.34 (br. s., 3 H) 3.89-4.21 (m, 2 H) 6.12-6.26 (m, 1 H) 6.43 (br. s., 2 H) 7.43- 7.66 (m, 3 H) 8.02 (d, J = 7 Hz, 2 H) 8.09-8.19 (m, 1 H) 10.61 (br. s., 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 0.98- 1.19 (m, 3 H) 3.19 (br. s., 3 H) 3.51-3.78 (m, 2 H) 6.24-6.42 (m, 2 H) 7.43- 7.65 (m, 3 H) 7.94-8.15 (m, 3 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 0.62- 0.77 (m, 2 H) 0.90-1.02 (m, 2 H) 3.01-3.18 (m, 4 H) 6.54 (br. s., 2 H) 7.45- 7.61 (m, 3 H) 7.96-8.16 (m, 3 H) 10.14 (br. s., 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 2.32 (s, 3 H) 3.23 (br. s., 3 H) 4.83 (br. s., 2 H) 6.05 (s, 1 H) 6.41 (br. s., 2 H) 7.45- 7.67 (m, 3 H) 8.03 (d, J = 7 Hz, 2 H) 8.10-8.20 (m, 1 H) 10.60 (br. s., 1 H)
A solution of 3-(benzenesulfonyl)-1-[(4-methoxyphenyl)methyl]-7-(prop-1-en-2-yl)-1H-pyrrolo[3,2-c]pyridin-2-amine (Intermediate 26; 58 mg, 134 μmol) in trifluoroacetic acid (1 mL) was heated at 90° C. for 12 h. The reaction mixture was concentrated in vacuo. The reaction mixture was partitioned between sat. aq. NaHCO3 solution and DCM. The organics were concentrated in vacuo. The crude product was purified by column chromatography (C18-silica, 5-95% MeOH/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.15 (s, 3H) 5.31-5.55 (m, 2H) 6.50 (s, 2H) 7.48-7.62 (m, 3H) 7.92-7.97 (m, 2H) 7.99 (br. s., 1H) 8.44 (br. s., 1H).
MS ES+: 314
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and 2-(2-methylpropyl)morpholine (CAS 927801-14-7; 348 mg, 2.43 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 3 h. The crude product was triturated with EtOAc/water to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.81-0.95 (m, 6H) 1.13-1.33 (m, 1H) 1.33-1.49 (m, 1H) 1.68-1.90 (m, 1H) 2.60-2.81 (m, 1H) 2.93-3.16 (m, 1H) 3.41-3.63 (m, 2H) 3.81-3.94 (m, 2H) 3.94-4.12 (m, 1H) 6.47 (br. s., 2H) 7.45-7.67 (m, 3H) 7.93-8.11 (m, 2H) 8.16 (br. s., 1H) 10.80 (br. s., 1H)
MS ES+: 416
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 1.00 g, 3.24 mmol) and 6-oxa-9-azaspiro[4.5]decane (CAS 130643-07-1; 686 mg, 4.86 mmol) in EtOH (16 mL) and the reaction mixture was heated under microwave irradiation at 150° C. for 2.5 h. The crude product was triturated with water, recrystallised from MeOH/water, de-colourised with charcoal, hot-filtered, washed with ice-cold MeOH and dried (desiccator at 75° C.) to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.47-1.75 (m, 8H) 3.65-3.87 (m, 6H) 7.57-7.74 (m, 3H) 8.12 (d, J=7 Hz, 2H) 8.37 (s, 1H).
MS ES+: 414
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and 2,2-diethylmorpholine (CAS 167947-91-3; 348 mg, 2.43 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 3 h. The crude product was triturated with EtOAc/water to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 0.68-0.87 (m, 6H) 1.32-1.49 (m, 2H) 1.49-1.70 (m, 2H) 3.38-3.63 (m, 3H) 3.63-3.82 (m, 3H) 6.49 (br. s., 2H) 7.46-7.64 (m, 3H) 8.02 (d, J=6 Hz, 2H) 8.13 (br. s., 1H) 10.67 (br. s., 1H)
MS ES+: 416
Prepared as described for 7-(benzenesulfonyl)-4-[(E)-2-cyclopropylethenyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 11) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and (4-methylphenyl)boronic acid (CAS 5720-05-8; 132 mg, 972 μmol) in dioxane (4 mL) and water (1 mL) and the reaction mixture was heated under microwave irradiation at 140° C. for 1.25 h. After this time an additional portion of di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (32 mg, 23 μmol) was added and the reaction mixture was heated under microwave irradiation at 140° C. for 2 h. The crude product was purified by column chromatography (C18-silica, 10-40% MeOH/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (s, 3H) 6.86 (s, 2H) 7.38 (d, J=8 Hz, 2H) 7.52-7.64 (m, 3H) 7.80 (d, J=8 Hz, 2H) 8.03-8.12 (m, 2H) 8.66 (s, 1H) 11.19 (br. s., 1H).
MS ES+: 365
To a stirred solution of 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and triethylamine (328 mg, 3.24 mmol) was added 3-methoxypiperidine (CAS 4045-29-8; 224 mg, 1.94 mmol) in EtOH (3 mL) and the reaction mixture was heated under microwave irradiation at 150° C. for 1 h. The reaction mixture was poured in water and neutralised with 2 M aq. HCl solution and extracted with EtOAc. The combined organic phases were washed with brine, dried (H frit) and concentrated in vacuo. The crude product was purified by column chromatography (basic silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.60 (m, 2H) 1.65-1.84 (m, 1H) 1.89-2.02 (m, 1H) 3.27-3.52 (m, 6H) 3.62-4.26 (m, 2H) 6.40 (br. s., 2H) 7.47-7.62 (m, 3H) 8.02 (d, J=7 Hz, 2H) 8.12 (s, 1H) 10.39-11.005 (m, 1H).
MS ES+: 388
To a stirred solution of 4-chloro-7-(4-methoxybenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 19; 200 mg, 590 μmol) and triethylamine (247 μL, 1.77 mmol) was added 3-methylpiperidine (CAS 626-56-2; 176 mg, 1.77 mmol) in EtOH (4 mL) and the reaction mixture was heated at 140° C. for 16 h. The reaction mixture was poured in dilute aq. citric acid solution and extracted with EtOAc. The combined organic phases were washed with brine, dried (H frit) and concentrated in vacuo. The crude product was purified by column chromatography (basic silica, 0-10% MeOH/DCM) to afford the title compound. The aqueous was neutralised with sat. aq. NaHCO3 solution and extracted with EtOAc. The combined organic phases were washed with water and brine, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (basic silica, 50-100% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (d, J=7 Hz, 3H) 1.08-1.22 (m, 1H) 1.41-1.73 (m, 3H) 1.73-1.84 (m, 1H) 2.54-2.64 (m, 1H) 2.86-2.99 (m, 1H) 3.79 (s, 3H) 3.98-4.16 (m, 2H) 6.42 (br. s., 2H) 7.05 (d, J=9 Hz, 2H) 7.96 (d, J=9 Hz, 2H) 8.13 (br. s., 1H) 10.61 (br. s., 1H).
MS ES+: 402
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(4-methoxybenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 19; 200 mg, 590 μmol) and 2-methylmorpholine (CAS 27550-90-9; 179 mg, 1.77 mmol) in EtOH (8 mL) and heated at 140° C. for 16 h. The crude product was purified by column chromatography (basic silica, 65-100% EtOAc/petroleum ether) to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.60-2.75 (m, 1H) 2.94-3.09 (m, 1H) 3.50-3.68 (m, 2H) 3.79 (s, 3H) 3.83-4.09 (m, 3H) 6.47 (br. s., 2H) 7.06 (d, J=9 Hz, 2H) 7.95 (d, J=9 Hz, 2H) 8.17 (br. s., 1H) 10.79 (br. s., 1H).
MS ES+: 404
Prepared as described for 7-(benzenesulfonyl)-4-[(E)-2-cyclopropylethenyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 11) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and (2-methylphenyl)boronic acid (CAS 16419-60-6; 132 mg, 972 μmol) in dioxane (4 mL) and water (1 mL) and the reaction mixture was heated under microwave irradiation at 140° C. for 4 h. After this time and additional portion of di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (32 mg, 23 μmol) was added and the reaction mixture was heated under microwave irradiation at 140° C. for 2 h. The crude product was purified by column chromatography (preparative HPLC, 10-40% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.19 (s, 3H) 6.80 (s, 2H) 7.29-7.44 (m, 4H) 7.52-7.64 (m, 3H) 8.05-8.15 (m, 2H) 8.67 (s, 1H) 11.05 (br. s., 1H).
MS ES+: 365
Prepared as described for 4-(cyclohex-1-en-1-yl)-7-(oxane-4-sulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 61) from 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 193 g, 917 μmol) and 2-(oxan-4-ylmethanesulfonyl)acetonitrile (Intermediate 27; 280 mg, 1.34 mmol) in anhydrous dioxane (6 mL) and heated at reflux for 3 h. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM). Further purification by column chromatography (preparative HPLC, 5-40% acetonitrile/water (with 0.1% formic acid)) afforded the title compound.
1H NMR (400 MHz, Methanol-d4) δ ppm 1.31-1.54 (m, 2H) 1.67-1.94 (m, 6H) 2.12-2.28 (m, 1H) 2.29-2.42 (m, 2H) 2.46-2.60 (m, 2H) 3.32-3.45 (m, 4H) 3.78-3.95 (m, 2H) 6.33-6.52 (m, 1H) 8.50 (s, 1H).
MS ES+: 377
To a stirred solution of 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 200 mg, 620 μmol) and triethylamine (173 μL, 1.24 mmol) was added 3-methylpiperidine (CAS 626-56-2; 218 μL, 1.86 mmol) in EtOH (6 mL) and the reaction mixture was heated under microwave irradiation at 150° C. for 1 h. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (preparative HPLC, 30-70% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (d, J=7 Hz, 3H) 1.06-1.28 (m, 1H) 1.37-1.96 (m, 4H) 2.31-2.46 (m, 3H) 2.54-2.73 (m, 1H) 2.83-3.04 (m, 1H) 4.12 (br. s., 2H) 6.27 (br. s., 2H) 7.34-7.68 (m, 3H) 7.80-8.24 (m, 2H) 10.46 (br. s., 1H).
MS ES+: 386
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 200 mg, 620 μmol) and 2-methylmorpholine (CAS 27550-90-9; 188 mg, 1.86 mmol) in EtOH (6 mL) and the reaction mixture was heated under microwave irradiation at 150° C. for 1 h. The crude product was purified by column chromatography (preparative HPLC, 20-60% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (d, J=7 Hz, 3H) 2.42 (br. s., 3H) 2.58-2.77 (m, 1H) 2.88-3.11 (m, 1H) 3.42-3.67 (m, 2H) 3.72-4.32 (m, 3H) 6.13-6.64 (m, 2H) 7.37-7.68 (m, 3H) 7.92-8.20 (m, 2H) 10.62 (br. s, 1H).
MS ES+: 388
To a stirred mixture of 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 50 mg, 162 μmol) and 4-(methoxymethyl)piperidine hydrochloride (CAS 916317-00-5; 107 mg, 648 μmol) in EtOH (2 mL) was added triethylamine (45 μL, 324 μmol). The reaction was heated under microwave irradiation at 160° C. for 1 h, cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in DMSO, filtered and purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.06-1.33 (m, 2H) 1.58-1.78 (m, 2H) 1.78-1.93 (m, 1H) 2.83-3.03 (m, 2H) 3.13-3.26 (m, 5H) 4.02-4.38 (m, 2H) 6.45 (br. s., 2H) 7.43-7.65 (m, 3H) 8.02 (d, J=6 Hz, 2H) 8.12 (br. s., 1H) 10.69 (br. s., 1H)
MS ES+: 402
1H NMR (300 MHz, DMSO-d6) δ ppm 0.91- 1.11 (m, 3 H) 1.34-1.59 (m, 2 H) 1.67-1.83 (m, 1 H) 1.87-2.03 (m, 1 H) 3.02-3.21 (m, 1 H) 3.21- 3.41 (m, 2 H) 3.41-3.62 (m, 2 H) 3.62-3.92 (m, 1 H) 3.92-4.32 (m, 1 H) 6.47 (br. s., 2 H) 7.44- 7.64 (m, 3 H) 8.02 (d, J = 6 Hz, 2 H) 8.12 (br. s., 1 H) 10.67 (br. s., 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 1.55- 1.74 (m, 1 H) 1.74-1.88 (m, 1 H) 2.04-2.21 (m, 2 H) 3.06-3.21 (m, 1 H) 3.35-3.52 (m, 1 H) 3.90- 4.19 (m, 1 H) 4.25-4.48 (m, 2 H) 6.24-6.32 (m, 1 H) 6.51 (br. s., 2 H) 7.43- 7.66 (m, 4 H) 7.82 (s, 1 H) 8.03 (d, J = 7 Hz, 2 H) 8.17 (s, 1 H) 10.76-10.99 (m, 1 H)
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and N-methyloxan-4-amine (CAS 220641-87-2; 280 mg, 2.43 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 3 h. The reaction mixture was concentrated in vacuo and purified by column chromatography (C18-silica, 5-50% acetonitrile/water (with 0.1% formic acid)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.60 (m, 2H) 1.69-1.90 (m, 2H) 3.08 (br. s., 3H) 3.36-3.46 (m, 2H) 3.81-4.02 (m, 2H) 4.62-4.91 (m, 1H) 6.40 (br. s., 2H) 7.44-7.62 (m, 3H) 8.01 (d, J=7 Hz, 2H) 8.09 (s, 1H) 10.46 (br. s., 1H)
MS ES+: 388
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and 4-(cyclopropylmethoxy)piperidine hydrochloride (CAS 1050509-48-2; 466 mg, 2.43 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 3 h. The crude product was triturated with EtOAc/water to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.05-0.23 (m, 2H) 0.36-0.61 (m, 2H) 0.91-1.01 (m, 1H) 1.001-1.11 (m, 1H) 1.37-1.52 (m, 2H) 1.76-1.95 (m, 2H) 3.17-3.29 (m, 3H) 3.48-3.68 (m, 1H) 3.76-4.05 (m, 2H) 6.42 (br. s., 2H) 7.46-7.65 (m, 3H) 8.01 (d, J=7 Hz, 2H) 8.12 (br. s., 1H) 10.69 (br. s., 1H)
MS ES+: 428
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and 3-methoxypyrrolidine hydrochloride (CAS 136725-50-3; 334 mg, 2.43 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 3 h. The crude product was triturated with EtOAc/water to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.90-2.14 (m, 2H) 3.26 (s, 3H) 3.53-3.66 (m, 2H) 3.66-3.78 (m, 2H) 3.98-4.16 (m, 1H) 6.35 (br. s., 2H) 7.45-7.62 (m, 3H) 7.94-8.11 (m, 3H) 10.50 (br. s., 1H)
MS ES+: 374
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and (2R)-2-(methoxymethyl)pyrrolidine (CAS 63126-47-6; 224 mg, 1.94 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 3 h. The crude product was triturated with EtOAc/water, and then triturated with hot EtOH to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.79-1.95 (m, 3H) 1.95-2.16 (m, 2H) 3.30 (s, 3H) 3.39-3.56 (m, 1H) 3.56-3.70 (m, 1H) 3.70-3.88 (m, 1H) 4.38-4.55 (m, 1H) 6.40 (br. s., 2H) 7.45-7.65 (m, 3H) 8.02 (d, J=6 Hz, 2H) 8.08 (s, 1H) 10.40 (br. s., 1H)
MS ES+: 388
To a stirred solution of oxolan-3-ylmethanol (CAS 15833-61-1; 66 mg, 648 μmol) in anhydrous THF (2 mL) was added sodium hydride (27 mg, 68 μmol, 60% dispersion in oil) and the reaction mixture was stirred at rt for 30 min. 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 100 mg, 324 μmol) was added and the reaction mixture was heated at 70° C. for 4.5 h. The reaction mixture was poured into dilute aq. citric acid solution and extracted with DCM. The organic phase was dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (preparative HPLC, 5-40% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.72 (m, 1H) 1.94-2.06 (m, 1H) 2.62-2.73 (m, 1H) 3.53-3.58 (m, 1H) 3.61-3.68 (m, 1H) 3.71-3.80 (m, 2H) 4.25-4.43 (m, 2H) 6.69 (s, 2H) 7.49-7.61 (m, 3H) 7.99-8.06 (m, 2H) 8.27 (s, 1H) 11.51 (br. s., 1H).
MS ES+: 375
To a stirred and nitrogen degassed solution of 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 107 mg, 469 μmol), 2-(2-methylbenzenesulfonyl)acetonitrile (Intermediate 30; 119 mg, 610 μmol), tetrakis(triphenylphosphane) palladium (27 mg, 23 μmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (17 mg, 23 μmol) in anhydrous dioxane (2.5 mL) was added sodiobis(trimethylsilyl)amine [1 M in THF] (1.03 mL, 1.03 mmol). The mixture was heated at 120° C. for 3 h. The reaction mixture was concentrated in vacuo, partitioned between MTBE and 0.2 M aq. NaOH solution. The organic phase was extracted with 0.2 M aq. NaOH solution. The combined aqueous phases were washed with MTBE and acidified with sat. citric acid solution. The organics were extracted with EtOAc/2-methyltetrahydrofuran (2:1), washed with water/brine (1:1), dried (H frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 20-100% EtOAc/petroleum ether). Further purification by column chromatography (preparative HPLC, 5-40% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.46 (s, 3H) 2.60-2.73 (m, 1H) 2.94-3.07 (m, 1H) 3.52-3.66 (m, 2H) 3.83-3.92 (m, 1H) 3.94-4.39 (m, 2H) 6.44 (hr. s., 2H) 7.28 (d, J=7 Hz, 1H) 7.35-7.43 (m, 1H) 7.43-7.49 (m, 1H) 8.03 (s, 1H) 8.03-8.09 (m, 1H) 10.60 (br. s, 1H).
MS ES+: 388
Prepared as described for 7-(2-methylbenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 120) from 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 183 mg, 800 μmol) and 2-(3-methylbenzenesulfonyl)acetonitrile (Intermediate 31; 203 mg, 1.04 mmol) in anhydrous dioxane (4 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 3 h. The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.18 (m, 3H) 2.35 (s, 3H) 2.63-2.72 (m, 1H) 2.94-3.09 (m, 1H) 3.49-3.64 (m, 2H) 3.79-4.42 (m, 3H) 6.46 (br. s., 2H) 7.31-7.47 (m, 2H) 7.74-7.88 (m, 2H) 8.16 (s, 1H) 10.86 (br. s, 1H).
MS ES+: 388
Prepared as described for 7-(2-methylbenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 120) from 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 64 mg, 279 μmol) and 2-(pyridine-3-sulfonyl)acetonitrile (Intermediate 32; 56 mg, 307 μmol) in anhydrous dioxane (1.5 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 3 h. The crude product was purified by column chromatography (preparative HPLC, 5-40% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, J=6 Hz, 3H) 2.61-2.75 (m, 1H) 2.95-3.09 (m, 1H) 3.47-3.64 (m, 2H) 3.81-4.20 (m, 3H) 6.59 (br. s., 2H) 7.55-7.63 (m, 1H) 8.18 (s, 1H) 8.34-8.42 (m, 1H) 8.73-8.79 (m, 1H) 9.16-9.21 (m, 1H) 10.90 (br. s., 1H).
MS ES+: 375
To a stirred and nitrogen degassed solution of 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 178 mg, 777 μmol), 2-(3-chloro-4-methoxybenzenesulfonyl)acetonitrile (Intermediate 33; 229 mg, 932 μmol), tetrakis(triphenylphosphane) palladium (22 mg, 19 μmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (14 mg, 19 μmol) in anhydrous DME (2 mL) was added sodiobis(trimethylsilyl)amine [1 M in THF] (1.71 mL, 1.71 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 2 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was filtered and concentrated in vacuo. The crude product was purified by column chromatography (C-18 silica, 5-95% acetonitrile/water (with 0.1% ammonia)). Further purification by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.62-2.75 (m, 1H) 2.93-3.10 (m, 1H) 3.50-3.65 (m, 2H) 3.86 (br. s., 1H) 3.90 (s, 3H) 4.02-4.27 (m, 2H) 6.42 (br. s., 2H) 7.25-7.33 (m, 1H) 7.93-8.00 (m, 1H) 8.03-8.08 (m, 1H) 8.17 (s, 1H).
MS ES+: 438
Prepared as described for 7-(3-chloro-4-methoxybenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 123) from 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 142 mg, 622 μmol) and 2-(3-fluoro-4-methoxybenzenesulfonyl)acetonitrile (Intermediate 34; 171 mg, 746 μmol) in anhydrous DME (2 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 2 h. The crude product was purified by column chromatography (C-18 silica, 5-95% acetonitrile/water (with 0.1% ammonia)). Further purification by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-1.29 (m, 3H) 2.63-2.76 (m, 1H) 2.96-3.09 (m, 1H) 3.50-3.68 (m, 2H) 3.82-3.97 (m, 4H) 4.01-4.41 (m, 2H) 6.42 (br. s., 2H) 7.21-7.41 (m, 1H) 7.76-7.93 (m, 2H) 8.18 (s, 1H) 10.73-11.16 (m, 1H).
MS ES+: 422
Prepared as described for 7-(3-chloro-4-methoxybenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 123) from 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 205 mg, 896 μmol) and 2-phenylmethanesulfonylacetonitrile (Intermediate 35; 175 mg, 896 μmol) in anhydrous DME (2 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 2 h. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) and triturated with hot EtOAc to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.17 (d, J=6 Hz, 3H) 2.66-2.78 (m, 1H) 2.99-3.12 (m, 1H) 3.53-3.76 (m, 2H) 3.84-4.19 (m, 3H) 4.63 (s, 2H) 6.07 (br. s., 2H) 6.96-7.19 (m, 2H) 7.20-7.39 (m, 3H) 8.29 (s, 1H) 10.78 (s, 1H).
MS ES+: 388
Prepared as described for 7-(3-chloro-4-methoxybenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 123) from 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 115 mg, 501 μmol) and 2-[4-(propan-2-yloxy)benzenesulfonyl]acetonitrile (CAS 886499-39-4; 120 mg, 501 μmol) in anhydrous DME (1.5 mL) and the reaction mixture was heated under microwave irradiation at 130° C. for 2 h. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) and triturated with hot EtOAc to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 1.25 (d, J=6 Hz, 6H) 2.59-2.77 (m, 1H) 2.92-3.11 (m, 1H) 3.48-3.70 (m, 2H) 3.84-4.08 (m, 3H) 4.58-4.76 (m, 1H) 6.47 (br. s., 2H) 7.02 (d, J=8 Hz, 2H) 7.92 (d, J=8 Hz, 2H) 8.18 (br. s., 1H) 10.80 (br. s., 1H).
MS ES+: 432
Prepared as described for 7-(benzenesulfonyl)-4-[(E)-2-cyclopropylethenyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 11) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 228 mg, 737 μmol) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 37; 270 mg, 1.11 mmol) in dioxane (4 mL) and water (1 mL) and the reaction mixture was heated under microwave irradiation at 140° C. for 1.25 h. After this time additional potions of di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium (26 mg, 37 μmol) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (540 mg, 2.22 mmol) were added and the reaction mixture was heated under microwave irradiation at 140° C. for 1.5 h. The crude product was purified by column chromatography (silica, 0-5% MeOH/DCM). Further purification by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.11-2.24 (m, 2H) 2.71-2.88 (m, 4H) 6.26-6.34 (m, 1H) 6.85 (s, 2H) 7.51-7.62 (m, 3H) 8.01-8.07 (m, 2H) 8.56 (s, 1H) 11.04 (br. s., 1H).
MS ES+: 391
To a stirred solution of 1H-pyrazole (CAS 288-13-1; 66 mg, 972 μmol) in anhydrous DMF (5 mL) under an atmosphere of nitrogen was added sodium hydride (49 mg, 1.22 mmol, 60% dispersion in oil) and stirred at rt for 5 min. 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) was added and the reaction mixture was heated under microwave irradiation at 200° C. for 2 h. Further portions of 1H-pyrazole (CAS 288-13-1; 66 mg, 972 μmol) and sodium hydride (49 mg, 1.22 mmol, 60% dispersion in oil) were added and stirred at rt for 10 min. The reaction mixture was heated under microwave irradiation at 200° C. for 1 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with water/brine (1:1), dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM). Further purification by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 6.61-6.72 (m, 1H) 7.17 (s, 2H) 7.52-7.65 (m, 3H) 7.98-8.11 (m, 3H) 8.52 (s, 1H) 8.72 (d, J=3 Hz, 1H) 10.99 (br. s., 1H).
MS ES+: 341
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(4-methoxybenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 19; 250 mg, 738 μmol) and 2,2-dimethylmorpholine (CAS 147688-58-2; 255 mg, 2.21 mmol) in EtOH (4 mL) and heated at 150° C. for 1 h. The crude product was purified by column chromatography (basic silica, 65-100% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (br. s., 6H) 3.37-3.57 (m, 4H) 3.69-3.77 (m, 2H) 3.79 (s, 3H) 6.46 (br. s., 2H) 7.06 (d, J=9 Hz, 2H) 7.95 (d, J=9 Hz, 2H) 8.14 (br. s., 1H) 10.64 (br. s., 1H).
MS ES+: 418
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(4-methoxybenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 19; 250 mg, 738 μmol) and (2R,6S)-2,6-dimethylmorpholine (CAS 6485-55-8; 255 mg, 2.21 mmol) in EtOH (4 mL) and heated at 150° C. for 1 h. The crude product was purified by column chromatography (basic silica, 65-100% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, J=6 Hz, 6H) 2.55-2.65 (m, 2H) 3.58-3.69 (m, 2H) 3.79 (s, 3H) 3.95-4.07 (m, 2H) 6.49 (br. s., 2H) 7.06 (d, J=9 Hz, 2H) 7-95 (d, J=9 Hz, 2H) 8.16 (br. s., 1H) 10.80 (br. s., 1H).
MS ES+: 418
To a stirred and nitrogen degassed solution of 4-chloro-6-cyclohexyl-2-cyclopropylpyrimidin-5-amine (Intermediate 41; 96 mg, 381 μmol), 2-(benzenesulfonyl)acetonitrile (CAS 7605-25-9; 76 mg, 419 μmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (27 mg, 38 μmol) in anhydrous dioxane (5 mL) was added sodiobis(trimethylsilyl)amine [1 M in THF] (500 μL, 1.00 mmol) and heated at reflux for 1.5 h. A further portion of di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (27 mg, 38 μmol) was added and the reaction mixture was heated at reflux for 2.5 h. A further portion of di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (27 mg, 38 μmol) was added and the reaction mixture was heated at reflux for 2.5 h. The reaction mixture was concentrated in vacuo, partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (basic silica, 0-100% EtOAc/petroleum ether, then 0-10% MeOH/DCM) and recrystallised from EtOAc/petroleum ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-0.94 (m, 4H) 1.18-1.42 (m, 3H) 1.49-1.73 (m, 5H) 1.78 (d, J=13 Hz, 2H) 2.01-2.09 (m, 1H) 2.81-2.91 (m, 1H) 6.82 (s, 2H) 7.51-7.62 (m, 3H) 8.06 (d, J=7 Hz, 2H) 11.19 (s, 1H).
MS ES+: 397
1H NMR (300 MHz, DMSO-d6) δ ppm 1.66- 1.89 (m, 4 H) 3.10-3.24 (m, 2 H) 3.79-4.14 (m, 2 H) 4.34-4.46 (m, 2 H) 6.36 (br. s., 2 H) 7.46- 7.64 (m, 3 H) 8.01 (d, J = 7 Hz, 2 H) 8.11 (s, 1 H) 10.36-10.78 (m, 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 2.88- 3.07 (m, 1 H) 3.09-3.26 (m, 1 H) 3.68-3.87 (m, 1 H) 3.97-4.13 (m, 1 H) 4.14-4.44 (m, 2 H) 4.52- 4.66 (m, 1 H) 6.45 (br. s., 2 H) 7.22-7.48 (m, 5 H) 7.48-7.64 (m, 3 H) 8.02 (d, J = 7 Hz, 2 H) 8.17 (br. s., 1 H) 10.95 (br. s, 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 2.89- 3.08 (m, 1 H) 3.10-3.26 (m, 1 H) 3.67-3.89 (m, 1 H) 3.97-4.25 (m, 3 H) 4.49-4.69 (m, 1 H) 6.56 (br. s., 2 H) 7.26-7.48 (m, 5 H) 7.48-7.64 (m, 3 H) 8.03 (d, J = 6 Hz, 2 H) 8.20 (br. s., 1 H) 10.88 (br. s., 1 H)
Prepared as described for 7-(benzenesulfonyl)-4-(cyclohex-1-en-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 2) from 4-chloro-6-(cyclohex-1-en-1-yl)pyrimidin-5-amine (Intermediate 2; 50 mg, 238 μmol) and 2-(phenylsulfanyl)acetonitrile (CAS 5219-61-4; 62 μL, 477 μmol) in anhydrous DME (3 mL). The reaction mixture was heated at 130° C. for 16 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, DMSO-d6) δ ppm 1.56-1.73 (m, 2H) 1.73-1.84 (m, 2H) 2.25-2.37 (m, 2H) 2.53-2.62 (m, 2H) 6.43 (br. s., 2H) 6.53 (br. s., 1H) 6.95-7.13 (m, 3H) 7.15-7.26 (m, 2H) 8.39 (s, 1H)
MS ES+: 323
Prepared as described for 7-(3-chloro-4-methoxybenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 123) from 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 163 mg, 731 μmol) and 2-[4-(trifluoromethyl)benzenesulfonyl]acetonitrile (CAS 186405-37-8; 213 mg, 855 μmol) in anhydrous dioxane (3.5 mL) and the reaction mixture heated under microwave irradiation at 120° C. for 3 h. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) and triturated with hot EtOAc to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.61-2.75 (m, 1H) 2.94-3.11 (m, 1H) 3.48-3.67 (m, 2H) 3.73-4.44 (m, 3H) 6.57 (br. s., 2H) 7.94 (d, J=8 Hz, 2H) 8.18 (s, 1H), 8.23 (d, J=8 Hz, 3H) 10.92 (br. s., 1H)
MS ES+: 442
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and (2R)-2-methylmorpholine hydrochloride (CAS 168038-14-0; 334 mg, 2.43 mmol) in EtOH (8 mL) and the reaction mixture heated under microwave irradiation at 160° C. for 3 h. The crude product was triturated with EtOAc/water and then triturated with EtOH to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.61-2.78 (m, 1H) 2.95-3.16 (m, 1H) 3.51-3.70 (m, 2H) 3.83-3.95 (m, 1H) 3.95-4.15 (m, 2H) 6.50 (br. s., 2H) 7.42-7.68 (m, 3H) 8.02 (d, J=7 Hz, 2H) 8.17 (s, 1H) 10.83 (br. s., 1H)
MS ES+: 374
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 250 mg, 775 μmol) and (2R,6S)-2,6-dimethylmorpholine (CAS 6485-55-8; 286 μL, 2.32 mmol) in EtOH (6 mL) and the reaction mixture heated under microwave irradiation at 150° C. for 1 h. The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.13 (s, 3H) 1.15 (s, 3H) 2.41 (br. s., 3H) 2.53-2.66 (m, 2H) 3.53-3.73 (m, 2H) 3.78-4.21 (m, 2H) 6.40 (br. s., 2H) 7.38-7.71 (m, 3H) 7.84-8.19 (m, 2H) 10.69 (br. s., 1H).
MS ES+: 402
Prepared as described 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 250 mg, 775 μmol) and 2,2-dimethylmorpholine (CAS 147688-58-2; 107 mg, 929 μmol) in EtOH (6 mL) and the reaction mixture heated under microwave irradiation at 150° C. for 1 h. The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, CDCl3) δ ppm 1.26 (s, 6H) 2.55 (s, 3H) 3.71-3.93 (m, 2H) 3.99-4.24 (m, 2H) 4.25-4.53 (m, 2H) 4.84 (br. s., 2H) 7.38-7.59 (m, 3H) 7.79-8.06 (m, 2H) 10.23 (br. s, 1H).
MS ES+: 402
Prepared as described for 7-(benzenesulfonyl)-4-(1H-pyrazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 128) 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and 3,5-dimethyl-1H-pyrazole (CAS 67-51-6; 93 mg, 972 μmol) in anhydrous DMF (5 mL). The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (s, 3H) 2.66 (s, 3H) 6.19 (s, 1H) 7.15 (br. s., 2H) 7.53-7.61 (m, 3H) 8.02-8.08 (m, 2H) 8.47 (s, 1H) 10.67 (br. s., 1H).
MS ES+: 369
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and 2-(trifluoromethyl)morpholine hydrochloride (CAS 1394909-69-3; 310 mg, 1.62 mmol) in EtOH (8 mL) and the reaction mixture heated under microwave irradiation at 160° C. for 3 h. The crude product was triturated with EtOAc/water and then triturated with EtOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.98-3.14 (m, 1H) 3.14-3.26 (m, 1H) 3.65-3.77 (m, 1H) 3.83-4.01 (m, 1H) 4.01-4.15 (m, 1H) 4.18-4.40 (m, 2H) 6.61 (br. s., 2H) 7.47-7.66 (m, 3H) 8.03 (d, J=7 Hz, 2H) 8.23 (br. s., 1H) 10.99 (br. s., 1H)
MS ES+: 428
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 200 mg, 620 μmol) and 4,4-difluoropiperidine hydrochloride (CAS 144260-52-4; 140 mg, 888 μmol) in EtOH (5 mL) and the reaction mixture heated under microwave irradiation at 150° C. for 1 h. The crude product was purified 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 1.89-2.18 (m, 4H) 2.44 (s, 3H) 3.39-4.17 (m, 4H) 5.96-6.56 (m, 2H) 7.43-7.66 (m, 3H) 7.91-8.17 (m, 2H) 10.42-11.44 (m, 1H).
MS ES+: 408
Prepared as described for 7-(3-chloro-4-methoxybenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 123) from 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 225 mg, 984 μmol) and 2-(4-chloro-3-fluorobenzenesulfonyl)acetonitrile (Intermediate 42; 230 mg, 984 μmol) in anhydrous DME (2 mL) and the reaction mixture was heated under microwave irradiation at 130° C. for 2 h. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether then 0-10% MeOH/DCM) and triturated with hot EtOAc to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.18 (m, 3H) 2.63-2.74 (m, 1H) 2.97-3.09 (m, 1H) 3.49-3.67 (m, 2H) 3.80-4.11 (m, 3H) 6.58 (br. s., 2H) 7.72-7.92 (m, 2H) 8.00-8.09 (m, 1H) 8.20 (br. s., 1H) 10.88 (br. s., 1H).
MS ES+: 426
To a stirred and nitrogen degassed solution of 2-(2-fluoro-4-methylbenzenesulfonyl)acetonitrile (Intermediate 45; 190 mg, 891 μmol) in DME (1 mL) was added sodium hydride (78 mg, 1.96 mmol, 60% dispersion in oil) and left to stir for 5 min. To this was added a solution of 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 204 mg, 891 μmol), tetrakis(triphenylphosphane) palladium (26 mg, 22 μmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (16 mg, 22 μmol) in anhydrous DME (2 mL) was added. The reaction mixture was heated under microwave irradiation at 130° C. for 1 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether then 0-10% MeOH/DCM). Further purification by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) and triturated with hot EtOAc afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.34 (s, 3H) 2.64-2.74 (m, 1H) 2.97-3.07 (m, 1H) 3.50-3.66 (m, 2H) 3.89-3.92 (m, 1H) 3.92-4.30 (m, 2H) 6.44 (br. s, 2H) 7.05-7.26 (m, 2H) 7.86-7.93 (m, 1H) 8.05 (s, 1H) 10.90 (s, 1H).
MS ES+: 406
Prepared as described for 7-(2-fluoro-4-methylbenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 146) from 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 204 mg, 891 μmol) and 2-(3,5-difluorobenzenesulfonyl)acetonitrile (Intermediate 46; 194 mg, 891 μmol) in anhydrous DME (3 mL) and the reaction mixture was heated under microwave irradiation at 130° C. for 2 h. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether then 0-10% MeOH/DCM) and triturated with hot EtOAc/petroleum ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.63-2.82 (m, 1H) 2.94-3.11 (m, 1H) 3.46-3.68 (m, 2H) 3.84-3.93 (m, 1H) 3.93-4.13 (m, 2H) 6.64 (br. s., 2H) 7.49-7.64 (m, 1H) 7.72-7.78 (m, 2H) 8.23 (br. s., 1H) 11.07 (s, 1H).
MS ES+: 410
Prepared as described for 7-(benzenesulfonyl)-4-[(E)-2-cyclopropylethenyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 11) from 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 200 mg, 620 μmol) and (3-methylphenyl)boronic acid (CAS 17933-03-8; 257 mg, 1.89 mmol) in dioxane (8 mL) and water (2 mL) and the reaction mixture was irradiated in the microwave at 140° C. for 1 h. The crude product was recrystallised from MeOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (s, 3H) 2.59 (s, 3H) 6.83 (br. s., 2H) 7.22-7.35 (m, 1H) 7.37-7.47 (m, 1H) 7.49-7.63 (m, 3H) 7.64-7.77 (m, 2H) 8.00-8.16 (m, 2H) 11.20 (br. s., 1H).
MS ES+: 379
Prepared as described for 7-(benzenesulfonyl)-4-[(E)-2-cyclopropylethenyl]-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 11) from 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 200 mg, 620 μmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (CAS 126726-62-3; 318 mg, 1.89 mmol) in dioxane (8 mL) and water (2 mL) and the reaction mixture was heated under microwave irradiation at 140° C. for 1 h. The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) and triturated with hot EtOAc to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 3H) 2.53 (s, 3H) 5.58 (d, J=16 Hz, 2H) 6.71 (s, 2H) 7.40-7.73 (m, 3H) 7.94-8.21 (m, 2H) 10.47-10.97 (m, 1H).
MS ES+: 329
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and bis(2-oxa-6-azaspiro[3.5]nonane); oxalic acid (CAS 1313369-53-7; 224 mg, 1.29 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 3 h. The crude product was purified by column chromatography (C18-silica, 5-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.68 (m, 2H) 1.82-1.92 (m, 2H) 3.36-3.64 (m, 2H) 3.68-3.97 (m, 2H) 4.18-4.33 (m, 4H) 6.46 (br. s., 2H) 7.46-7.71 (m, 3H) 8.02 (d, J=7 Hz, 2H) 8.15 (br. s., 1H) 10.69 (br. s., 1H)
MS ES+: 400
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 4-oxa-7-azaspiro[2.5]octane (CAS 220291-92-9; 220 mg, 1.29 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 2 h. The crude product was purified by column chromatography (basic silica, 0-20% MeOH/DCM) and triturated with MeOH/DCM to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.55-0.64 (m, 2H) 0.69-0.76 (m, 2H) 3.47-3.71 (m, 3H) 3.73-3.89 (m, 3H) 6.46 (br. s., 2H) 7.42-7.66 (m, 3H) 8.02 (d, J=7 Hz, 2H) 8.14 (br. s., 1H) 10.73 (br. s., 1H)
MS ES+: 386
Prepared as described for 7-(2-methylbenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 120) from 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 95 mg, 414 μmol) and 2-(2-methoxybenzenesulfonyl)acetonitrile (Intermediate 47; 105 mg, 4.97 mmol) in anhydrous dioxane (1.5 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 3 h. The crude product was purified by column chromatography (preparative HPLC, 5-40% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.59-2.74 (m, 1H) 2.92-3.08 (m, 1H) 3.52-3.67 (m, 2H) 3.76 (s, 3H) 3.84-3.92 (m, 1H) 3.92-4.71 (m, 2H) 6.41 (br. s, 2H) 7.03-7.13 (m, 2H) 7.48-7.58 (m, 1H) 7.94-8.01 (m, 1H) 8.03 (s, 1H).
MS ES+: 404
Prepared as described for 7-(2-methylbenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 120) from 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 187 mg, 816 μmol) and 2-(2-phenylethanesulfonyl)acetonitrile (Intermediate 48; 205 mg, 980 μmol) in anhydrous dioxane (3.5 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 3 h. The crude product was purified by column chromatography (preparative HPLC, 5-40% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (d, J=6 Hz, 3H) 2.63-2.76 (m, 1H) 2.82-2.96 (m, 2H) 2.96-3.11 (m, 1H) 3.50-3.72 (m, 4H) 3.86-3.95 (m, 1H) 3.96-4.21 (m, 2H) 6.39 (br. s., 2H) 7.04-7.26 (m, 5H) 8.17 (s, 1H) 11.16 (br. s., 1H).
MS ES+: 402
Prepared as described for 7-(2-methylbenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 120) from 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 187 mg, 816 μmol) and 2-(3-methoxybenzenesulfonyl)acetonitrile (Intermediate 49; 224 mg, 1.06 mmol) in anhydrous dioxane (2.5 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 3 h. The crude product was purified by column chromatography (preparative HPLC, 5-40% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.61-2.78 (m, 1H) 2.93-3.12 (m, 1H) 3.47-3.67 (m, 2H) 3.80 (s, 3H) 3.83-4.21 (m, 3H) 6.51 (br. s., 2H) 7.10-7.17 (m, 1H) 7.40-7.48 (m, 1H) 7.52-7.60 (m, 1H) 7.66 (br. s., 1H) 8.20 (br. s, 1H) 10.83 (br. s., 1H).
MS ES+: 404
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 7-(benzenesulfonyl)-4-(4,4-difluorocyclohex-1-en-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 127; 100 mg, 256 μmol) in anhydrous MeOH (5 mL) and the reaction mixture stirred at rt for 16 h. The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.78-1.91 (m, 5H) 2.07-2.22 (m, 2H) 2.72-2.88 (m, 1H) 3.03-3.18 (m, 1H) 7.04 (s, 2H) 7.52-7.59 (m, 3H) 8.05 (d, J=7 Hz, 2H) 8.52 (S, 1H) 11.41 (br. s., 1H).
MS ES+: 393
To a stirred solution of sodium hydride (27.2 mg, 0.680 mmol, 60% in mineral oil) in anhydrous THF (2 mL) under an atmosphere of nitrogen was added oxan-2-ylmethanol (CAS 100-72-1; 75 mg, 648 μmol). The reaction was stirred at room temperature for 5 min. 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 100 mg, 324 μmol) was added and the reaction mixture heated in a sealed tube at 70° C. for 16 h. The reaction was diluted with 5% aq. citric acid solution and DCM, passed through a phase separator and concentrated in vacuo. The crude product was purified to by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.21-1.38 (m, 1H) 1.39-1.54 (m, 3H) 1.57-1.69 (m, 1H) 1.72-1.87 (m, 1H) 3.32-3.40 (m, 1H) 3.58-3.70 (m, 1H) 3.82-3.92 (m, 1H) 4.28-4.44 (m, 2H) 6.63 (br. s., 2H) 7.49-7.63 (m, 3H) 7.97-8.08 (m, 2H) 8.22-8.31 (m, 1H) 11.58 (br. s., 1H).
MS ES+: 389
1H NMR (400 MHz, DMSO-d6) δ ppm 1.30- 1.63 (m, 3 H) 1.76-1.88 (m, 1 H) 1.96-2.07 (m, 1 H) 3.22-3.29 (m, 1 H) 3.32-3.39 (m, 1 H) 3.68- 3.77 (m, 1 H) 3.86-3.95 (m, 1 H) 4.17-4.25 (m, 1 H) 4.28-4.35 (m, 1 H) 6.69 (s, 2 H) 7.50-7.59 (m, 3 H) 7.99-8.05 (m, 2 H) 8.26 (s, 1 H) 11.51 (br. s., 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 1.96- 2.11 (m, 1 H) 2.16-2.34 (m, 1 H) 3.70-3.97 (m, 4 H) 5.61-5.72 (m, 1 H) 6.67 (br.s., 2 H) 7.49- 7.61 (m, 3 H) 8.02 (d, J = 7 Hz, 2 H) 8.24-8.31 (m, 1 H) 11.53 (br. s., 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.97- 2.08 (m, 1 H) 2.19-2.31 (m, 1 H) 3.72-3.93 (m, 4 H) 5.63-5.71 (m, 1 H) 6.66 (s, 2 H) 7.51-7.59 (m, 3 H) 7.98-8.05 (m, 2 H) 8.27 (s, 1 H) 11.54 (br. s., 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 1.19- 1.59 (m, 6 H) 1.66-1.82 (m, 2 H) 1.87-2.02 (m, 2 H) 5.10-5.24 (m, 1H) 6.59 (s, 2 H) 7.48-7.61 (m, 3 H) 7.98-8.07 (m, 2 H) 8.24 (s, 1 H) 11.46 (br. s., 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 2.29- 2.42 (m, 3 H) 5.67-5.78 (m, 2 H) 6.73 (br.s., 2 H) 7.27 (br. s., 1 H) 7.49- 7.64 (m, 3 H) 7.97-8.08 (m, 2 H) 8.29-8.35 (m, 1 H) 11.70 (br. s., 1H)
1H NMR (300 MHz, DMSO-d6) δ ppm 1.64 (d, J = 7 Hz, 3 H) 6.27-6.38 (m, 1 H) 6.69 (s, 2 H) 7.22- 7.33 (m, 1 H) 7.44-7.61 (m, 4 H) 7.70-7.80 (m, 1 H) 8.02 (d, J = 8 Hz, 2 H) 8.20 (s, 1 H) 8.53 (d, J = 4 Hz, 1 H) 11.65 (br. s., 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 2.27- 2.35 (m, 6 H) 5.28 (s, 2 H) 6.62 (s, 2 H) 7.51-7.59 (m, 3 H) 7.98-8.04 (m, 2 H) 8.31 (s, 1 H) 11.53 (br. s., 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 1.53- 1.67 (m, 3 H) 6.30-6.44 (m, 1 H) 6.67 (br. s., 2 H) 7.21-7.39 (m, 3 H) 7.41- 7.61 (m, 5 H) 7.97-8.06 (m, 2 H) 8.18-8.25 (m, 1 H) 11.57 (br.s., 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 0.95- 1.28 (m, 5 H) 1.58-1.83 (m, 6 H) 4.21 (d, J = 6 Hz, 2 H) 6.64 (s, 2 H) 7.50- 7.59 (m, 3 H) 7.99-8.05 (m, 2 H) 8.25 (s, 1 H) 11.47 (br. s., 1 H)
1H HMR (300 MHz, DMSO-d6) δ ppm 1.58- 1.75 (m, 2 H) 1.93-2.09 (m, 2 H) 3.44-3.58 (m, 2 H) 3.80-3.94 (m, 2 H) 5.30-5.43 (m, 1H) 6.66 (br. s., 2 H) 7.47-7.63 (m, 3 H) 8.02 (d, J =7 Hz, 2 H) 8.23-8.30 (m, 1 H) 11.48 (br. s., 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.59- 1.85 (m, 2 H) 2.02-2.16 (m, 2 H) 2.34-2.46 (m, 2 H) 5.24-5.33 (m, 1 H) 6.63 (br. s., 2 H) 7.49- 7.60 (m, 3 H) 8.01 (d, J = 7 Hz, 2 H) 8.22 (s, 1 H) 11.62 (br. s., 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 5.44- 5.54 (m, 2 H) 6.66 (br. s., 2 H) 7.26-7.64 (m, 8 H) 8.03 (d, J = 6 Hz, 2 H) 8.26- 8.35 (m, 1H) 11.66 (br. s., 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.25- 1.40 (m, 2 H) 1.60-1.69 (m, 2 H) 1.94-2.09 (m, 1 H) 3.27 (s, 2 H) 3.80- 3.90 (m, 2 H) 4.26 (d, J = 7 Hz, 2 H) 6.66 (s, 2 H) 7.51- 7.60 (m, 3 H) 7.99-8.05 (m, 2 H) 8.26 (s, 1H) 11.53 (br. s., 1H)
1H NMR (300 MHz, DMSO-d6) δ ppm 0.24- 0.59 (m, 4 H) 1.05-1.21 (m, 1 H) 1.28-1.41 (m, 3 H) 4.76-4-91 (m, 1 H) 6.60 (br. s., 2 H) 7.46- 7.63 (m, 3 H) 7.96-8.09 (m, 2 H) 8.18-8.25 (m, 1 H) 11.57 (br.s., 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 2.54- 2.79 (m, 5 H) 4.48 (br. s., 2 H) 6.69 (br. s., 2 H) 7.47- 7.62 (m, 3 H) 7.96-8.07 (m, 2 H) 8.24-8.30 (m, 1 H) 11.47 (br. s., 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 0.24- 0.36 (m, 1 H) 0.45-0.57 (m, 1 H) 0.71-0.86 (m, 1 H) 0.93-1.12 (m, 4 H) 4.12-4.37 (m, 2 H) 6.62 (br. s., 2 H) 7.49-7.62 (m, 3 H) 7.97-8.07 (m, 2 H) 8.22-8.29 (m, 1 H) 11.55 (br. s., 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 0.34- 0.40 (m, 2 H) 0.53-0.58 (m, 2 H) 1.17 (s, 3 H) 4.22 (s, 2 H) 6.63 (s, 2 H) 7.51- 7.59 (m, 3 H) 7.99-8.04 (m, 2 H) 8.24 (s, 1 H) 11.50 (br. s., 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 3.22- 3.29 (m, 3 H) 3.62-3.72 (m, 2 H) 4.48-4.59 (m, 2 H) 6.63 (br. s., 2 H) 7.48- 7.63 (m, 3 H) 7.97-8.06 (m, 2 H) 8.23-8.30 (m, 1 H) 11.59 (br. s., 1 H)
1H NMR (300 MHz, DMSO-d6) δ ppm 1.44- 1.79 (m, 2 H) 2.15-2.37 (m, l H) 4.24-4.37 (m, 1 H) 4.59-4.73 (m, 1 H) 6.66 (br. s., 2 H) 7.49- 7.62 (m, 3 H) 7.95-8.09 (m, 2 H) 8.23-8.34 (m, 1 H) 11.63 (br.s., 1 H)
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 250 mg, 734 μmol) and 2-methylmorpholine (CAS 27550-90-9; 111 mg, 1.10 mmol) in EtOH (6 mL) and the reaction mixture was heated under microwave irradiation at 130° C. for 1 h. The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)). Further purification by column chromatography (silica, 0-100% EtOAc/petroleum ether) afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.26 (br. s., 3H) 2.57-2.77 (m, 1H) 2.87-3.13 (m, 1H) 3.41-3.71 (m, 2H) 3.77-4.19 (m, 3H) 6.47 (br. s., 2H) 7.11-7.49 (m, 2H) 7.52-7.74 (m, 1H) 8.01 (t, J=7 Hz, 1H) 10.76 (br. s., 1H).
MS ES+: 406
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 250 mg, 734 μmol) and 6-oxa-9-azaspiro[4.5]decane (CAS 130643-07-1; 155 mg, 1.10 mmol) in EtOH (5 mL) and the reaction mixture was heated under microwave irradiation at 140° C. for 1 h. The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) and recrystallised from MeOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.28-1.85 (m, 8H) 2.27 (br. s., 3H) 3.37-4.40 (m, 6H) 6.45 (br. s., 2H) 7.16-7.47 (m, 2H) 7.53-7.73 (m, 1H) 7.81-8.16 (m, 1H) 10.63 (br. s., 1H).
MS ES+: 446
Prepared as described for 7-(2-methylbenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 120) from 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 200 mg, 887 μmol) and 2-(4-fluoro-2-methylbenzenesulfonyl)acetonitrile (Intermediate 51; 243 mg, 1.14 mmol) in anhydrous dioxane (3.5 mL). The reaction mixture was heated under microwave irradiation at 120° C. for 3 h, after this additional sodium hydride (70 mg, 1.75 mmol, 60% dispersion in oil) was added and the reaction mixture was heated under microwave irradiation at 130° C. for 3 h. The crude product was purified by column chromatography (silica, 20-75% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.46 (s, 3H) 2.60-2.73 (m, 1H) 2.94-3.09 (m, 1H) 3.52-3.67 (m, 2H) 3.83-4.08 (m, 3H) 6.53 (br. s., 2H) 7.13-7.21 (m, 1H) 7.21-7.29 (m, 1H) 8.05 (s, 1H) 8.10-8.20 (m, 1H) 10.87 (s, 1H)
MS ES+: 406
To a stirred solution of 4-chloro-7-(3-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 52; 200 mg, 587 μmol) in EtOH (3 mL) was added (2R,6S)-2,6-dimethylmorpholine (CAS 6485-55-8; 149 mg, 1.29 mmol) and the reaction mixture was heated under microwave irradiation at 150° C. for 1 h. The reaction mixture was concentrated in vacuo and partitioned between DCM and water. The organic phase was concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) then recrystallised from EtOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 6H) 2.42 (br. s., 3H) 2.52-2.62 (m, 2H) 3.50-3.73 (m, 2H) 3.82-4.21 (m, 2H) 6.48 (br. s., 2H) 7.40-7.49 (m, 1H) 7.56-7.66 (m, 1H) 7.84-7.95 (m, 2H) 10.58-10.84 (m, 1H).
MS ES+: 420
Prepared as described for 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-(3-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 179) from 4-chloro-7-(3-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 52; 200 mg, 587 μmol) and 2-methylmorpholine (CAS 27550-90-9; 131 mg, 1.29 mmol) in EtOH (3 mL) and the reaction mixture was heated under microwave irradiation at 150° C. for 1 h. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) then recrystallised from EtOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.42 (br. s., 3H) 2.60-2.77 (m, 1H) 2.90-3.09 (m, 1H) 3.46-3.68 (m, 2H) 3.83-4.12 (m, 3H) 6.47 (br. s., 2H) 7.38-7.48 (m, 1H) 7.57-7.64 (m, 1H) 7.80-7.99 (m, 2H) 10.57-10.91 (m, 1H).
MS ES+: 406
Prepared as described for 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-(3-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 179) from 4-chloro-7-(3-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 52; 200 mg, 587 μmol) and 4,4-difluoropiperidine hydrochloride (CAS 144260-52-4; 111 mg, 704 μmol) and ethylbis(propan-2-yl)amine (152 mg, 1.17 mmol) in EtOH (3 mL) and the reaction mixture was heated under microwave irradiation at 150° C. for 1 h. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) then recrystallised from EtOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.88-2.14 (m, 4H) 2.44 (br. s., 3H) 3.46-3.82 (m, 4H) 6.51 (br. s., 2H) 7.35-7.50 (m, 1H) 7.57-7.64 (m, 1H) 7.84-7.98 (m, 2H) 10.70-10.88 (m, 1H).
MS ES+: 426
A mixture of 2-(2,3-difluorobenzenesulfonyl)-2-[2-methyl-6-(2-methylmorpholin-4-yl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 78; 103 mg, 227 μmol), zinc (44.6 mg, 681 μmol), AcOH (1.14 mL) and MeOH (1.14 mL) was sonicated for to min then stirred at rt for 20 h. A second portion of zinc (29.7 mg, 454 μmol) was added and the reaction stirred at room temperature for 24 h. The reaction mixture was warmed at 50° C. for 1 h, and then stirred at rt for 20 h. The reaction mixture was diluted with MeOH, filtered through Celite, washed with MeOH and concentrated in vacuo. The crude product was purified by column chromatography (silica, 20-75% EtOAc/petroleum ether) followed by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.17 (d, J=6 Hz, 3H) 2.61 (s, 3H) 2.94-3.05 (m, 1H) 3.21-3.34 (m, 1H) 3.51-3.68 (m, 2H) 3.89-3.99 (m, 1H) 4.26-4.38 (m, 2H) 7.34 (br. s., 1H) 7.43-7.53 (m, 1H) 7.76-7.86 (m, 1H) 7.90-7.98 (m, 1H).
MS ES+: 424
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 7-(benzenesulfonyl)-4-(4,4-difluorocyclohex-1-en-1-yl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 56; 320 mg, 791 μmol) in anhydrous MeOH (10 mL). The crude product was purified 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 1.72-1.97 (m, 6H) 2.05-2.22 (m, 2H) 2.98-3.11 (m, 1H) 6.94 (s, 2H) 7.51-7.61 (m, 3H) 8.02-8.10 (m, 2H) 11.28 (br. s., 1H).
MS ES+: 407
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and 2-(propan-2-yl)morpholine hydrochloride (CAS 89855-02-7; 402 mg, 2.43 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 160° C. for 2 h. The crude product was dissolved in MeOH (under sonication) and passed through a thiol cartridge. The organics were concentrated in vacuo and recrystallised from EtOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.90-0.98 (m, 6H) 1.66-1.81 (m, 1H) 2.84-2.98 (m, 1H) 3.12-3.28 (m, 3H) 3.47-3.61 (m, 2H) 3.92-4.00 (m, 1H) 6.77 (br. s., 2H) 7.51-7.68 (m, 3H) 8.06 (d, J=7 Hz, 2H) 8.27 (br. s., 1H)
MS ES+: 402
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 250 mg, 734 μmol) and 2,2-dimethylmorpholine (CAS 147688-58-2; 127 mg, 1.1 mmol) in EtOH (6 mL) and the reaction mixture was heated under microwave irradiation at 140° C. for 3 h. The crude product was purified by column chromatography (preparative HPLC, 20-60% acetonitrile/water (with 0.1% ammonia)) and recrystallised from chloroform/petroleum ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.18 (s, 6H) 2.60 (s, 3H) 3.59-3.90 (m, 6H) 7.34-7.53 (m, 2H) 7.74 (m, 1H) 8.06-8.23 (m, 1H).
MS ES+: 420
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 250 mg, 734 μmol) and 4,4-difluoropiperidine hydrochloride (CAS 144260-52-4; 116 mg, 734 μmol) in EtOH (6 mL) and the reaction mixture was heated under microwave irradiation at 150° C. for 1 h. The crude product was purified by column chromatography (preparative HPLC, 20-60% acetonitrile/water (with 0.1% ammonia)) and recrystallised from MeOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.91-2.14 (m, 4H) 2.29 (br. s., 3H) 3.53-4.62 (m, 4H) 6.31-6.67 (m, 2H) 7.18-7.48 (m, 2H) 7.54-7.73 (m, 1H) 7.92-8.10 (m, 1H) 10.85 (br. s., 1H).
MS ES+: 426
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 200 mg, 587 μmol) and (2R,6S)-2,6-dimethylmorpholine (CAS 6485-55-8; 135 mg, 1.17 mmol) in EtOH (5 mL) and the reaction mixture was heated under microwave irradiation at 140° C. for 1.5 h. The crude product was purified by column chromatography (preparative HPLC, 20-60% acetonitrile/water (with 0.1% ammonia)). Further purification by column chromatography (silica, 50-100% EtOAc/petroleum ether) afforded the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.17 (d, J=6 Hz, 6H) 2.62 (s, 3H) 2.79-2.97 (m, 2H) 3.50-3.83 (m, 2H) 4.34 (m, 2H) 7.38-7.58 (m, 2H) 7.64-7.86 (m, 1H) 8.05-8.22 (m, 1H).
MS ES+: 420
To a stirred mixture of 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 50 mg, 162 μmol) and ethyl(oxan-4-ylmethyl)amine (CAS 914260-86-9; 93 mg, 648 μmol) in EtOH (2 mL) was added triethylamine (45 μL, 324 μmol). The reaction was heated under microwave irradiation at 155° C. for 2 h, cooled to room temperature and concentrated in vacuo. The resulting residue was partitioned between DCM and water and extracted with DCM. The combined organic layers were dried (H-frit) and concentrated in vacuo. Purification by column chromatography (preparative HPLC, 20-60% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.17 (m, 3H) 1.17-1.34 (m, 2H) 1.42-1.62 (m, 2H) 1.82-2.03 (m, 1H) 3.09-3.28 (m, 2H) 3.37-3.52 (m, 2H) 3.52-3.70 (m, 2H) 3.73-3.95 (m, 2H) 6.45 (br. s., 2H) 7.42-7.71 (m, 3H) 7.90-8.20 (m, 3H) 10.22 (br. s., 1H)
MS ES+: 416
To a stirred mixture of 4-chloro-7-(phenylsulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 50 mg, 162 μmol) and N,2,2-trimethyloxan-4-amine (CAS 90226-98-5; 93 mg, 648 μmol) in EtOH (2 mL) was added triethylamine (45 μL, 324 μmol). The reaction was heated under microwave irradiation at 155° C. for 2 h, cooled to room temperature and concentrated in vacuo. The resulting residue was partitioned between DCM and water and extracted with DCM. The combined organic layers were dried (H-frit) and concentrated in vacuo. Purification by column chromatography (preparative HPLC, 20-60% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (300 MHz, DMSO-d6) δ ppm 1.16 (s, 3H) 1.22 (S, 3H) 1.38-1.62 (m, 3H) 1.62-1.79 (m, 1H) 3.06 (br. s., 3H) 3.63-3.80 (m, 2H) 4.83-5.13 (m, 1H) 6.41 (br. s., 2H) 7.44-7.64 (m, 3H) 7.94-8.06 (m, 2H) 8.10 (br. s., 1H) 10.47 (br. s., 1H)
MS ES+: 416
Prepared as described for 7-(benzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 52) from 4-chloro-7-(4-methoxybenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 19; 200 mg, 590 μmol) and 2-ethylmorpholine (CAS 52769-10-5; 204 mg, 1.77 mmol) in EtOH (4 mL) and heated at 150° C. for 1 h. The crude product was purified by column chromatography (basic silica, 60-100% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 0.92 (t, J=7 Hz, 3H) 1.40-1.59 (m, 2H) 2.98-3.09 (m, 1H) 3.26-3.43 (m, 2H) 3.50-3.60 (m, 1H) 3.83 (s, 3H) 3.92-3.99 (m, 1H) 4.21-4.35 (m, 2H) 7.14 (d, J=9 Hz, 2H) 8.05 (d, J=9 Hz, 2H) 8.38 (s, 1H).
MS ES+: 418
To a stirred solution of 4-chloro-7-(3-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 52; 200 mg, 587 μmol) in EtOH (3 mL) was added 2,2-dimethylmorpholine (CAS 147688-58-2; 149 mg, 1.29 mmol) and the reaction mixture was heated under microwave irradiation at 150° C. for 1 h. The reaction mixture was filtered and the solid recrystallised from EtOH/water to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.17 (br. s., 6H) 2.64 (s, 3H) 3.63-3.85 (m, 6H) 7.50-7.63 (m, 1H) 7.66-7.74 (m, 1H) 7.96-8.19 (m, 2H).
MS ES+: 420
To a stirred solution of 4-chloro-7-(3-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 52; 200 mg, 587 μmol) in EtOH (3 mL) was added 4-oxa-7-azaspiro[2.5]octane (CAS 220291-92-9; 146 mg, 1.29 mmol) and the reaction mixture was heated under microwave irradiation at 150° C. for 1 h. The reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM). Further purification by column chromatography (preparative HPLC, 30-70% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.55-0.64 (m, 2H) 0.68-0.79 (m, 2H) 2.42 (br. s., 3H) 3.43-3.83 (m, 6H) 6.41 (s, 2H) 7.38-7.50 (m, 1H) 7.57-7.64 (m, 1H) 7.82-7.97 (m, 2H) 10.64 (br. s. 1H).
MS ES+: 418
To a stirred solution of 4-chloro-7-(3-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 52; 200 mg, 587 μmol) in EtOH (3 mL) was added methyl(propan-2-yl)amine (CAS 4747-21-1; 94 mg, 1.29 mmol) and the reaction mixture was heated under microwave irradiation at 150° C. for 1 h. The reaction mixture was filtered and the solid recrystallised from EtOH/water to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (d, J=7 Hz, 6H) 2.37 (br. s., 3H) 3.01 (br. s., 3H) 4.71-5.04 (m, 1H) 6.34 (br. s., 2H) 7.32-7.50 (m, 1H) 7.56-7.63 (m, 1H) 7.84-7.89 (m, 1H) 7.91-7.97 (m, 1H) 10.34 (s, 1H).
MS ES+: 378
To a stirred solution of cyclopropylmethanol (CAS 2516-33-8; 85 mg, 1.17 mmol) in anhydrous THF (3 mL) at 0° C. was added sodium hydride (47 mg, 1.17 mmol, 60% dispersion in oil) and stirred for 15 min at 0° C. 4-chloro-7-(3-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 52; 200 mg, 587 μmol) was added and the reaction mixture was heated at reflux for 16 h. The reaction mixture was concentrated in vacuo. The crude product was partitioned between EtOAc and water. The organic phase was dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) and triturated with EtOAc/petroleum ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.28-0.41 (m, 2H) 0.51-0.59 (m, 2H) 1.19-1.32 (m, 1H) 2.47 (s, 3H) 4.23 (d, J=7 Hz, 2H) 6.59 (s, 2H) 7.40-7.49 (m, 1H) 7.56-7.65 (m, 1H) 7.78-8.03 (m, 2H) 11.48 (s, 1H).
MS ES+: 377
To a stirred solution of 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and triethylamine (361 μL, 2.59 mmol) in EtOH (8 mL) was added 2-methylthiomorpholine (CAS 3970-88-5; 152 mg, 1.30 mmol) and the reaction mixture was heated under microwave irradiation at 160° C. for 2 h. The reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% MeOH/DCM). Further purification by column chromatography (C18-silica, 5-60% MeOH/water (with 0.1% ammonia)) and trituration with DCM/petroleum ether afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.26 (m, 3H) 2.57-2.73 (m, 1H) 2.73-2.88 (m, 1H) 2.88-3.01 (m, 1H) 3.01-3.12 (m, 1H) 4.22-4.50 (m, 3H) 6.51 (br. s., 2H) 7.47-7.65 (m, 3H) 8.03 (d, J=7 Hz, 2H) 8.16 (br. s., 1H) 10.63-10.81 (m, 1H)
MS ES+: 390
To a stirred solution of 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and triethylamine (361 μL, 2.59 mmol) in EtOH (8 mL) was added 2-ethylthiomorpholine (CAS 30188-20-6; 170 mg, 1.30 mmol) and the reaction mixture was heated under microwave irradiation at 160° C. for 2 h. The reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% MeOH/DCM). Further purification by column chromatography (C18-silica, 5-60% MeOH/water (with 0.1% ammonia)) and trituration with DCM/petroleum ether afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.88-1.03 (m, 3H) 1.29-1.49 (m, 1H) 1.49-1.65 (m, 1H) 2.59-2.70 (m, 1H) 2.70-2.86 (m, 2H) 3.11-3.24 (m, 1H) 3.36-3.53 (m, 1H) 4.17-4.46 (m, 2H) 6.49 (br. s, 2H) 7.48-7.63 (m, 3H) 8.03 (d, J=7 Hz, 2H) 8.16 (br. s., 1H) 10.71 (br. s., 1H)
MS ES+: 404
To a stirred solution of 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and triethylamine (361 μL, 2.59 mmol) in EtOH (8 mL) was added 2,6-dimethylthiomorpholine (CAS 53651-62-0; 170 mg, 1.30 mmol) and the reaction mixture was heated under microwave irradiation at 160° C. for 2 h. The reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% MeOH/DCM). Further purification by column chromatography (C18-silica, 5-60% MeOH/water (with 0.1% ammonia)) and trituration with DCM/petroleum ether afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.22 (m, 6H) 2.72-2.87 (m, 2H) 2.95-3.08 (m, 2H) 4.40 (br. s., 2H) 6.54 (br. s., 2H) 7.48-7.64 (m, 3H) 7.95-8.11 (m, 2H) 8.17 (br. s., 1H) 10.68 (br. s., 1H)
MS ES+: 404
To a stirred solution of 4-chloro-7-(3-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 52; 200 mg, 587 μmol) in EtOH (3 mL) was added 3-methylpiperidine (CAS 626-56-2; 128 mg, 1.29 mmol) and the reaction mixture was heated under microwave irradiation at 150° C. for 1 h. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) and triturated with EtOAc to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 0.89-0.95 (m, 3H) 1.18-1.31 (m, 1H) 1.45-1.84 (m, 4H) 2.63 (s, 3H) 2.85-2.94 (m, 1H) 3.15-3.24 (m, 1H) 4.28-4.37 (m, 2H) 7.54-7.60 (m, 1H) 7.67-7.74 (m, 1H) 7.99-8.04 (m, 1H) 8.06-8.11 (m, 1H).
MS ES+: 404
To a stirred solution of 4-chloro-7-(3-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 52; 200 mg, 587 μmol) in EtOH (3 mL) was added 6-oxa-9-azaspiro[4.5]decane (CAS 130643-07-1; 182 mg, 1.29 mmol) and the reaction mixture was heated under microwave irradiation at 150° C. for 1 h. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) and triturated with EtOAc to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.49-1.72 (m, 8H) 2.63 (s, 3H) 3.68-3.75 (m, 2H) 3.77-3.85 (m, 4H) 7.53-7.59 (m, 1H) 7.67-7.73 (m, 1H) 7.98-8.06 (m, 1H) 8.08-8.13 (m, 1H).
MS ES+: 446
To a stirred solution of 4-chloro-7-(3-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 52; 200 mg, 587 μmol) in EtOH (3 mL) was added (2R,6R)-2,6-dimethylmorpholine (CAS 171753-74-5; 149 mg, 1.29 mmol) and the reaction mixture was heated under microwave irradiation at 150° C. for 1 h. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) and triturated with EtOAc to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.07-1.18 (m, 6H) 2.64 (s, 3H) 3.56-3.66 (m, 2H) 3.83-3.91 (m, 2H) 4.04-4.14 (m, 2H) 7.52-7.60 (m, 1H) 7.67-7.75 (m, 1H) 8.00-8.06 (m, 1H) 8.07-8.16 (m, 1H).
MS ES+: 420
To a stirred solution of cyclopentylmethanol (CAS 3637-61-4; 130 mg, 1.30 mmol) in anhydrous THF (3 mL) at 0° C. was added sodium hydride (55 mg, 1.36 mmol, 60% dispersion in oil) and stirred for 30 min at 0° C. 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) was added and the reaction mixture was heated under microwave irradiation at 110° C. for 2 h. The reaction mixture was poured into water, neutralised with 2 M aq. HCl solution and extracted with EtOAc. The organic phase was washed with brine, dried (H-frit) and concentrated in vacuo. The aqueous phase was acidified to pH4 with 2 M aq. HCl solution and extracted with EtOAc. The organics were concentrated in vacuo. The combined crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) and triturated with EtOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.26-1.38 (m, 2H) 1.46-1.66 (m, 4H) 1.68-1.80 (m, 2H) 2.26-2.39 (m, 1H) 4.29 (d, J=7 Hz, 2H) 6.64 (s, 2H) 7.50-7.59 (m, 3H) 7.99-8.05 (m, 2H) 8.26 (s, 1H) 11.45 (s, 1H).
MS ES+: 373
To a stirred solution of cyclopentanol (CAS 96-41-3; 112 mg, 1.30 mmol) in anhydrous THF (3 mL) at 0° C. was added sodium hydride (55 mg, 1.36 mmol, 60% dispersion in oil) and stirred for 30 min at 0° C. 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) was added and the reaction mixture was heated under microwave irradiation at 110° C. for 2 h. The reaction mixture was poured into water, acidified to pH4 with 2 M aq. HCl solution and extracted with EtOAc. The organic phase was washed with brine and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM). Further purification by column chromatography (silica, 0-100% EtOAc/petroleum ether). Further purification by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.82 (m, 6H) 1.85-2.01 (m, 2H) 5.48-5.57 (m, 1H) 6.61 (s, 2H) 7.50-7.60 (m, 3H) 7.99-8.05 (m, 2H) 8.26 (s, 1H) 11.38 (br. s., 1H).
MS ES+: 373
To a stirred solution of 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 500 mg, 1.47 mmol) and triethylamine (409 μL, 2.93 mmol) in EtOH (10 mL) was added (2R,6R)-2,6-dimethylmorpholine (CAS 171753-74-5; 338 mg, 2.93 mmol) and the reaction mixture was heated under microwave irradiation at 140° C. for 2 h. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and water. The resulting precipitate was filtered and triturated with hot EtOH. The crude product was purified by column chromatography (preparative HPLC, 5-95% acetonitrile/water (with 0.1% ammonia)) and recrystallised from EtOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.25 (m, 6H) 2.61 (s, 3H) 3.53-3.73 (m, 2H) 3.80-3.96 (m, 2H) 4.00-4.21 (m, 2H) 7.38-7.52 (m, 2H) 7.66-7.84 (m, 1H) 8.05-8.22 (m, 1H).
MS ES+: 420
To a stirred solution of 4-chloro-7-(4-methoxybenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 57; 400 mg, 1.13 mmol) and triethylamine (316 μL, 2.27 mmol) in EtOH (10 mL) was added 2,2-dimethylmorpholine (CAS 147688-58-2; 196 mg, 1.70 mmol) and the reaction mixture was heated under microwave irradiation at 160° C. for 5 h. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and water. The organic phase was dried (H-frit). The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) and recrystallised from EtOH/water to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.16 (s, 6H) 2.63 (s, 3H) 3.68 (s, 2H) 3.71-3.81 (m, 4H) 3.83 (s, 3H) 7.13 (d, J=9 Hz, 2H) 8.12 (d, J=9 Hz, 2H)
MS ES+: 432
To a stirred solution of 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 940 mg, 2.91 mmol) and triethylamine (812 μL, 5.82 mmol) in EtOH (8 mL) was added 4-oxa-7-azaspiro[2.5]octane (CAS 220291-92-9; 389 mg, 3.44 mmol) and the reaction mixture was heated under microwave irradiation at 155° C. for 9 h. The reaction mixture was concentrated in vacuo and purified by column chromatography (silica, 30-75% EtOAc/petroleum ether) and recrystallised from EtOAc/EtOH (4:1) to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 0.59-0.70 (m, 2H) 0.70-0.78 (m, 2H) 2.63 (s, 3H) 3.69-3.80 (m, 2H) 3.82 (br. S., 2H) 3.86-3.96 (m, 2H) 7.36 (br. s., 1H) 7.58-7.67 (m, 2H) 7.67-7.74 (m, 1H) 8.13-8.20 (m, 1H).
MS ES+: 400
Prepared as described for 7-(2-methylbenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 120) from 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 287 mg, 125 μmol) and benzyl 4-(cyanomethanesulfonyl)piperidine-1-carboxylate (Intermediate 58; 485 mg, 1.50 mmol) in anhydrous dioxane (1.5 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 3 h. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether). The crude product was further purified by column chromatography (silica, 0-10% MeOH/DCM). Further purification by column chromatography (preparative HPLC, 5-95% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.19 (d, J=6 Hz, 3H) 1.41-1.57 (m, 2H) 1.97-2.08 (m, 2H) 2.84 (br. s., 2H) 2.97-3.08 (m, 1H) 3.24-3.39 (m, 1H) 3.42-3-54 (m, 1H) 3.54-3.71 (m, 2H) 3.91-4.02 (m, 1H) 4.06-4.16 (m, 2H) 4.28-4.37 (m, 2H) 5.07 (br. S., 2H) 7.23 (br. s., 1H) 7.29-7.41 (m, 5H) 8.34 (s, 1H) 12.09 (hr. s., 1H).
MS ES+: 515
To a stirred solution of 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 990 mg, 3.07 mmol) and triethylamine (855 μL, 6.13 mmol) in EtOH (6 mL) was added 6-azaspiro[2.5]octane (CAS 872-64-0; 477 mg, 4.29 mmol) and the reaction mixture was heated under microwave irradiation at 160° C. for 2 h. The reaction mixture was concentrated in vacuo, diluted with 1% aq. AcOH solution and extracted with EtOAc. The combined organics were washed with aq. NaHCO3 solution, brine, dried (H-frit) and concentrated in vacuo. The crude product was and recrystallised from EtOH/water to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 0.40 (s, 4H) 1.37-1.51 (m, 4H) 2.63 (s, 3H) 3.77-3.92 (m, 4H) 7.19 (br. s., 1H) 7.58-7.67 (m, 2H) 7.67-7.73 (m, 1H) 8.12-8.20 (m, 2H) 11.75 (br. s, 1H) 12.85 (br. s, 1H).
MS ES+: 398
To a stirred solution of 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 750 mg, 2.20 mmol) in EtOH (8 mL) was added 4-oxa-7-azaspiro[2.5]octane (CAS 220291-92-9; 548 mg, 4.84 mmol) (and the reaction mixture was heated under microwave irradiation at 150° C. for 2 h. The reaction mixture was concentrated in vacuo, partitioned between water and DCM and the organic phase concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether). Further purification by column chromatography (C-18 silica, 5-95% acetonitrile/water (with 0.1% ammonia)) and recrystallised from EtOH/water afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.65-0.79 (m, 4H) 2.61 (s, 3H) 3.74-3.82 (m, 2H) 3.84-3.91 (m, 2H) 3.92-3.99 (m, 2H) 7.40-7.49 (m, 2H) 7.72-7.81 (m, 1H) 8.10-8.18 (m, 1H).
MS ES+: 416
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 4-(cyclopent-1-en-1-yl)-7-(3-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 59; 137 mg, 368 mmol) in MeOH (2 mL) and THF (1 mL). The reaction mixture was stirred at rt for 16 h. A further portion of palladium on carbon (20 mg, 18 μmol) was added and the reaction was stirred at rt for 4 h. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 1.63-1.78 (m, 2H) 1.80-1.94 (m, 4H) 2.06-2.28 (m, 2H) 2.57 (s, 3H) 3.17-3.40 (m, 1H) 6.24 (br. s., 2H) 7.25-7.37 (m, 1H) 7.49-7.61 (m, 1H) 7.89-8.02 (m, 2H) 9.32 (br. s., 1H).
MS ES+: 375
Prepared as described for 7-(benzenesulfonyl)-4-(cyclopentylmethoxy)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 201) from 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 2,6-dimethyloxan-4-ol (CAS 41866-70-0; 169 mg, 1.30 mmol) in THF (3 mL) and heated at reflux for 16 h. The crude product was purified by column chromatography (C-18 silica, 5-40% acetonitrile/water (with 0.1% ammonia)) and triturated with DCM to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (s, 3H) 1.14 (s, 3H) 1.15-1.26 (m, 2H) 2.05-2.14 (m, 2H) 3.51-3.61 (m, 2H) 5.27-5.39 (m, 1H) 6.64 (s, 2H) 7.50-7.61 (m, 3H) 7.99-8.06 (m, 2H) 8.26 (s, 1H) 11.46 (br. s., 1H).
MS ES+: 403
Prepared as described for 7-(benzenesulfonyl)-4-(cyclopentylmethoxy)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 201) from 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 4,4-difluorocyclohexan-1-ol (CAS 22419-35-8; 176 mg, 1.30 mmol) in THF (3 mL) and heated at reflux for 16 h. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) and triturated with DCM and then DCM/MeOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-2.05 (m, 6H) 2.06-2.23 (m, 2H) 5.35-5.45 (m, 1H) 6.73 (s, 2H) 7.51-7.59 (m, 3H) 8.00-8.05 (m, 2H) 8.27 (s, 1H) 11.47 (br. s., 1H).
MS ES+: 409
Prepared as described for 7-(benzenesulfonyl)-4-(cyclopentylmethoxy)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 201) from 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and 1-cyclopentylethan-1-ol (CAS 52829-98-8; 148 mg, 1.30 mmol) in THF (3 mL) and heated at reflux for 16 h. After this time an additional mixture of 1-cyclopentylethan-1-ol (CAS 52829-98-8; 296 mg, 2.60 mmol) and sodium hydride (109 mg, 2.72 mmol, 60% dispersion in oil) were added to the reaction mixture and heater under microwave irradiation at 110° C. for 6 h. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.39 (m, 5H) 1.41-1.64 (m, 4H) 1.65-1.79 (m, 2H) 2.06-2.19 (m, 1H) 5.19-5.28 (m, 1H) 6.61 (s, 2H) 7.50-7.60 (m, 3H) 7.99-8.06 (m, 2H) 8.25 (s, 1H) 11.37 (s, 1H).
MS ES+: 387
Prepared as described for 7-(benzenesulfonyl)-4-(cyclopentylmethoxy)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 201) from 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 200 mg, 648 μmol) and pentan-3-ol (CAS 584-02-1; 114 mg, 1.30 mmol) in THF (3 mL) and heated under microwave irradiation at 110° C. for 6 h and then at 120° C. for 16 h. The crude product was purified by column chromatography (silica, 0-5% MeOH/DCM) and triturated with DCM to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 (t, J=7 Hz, 6H) 1.59-1.74 (m, 4H) 5.16-5.25 (m, 1H) 6.61 (s, 2H) 7.51-7.61 (m, 3H) 8.00-8.07 (m, 2H) 8.25 (s, 1H) 11.45 (s, 1H).
MS ES+: 361
To a stirred solution of 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 750 mg, 2.20 mmol) in EtOH (8 mL) was added 6-azaspiro[2.5]octane (CAS 872-64-0; 538 mg, 4.84 mmol) and the reaction mixture was heated under microwave irradiation at 150° C. for 2 h. The reaction mixture was concentrated in vacuo and partitioned between DCM and water. The organic phase was concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether). Further purification by column chromatography (C-18 silica, 5-95% acetonitrile/water (with 0.1% ammonia)) and recrystallisation from EtOH/water afforded the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 0.41 (s, 4H) 1.32-1.57 (m, 4H) 2.60 (s, 3H) 3.77-3.98 (m, 4H) 7.39-7.52 (m, 2H) 7.66-7.82 (m, 1H) 8.10-8.18 (m, 1H).
MS ES+: 416
Prepared as described for 7-(benzenesulfonyl)-2-methyl-4-{4-oxa-7-azaspiro[2.5]octan-7-yl}-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 205) from 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and octahydrocyclopenta[b]morpholine (CAS 1018639-83-2; 257 mg, 2.02 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 130° C. for 5 h. The crude product was purified by column chromatography (silica, 0-20% MeOH/DCM). Further purification by column chromatography (C-18 silica, 5-60% acetonitrile/water (with 0.1% ammonia)) and trituration with DCM/petroleum ether afforded the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.30-1.43 (m, 1H) 1.43-1.55 (m, 1H) 1.57-1.76 (m, 2H) 1.79-1.97 (m, 1H) 2.57-2.73 (m, 1H) 3.18-3.33 (m, 2H) 3.49-3.65 (m, 1H) 3.84-4.06 (m, 3H) 7.52-7.74 (m, 3H) 8.07-8.17 (m, 2H) 8.43 (s, 1H)
MS ES+: 400
Prepared as described for 7-(benzenesulfonyl)-2-methyl-4-{4-oxa-7-azaspiro[2.5]octan-7-yl}-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 205) from 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and morpholine-2-carbonitrile hydrochloride (CAS 1205751-24-0; 301 mg, 2.02 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 130° C. for 8 h. The crude product was purified by column chromatography (silica, 0-20% MeOH/DCM). Further purification by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) and trituration with DCM/petroleum ether afforded the title compound.
1H NMR (300 MHz, DMSO-d6+TFA-d) δ ppm 3.61-4.09 (m, 5H) 4.29-4.47 (m, 1H) 5.04 (br. s., 1H) 7.48-7.68 (m, 3H) 8.004-8.15 (m, 2H) 8.38 (s, 1H)
MS ES+: 385
To a stirred solution of 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 554 mg, 1.72 mmol) and triethylamine (520 μL, 5.15 mmol) in EtOH (4 mL) was added (2R,5R)-2,5-dimethylmorpholine hydrochloride (CAS 67804-27-7; 390 mg, 2.57 mmol) and the reaction mixture was heated under microwave irradiation at 165° C. for 4 h. The reaction mixture was concentrated in vacuo and purified by column chromatography (silica, 30-70% EtOAc/petroleum ether), triturated with DCM/diethyl ether and recrystallised from EtOH/water to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.19 (d, J=6 Hz, 3H) 1.27 (d, J=7 Hz, 3H) 2.64 (s, 3H) 3.09-3.24 (m, 1H) 3.50-3.62 (m, 1H) 3.64-3.80 (m, 2H) 3.99-4.21 (m, 1H) 4.53-4.73 (m, 1H) 7.37 (br. s., 1H) 7.58-7.74 (m, 3H) 8.11-8.20 (m, 2H).
MS ES+: 402
To a stirred solution of 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 750 mg, 2.20 mmol) and triethylamine (614 μL, 4.40 mmol) in EtOH (8 mL) was added (2S)-2-methylmorpholine (CAS74572-13-7; 445 mg, 4.40 mmol) and the reaction mixture was heated under microwave irradiation at 140° C. for 2 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was concentrated in vacuo. The crude product was purified by column chromatography (C-18 silica, 5-95% acetonitrile/water (with 0.1% ammonia)) and recrystallised from EtOH/water afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (d, J=6 Hz, 3H) 2.61 (s, 3H) 2.85-3.09 (m, 1H) 3.18-3.37 (m, 1H) 3.48-3.72 (m, 2H) 3.81-4.04 (m, 1H) 4.19-4.44 (m, 2H) 7.33-7.55 (m, 2H) 7.65-7.84 (m, 1H) 8.14 (s, 1H).
MS ES+: 406
To a stirred and nitrogen degassed solution of 2-(benzenesulfonyl)acetonitrile (CAS 7605-25-9; 330 mg, 1.86 mmol) in anhydrous DME (5 mL) was added sodium hydride (220 mg, 5.59 mmol, 60% dispersion in oil) at 0° C. The mixture was stirred at 0° C. for 5 min and then at rt for 5 min. This mixture was added to a previously nitrogen degassed solution of 2-chloro-4-(4,4-difluoropiperidin-1-yl)pyridin-3-amine (Intermediate 62; 230 mg, 931 μmol), tetrakis(triphenylphosphane) palladium (107 mg, 91 μmol) and di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (65 mg, 91 μmol) in anhydrous DME (5 mL). The reaction mixture was heated under microwave irradiation at 130° C. for 2 h. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was dried (Na2SO4). The reaction mixture was concentrated in vacuo and purified by column chromatography (silica, 0-5% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 2.09-2.22 (m, 4H) 3.57-3.68 (m, 4H) 6.91-6.97 (m, 1H) 7.60-7.73 (m, 3H) 7.85-7.92 (m 1H) 8.09-8.15 (m, 2H).
MS ES+: 393
To a stirred solution of 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 938 mg, 2.91 mmol) and triethylamine (1.62 mL, 11.62 mmol) in EtOH (14 mL) was added (2S,5S)-2,5-dimethylmorpholine hydrochloride (CAS 1258277-12-1; 991 mg, 6.54 mmol) and the reaction mixture was heated under microwave irradiation at 170° C. for 14 h. The reaction mixture was concentrated in vacuo, sonicated in water, filtered, washed with water and dried (oven). The crude product was dissolve in hot EtOH and decolurised with charcoal, filtered and crystallised to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.19 (d, J=6 Hz, 3H) 1.27 (d, J=7 Hz, 3H) 2.64 (s, 3H) 3.07-3.23 (m, 1H) 3.50-3.63 (m, 1H) 3.65-3.79 (m, 2H) 4.09 (m, 1H) 4.63 (br. s., 1H) 7.59-7.73 (m, 3H) 8.17 (d, J=7 Hz, 2H).
MS ES+: 402
Prepared as described for 7-(benzenesulfonyl)-2-methyl-4-{4-oxa-7-azaspiro[2.5]octan-7-yl}-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 205) from 7-(benzenesulfonyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 3; 250 mg, 810 μmol) and 2-ethyl-2-methylmorpholine (CAS 1240527-64-3; 262 mg, 2.02 mmol) in EtOH (8 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 4 h. The crude product was purified by column chromatography (silica, 0-20% MeOH/DCM and recrystallised for EtOH/water to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.83 (t, J=8 Hz, 3H) 1.01-1.15 (m, 4H) 1.31-1.47 (m, 1H) 1.58-1.77 (m, 1H) 3.34-3.55 (m, 3H) 3.62-3.84 (m, 2H) 6.34-6.62 m, 2H) 7.42-7.69 (m, 3H) 8.03 (d, J=7 Hz, 2H) 8.14 (br. s., 1H) 10.66 (br. s., 1H).
MS ES+: 402
Prepared as described for 7-(2-methylbenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 120) from 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 155 mg, 678 μmol) and 2-(4-fluoro-2-methoxybenzenesulfonyl)acetonitrile (Intermediate 63; 202 mg, 881 μmol) in anhydrous dioxane (2.7 mL) and the reaction mixture was heated under microwave irradiation at 120° C. for 3 h. After this time additional portions of di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl] phosphanium (14 mg, 20 μmol) and tetrakis(triphenylphosphane) palladium (24 mg, 20 μmol) were added and the reaction mixture was heated under microwave irradiation at 120° C. for 3 h. The crude product was purified by column chromatography (silica, 20-100% EtOAc/petroleum ether then 0-10% MeOH/DCM). Further purification by column chromatography (preparative HPLC, 5-40% acetonitrile/water (with 0.1% ammonia)) afforded the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.17 (d, J=6 Hz, 3H) 2.95-3.06 (m, 1H) 3.22-3.35 (m, 1H) 3.53-3.69 (m, 2H) 3.77 (s, 3H) 3.87-3.99 (m, 1H) 4.26-4.38 (m, 1H) 6.98-7.06 (m, 1H) 7.10-7.18 (m, 1H) 7.19-7.40 (m, 2H) 8.11-8.19 (m, 1H) 8.37 (s, 1H), 12.16 (br. s, 1H).
MS ES+: 422
To a stirred solution of 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 900 mg, 2.64 mmol) in EtOH (8 mL) was added (2S,5S)-2,5-dimethylmorpholine hydrochloride (CAS 1258277-12-1; 481 mg, 3.17 mmol) and ethylbis(propan-2-yl)amine and the reaction mixture was heated under microwave irradiation at 150° C. for 2 h. The reaction mixture was concentrated in vacuo. The crude product was partitioned between DCM and water. The combined organic fractions were concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether). Further purification by column chromatography (C-18 silica, 5-95% acetonitrile/water (with 0.1% ammonia)) and recrystallisation from EtOH afforded the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.20 (d, J=6. Hz, 3H) 1.29 (d, J=7 Hz, 3H) 2.61 (s, 3H) 3.11-3.24 (m, 1H) 3.52-3.66 (m, 1H) 3.68-3.80 (m, 2H) 4.03-4.21 (m, 1H) 4.57-4.77 (m, 1H) 7.39-7.49 (m, 2H) 7.71-7.79 (m, 1H) 8.08-8.22 (m, 1H).
MS ES+: 420
To a stirred and nitrogen degassed solution of 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 900 mg, 2.64 μmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (CAS 126726-62-3; 1.35 g, 8.06 mmol) and potassium phosphate (1.68 g, 7.92 mmol) in dioxane (36 mL) and water (9 mL) was added di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl] phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium (187 mg, 264 μmol) and the reaction mixture was irradiated in the microwave at 140° C. for 1.5 h. The reaction mixture was concentrated in vacuo. The crude product was partitioned between EtOAc and water. The organic phase was concentrated in vacuo. The crude product was purified by column chromatography (silica, 100% EtOAc), triturated with EtOAc and recrystallised from EtOH/water to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 3H) 2.41 (s, 3H) 5.61 (d, J=13 Hz, 2H) 6.78 (br. s, 2H) 7.23-7.50 (m, 2H) 7.56-7.75 (m, 1H) 7.95-8.18 (m, 1H) 10.75-11.02 (m, 1H).
MS ES+: 347
To a stirred solution of 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 938 mg, 2.91 mmol) and triethylamine (1.30 mL, 9.30 mmol) in EtOH (14 mL) was added 2-(trifluoromethyl)morpholine hydrochloride (CAS 1394909-69-3; 900 mg, 4.70 mmol) and the reaction mixture was heated under microwave irradiation at 170° C. for 5 h. The reaction mixture was concentrated in vacuo. The crude product was partitioned between EtOAc and water. The organic phase was washed with water, washed with brine, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 30-60% EtOAc/petroleum ether). Further purification by column chromatography (silica, 0-35% EtOAc/DCM) and recrystallisation from EtOH/heptane afforded the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 2.67 (s, 3H) 3.34-3.51 (m, 2H) 3.67-3.80 (m, 1H) 4.02-4.14 (m, 1H) 4.18-4.30 (m, 1H) 4.31-4.44 (m, 1H) 4.45-4.57 (m, 1H) 7.58-7.75 (m, 3H) 8.18 (d, J=7 Hz, 2H).
MS ES+: 442
To a stirred solution of 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 910 mg, 2.82 mmol) and triethylamine (629 L, 4.51 mmol) in EtOH (12 mL) was added (2S)-2-methylmorpholine (CAS 74572-13-7; 456 mg, 4.51 mmol) and the reaction mixture was heated under microwave irradiation at 160° C. for 2 h. The reaction mixture was concentrated in vacuo. The crude product was partitioned between EtOAc and water. The organic phase was washed with water, washed with brine, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 50-80% EtOAc/DCM) and recrystallised from EtOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.15 (d, J=6 Hz, 3H) 2.64 (s, 3H) 2.90-3.02 (m, 1H) 3.19-3.31 (m, 1H) 3.49-3.65 (m, 2H) 3.87-3.97 (m, 1H) 4.22-4.37 (m, 2H) 7.57-7.75 (m, 3H) 8.16 (d, J=7 Hz, 2H).
MS ES+: 388
Prepared as described for 7-(benzenesulfonyl)-4-(cyclohex-1-en-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 2) from 5-chloro-3-(cyclohex-1-en-1-yl)pyridazin-4-amine (Intermediate 65; 100 mg, 477 μmol) in DME (5 mL). The reaction mixture was heated under microwave irradiation at 130° C. for 3 h, poured into water and extracted with EtOAc. The organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was triturated with EtOAc and then with EtOH/water to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.82 (m, 4H) 2.23-2.32 (m, 2H) 2.54-2.65 (m, 2H) 6.57 (br. s., 2H) 7.50-7.62 (m, 3H) 7.50-7.61 (m, 2H) 8.82 (br. s., 1H).
MS ES+: 355
Prepared as described for 7-(benzenesulfonyl)-4-cyclohexyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 3) from 3-(benzenesulfonyl)-7-(cyclohex-1-en-1-yl)-1H-pyrrolo[2,3-d]pyridazin-2-amine (Example 227; 50 mg, 141 μmol) in anhydrous MeOH (1 mL) and anhydrous THF (1 mL). The crude product was purified by column chromatography (silica, 0-20% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.46 (m, 2H) 1.59-1.91 (m, 6H) 2.23-2.31 (m, 1H) 2.54-2.61 (m, 1H) 3.19-3.29 (m, 1H) 6.67 (br. s., 2H) 7.50-7.62 (m, 3H) 7.93-8.01 (m, 2H) 8.84 (br. s, 1H) 14.41 (br. s, 1H).
MS ES+: 357
A solution of 2-(2,5-difluorobenzenesulfonyl)-2-[2-methyl-6-(2-methylmorpholin-4-yl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 67; 0.21 g, 0.463 mmol) in acetic acid (2.50 mL) was treated with zinc (85 mg, 1.300 μmol) and stirred at RT for 20 h. The reaction mixture was sonicated for 20 min and stirred at 50° C. for 24 h. The reaction mixture was filtered through Celite, washing with MeOH and the filtrated concentrated in vacuo. The crude product was purified by column chromatography (silica, 20-75% ethyl acetate/petroleum ether to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.17 (d, J=6 Hz, 3H) 2.62 (s, 3H) 2.93-3.05 (m, 1H) 3.21-3.32 (m, 1H) 3.52-3.67 (m, 2H) 3.89-3.98 (m, 1H) 4.24-4.38 (m, 2H) 7.37 (br. s., 1H) 7.48-7.58 (m, 1H) 7.59-7.68 (m, 1H) 7.98-8.05 (m, 1H)
MS ES+: 424
To a stirred solution of 1-cyclopropylethan-1-ol (CAS765-42-4; 551 μL, 5.64 mmol) in THF (7 mL) was added (sodium hydride (231 mg, 5.78 mmol, 60% dispersion in oil) and left to stir at rt for 15 min. 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 910 mg, 2.82 mmol) in THF (7 mL) was then added via cannula and the reaction mixture was heated at 70° C. for 16 h then under microwave irradiation at 100° C. for 3 h. The reaction mixture was concentrated in vacuo. The crude product was poured into sat. aq. NH4Cl solution and extracted with EtOAc. The organic phase was washed with water/brine (1:1), brine, dried (H-frit) and concentrated in vacuo. The crude product was triturated with petroleum ether and purified by column chromatography (silica, 15-55% EtOAc/petroleum ether). Recrystallisation from EtOH/heptane afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 0.29-0.58 (m, 4H) 1.05-1.17 (m, 1H) 1.35 (d, J=6 Hz, 3H) 2.44 (s, 3H) 4.77-4.89 (m, 1H) 6.52 (s, 2H) 7.48-7.64 (m, 3H) 7.99-8.10 (m, 2H) 11.34 (s, 1H).
MS ES+: 373
To a stirred solution of 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 750 mg, 2.20 mmol) and triethylamine (982 μL, 7.04 mmol) in EtOH (8 mL) was added 2-(trifluoromethyl)morpholine hydrochloride (CAS 1394909-69-3; 650 mg, 3.39 mmol) and the reaction mixture was heated under microwave irradiation at 170° C. for 6 h. The reaction mixture was concentrated in vacuo. The crude product was partitioned between EtOAc and water. The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-50% EtOAc/petroleum ether). Further purification by column chromatography (silica, 0-30% EtOAc/DCM) and recrystallisation from methyl acetate and pentane afforded the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 2.64 (s, 3H) 3.32-3.53 (m, 2H) 3.65-3.86 (m, 1H) 4.02-4.16 (m, 1H) 4.18-4.31 (m, 1H) 4.32-4.46 (m, 1H) 4.47-4.63 (m, 1H) 7.34-7.53 (m, 2H) 7.65-7.82 (m, 1H) 8.04-8.24 (m, 1H).
MS ES+: =460
To a stirred solution of 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 1.00 g, 2.93 mmol) and ethylbis(propan-2-yl)amine (1.54 mL, 8.80 mmol) in EtOH (8 mL) was added (2R,5R)-2,5-dimethylmorpholine (CAS 1130061-44-7; 534 mg, 3.52 mmol) and the reaction mixture was heated under microwave irradiation at 150° C. for 2 h. Further portions of (2R,5R)-2,5-dimethylmorpholine (CAS 1130061-44-7; 200 mg, 1.31 mmol) and ethylbis(propan-2-yl)amine (1.00 mL, 5.71 mmol) were added and the reaction mixture was heated under microwave irradiation at 160° C. for 3 h. The reaction mixture was concentrated in vacuo. The crude product was partitioned between EtOAc and water. The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether). Further purification by column chromatography (C-18 silica, 5-95% acetonitrile/water (with 0.1% ammonia)), triutation with diethyl ether, then EtOAc, then MTBE and recrystallisation from EtOH afforded the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.20 (d, J=6 Hz, 3H) 1.29 (d, J=7 Hz, 3H) 2.62 (s, 3H) 3.12-3.25 (m, 1H) 3.54-3.63 (m, 1H) 3.68-3.81 (m, 2H) 4.06-4.21 (m, 1H) 4.57-4.68 (m, 1H) 7.41-7.51 (m, 2H) 7.70-7.80 (m, 1H) 8.09-8.19 (m, 1H) 8.11-8.18 (m, 1H).
MS ES+: 420
To a stirred solution of 4-chloro-7-(2-fluoro-4-methoxybenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 69; 245 mg, 661 μmol) and triethylamine (276 μL, 1.98 mmol) in EtOH (2 mL) was added (2S)-2-methylmorpholine (CAS74572-13-7; 100 mg, 991 μmol) and the reaction mixture was heated under microwave irradiation at 160° C. for 2 h. The reaction mixture was concentrated in vacuo. The crude product was partitioned between MTBE and 2 M aq. NaOH solution. The aqueous phase was acidified with sat. aq. citric acid solution and extracted with EtOAc/THF (2:1), dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)). Further purification by column chromatography (silica, 50-80% EtOAc/petroleum ether) afforded the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.17 (d, J=6 Hz, 3H) 2.61 (s, 3H) 2.99 (m, 1H) 3.21-3.33 (m, 1H) 3.52-3.68 (m, 2H) 3.85 (s, 3H) 3.90-3.97 (m, 1H) 4.26-4.38 (m, 2H) 6.96-7.02 (m, 1H) 7.02-7.09 (m, 1H) 7.22 (br. s., 1H) 8.04-8.12 (m, 1H), 12.02 (br. s, 1H) 12.84 (br. s, 1H).
MS ES+: 436
A stirred solution of 7-(2,2-dimethylmorpholino)-3-((2-fluorophenyl)sulfonyl)-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-d]pyridazin-2-amine (Intermediate 72; 86 mg, 164 μmol) in TFA (1.5 mL, 19.5 mmol) was heated in a sealed tube at 80° C. for 16 h. The reaction mixture was allowed to cool, concentrated in vacuo and the resulting residue was taken up in sat. aq. NaHCO3 solution and extracted with EtOAc. The combined organics were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (preparative HPLC, 5-40% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (s, 6H) 3.58-3.74 (m, 4H) 3.82 (br. s., 2H) 6.20 (br. s, 2H) 7.16-7.34 (m, 2H) 7.49-7.60 (m, 1H) 7.92-8.00 (m, 1H) 8.41 (s, 1H).
MS ES+: 406
To a stirred suspension of 2-(4-chloro-2-fluorobenzenesulfonyl)-2-{2-methyl-6-[(2S)-2-methylmorpholin-4-yl]-5-nitropyrimidin-4-yl}acetonitrile (Intermediate 75; 353 mg, 0.751 mmol) in AcOH (3 mL) and MeOH (1.5 mL) at 0° C. was added iron (126 mg, 2.25 mmol) portionwise. The reaction mixture was allowed to stir at rt for 4 hours. A second portion of iron (126 mg, 2.25 mmol) was added and the reaction mixture stirred at 35° C. for 16 h. The reaction mixture was then filtered through celite and washed through with acetic acid, methanol and then EtOAc. The filtrate was concentrated and the resulting residue was partitioned between water and EtOAc. The organics were separated and the aqueous phase was basified to pH7 with 2M aq. NaOH solution. The aqueous phase was re-extracted with EtOAc and the combined organics were dried (MgSO4) and concentrated in vacuo.
The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) followed by recrystallisation from EtOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.16 (d, J=6 Hz, 3H) 2.60 (s, 3H) 2.94-3.06 (m, 1H) 3.20-3.35 (m, 1H) 3.49-3.71 (m, 2H) 3.91-3.97 (m, 1H) 4.28-4.37 (m, 2H) 7.55-7.60 (m, 1H) 7.70-7.76 (m, 1H) 8.12-8.19 (m, 1H).
MS ES+: 440
Prepared as described for 7-(benzenesulfonyl)-4-(cyclohex-1-en-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 2) from 4-chloro-6-(2-methylmorpholin-4-yl)pyrimidin-5-amine (Intermediate 29; 500 mg, 2.19 mmol) and 2-(phenylsulfanyl)acetonitrile (CAS 5219-61-4; 359 mg, 2.41 mmol). Upon completion the reaction mixture was poured into sat. aq. NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water, brine, dried (H-frit) and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) followed by further column chromatography (silica, 0-7% MeOH/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (d, J=6 Hz, 3H) 2.64-2.75 (m, 1H) 2.98-3.10 (m, 1H) 3.58-3.73 (m, 2H) 3.88-3.96 (m, 1H) 3.96-4.17 (m, 2H) 6.03 (br. s., 2 H) 6.95-7.01 (m, 2H) 7.02-7.08 (m, 1H) 7.15-7.23 (m, 2H) 8.09 (s, 1H) 10.67 (br. s., 1H).
MS ES+: 342
A stirred suspension of 4-chloro-7-((2-fluorophenyl)sulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 750 mg, 2.20 mmol), 5-oxa-8-azaspiro[3.5]nonane (CAS 220291-93-0; 420 mg, 3.30 mmol) and triethylamine (0.920 mL, 6.60 mmol) in EtOH (10 mL) was heated under microwave irradiation at 150° C. for 1 h. The reaction mixture was concentrated under reduced pressure directly onto loose silica and purified by column chromatography (silica, 0-20% MeOH/DCM) followed by further column chromatography (C18 silica, 5-95% acetonitrile/water (with 0.05% ammonia)). The resulting material was recrystallised from EtOH/water to afford the title compound.
1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.71-1.84 (m, 2H) 1.90-2.11 (m, 4H) 2.56 (s, 3H) 3.62-3.73 (m, 2H) 4.13-4.24 (m, 2H) 4.24-4.37 (m, 2H) 7.03-7.21 (m, 1H) 7.31 (t, J=8 Hz, 1H) 7.48-7.63 (m, 1H) 8.00 (t, J=8 Hz, 1H).
MS ES+: 432
A stirred solution of 7-(benzenesulfonyl)-4-chloro-2-(methylsulfanyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 76; 135 mg, 380 μmol), 2-methylmorpholine (CAS 27550-90-9; 51 mg, 500 μmol), triethylamine (150 μL, 1.08 mmol) in EtOH (2 mL) was heated under microwave irradiation at 150° C. for 20 min. The mixture was further heated under microwave irradiation at 160° C. for 20 min. The mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic phase was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-8% MeOH/DCM) followed by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) and the resulting solid was triturated with MeOH to afford the title compound
1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, J=6 Hz, 3H) 2.45 (s, 3H) 2.62-2.72 (m, 1H) 2.93-3.05 (m, 1H) 3.51-3.62 (m, 2H) 3.83-4.01 (m, 3H) 6.48 (s, 2H) 7.50-7.62 (m, 3H) 7.98-8.07 (m, 2H) 10.71 (s, 1H).
MS ES+: 420
A solution of 7-(4-bromo-2-fluorobenzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 79; 170 mg, 405 μmol), (2S)-2-methylmorpholine (CAS 74572-13-7; 65.6 mg, 648 μmol), triethylamine (113 μL, 810 μmol) and EtOH (1.35 mL) was heated under microwave irradiation at 155° C. for 3 h. The reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) followed by column chromatography (preparative HPLC, 10-50% acetonitrile/water (with 0.1% ammonia)) to afford the title compounds.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.32 (br. s., 3H) 2.58-2.74 (m, 1H) 2.91-3.07 (m, 1H) 3.50-3.66 (m, 2H) 3.79-3.94 (m, 1H) 4.09 (br. s., 2H) 6.37 (br. s., 2H) 7.59-7.66 (m, 1H) 7.68-7.76 (m, 1H) 7.89-7.99 (m, 1H).
MS ES+: 483/485
1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (d, J=6 Hz, 3H) 1.14 (d, J=6 Hz, 3H) 2.17 (s, 3H) 2.29-2.49 (m, 3H) 2.57-2.83 (m, 2H) 2.85-2.99 (m, 1H) 3.47-3.75 (m, 5H) 3.82-4.03 (m, 3H) 6.49 (br. s, 2H) 7.51-7.65 (m, 2H) 8.05 (d, J=8 Hz, 1H) 10.73 (s, 1H).
MS ES+: 565/567
A solution of 4-chloro-7-(2-fluoro-4-methoxybenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 69; 50 mg, 135 μmol), 2,2-dimethylmorpholine (31.1 mg, 270 μmol), triethylamine (56 μL, 405 μmol) and EtOH (1.5 mL) was heated under microwave irradiation at 155° C. for 3 h. The reaction mixture was concentrated in vacuo and the resulting residue diluted with water, acidified (pH 4) with 5% aq. citric acid solution and extracted with EtOAc. The combined organics were washed with brine, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (preparative HPLC, 20-60% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.19 (s, 6H) 2.61 (s, 3H) 3.70 (s, 2H) 3.74-3.83 (m, 4H) 3.85 (s, 3H) 6.97-7.02 (m, 1H) 7.003-7.09 (m, 1H) 7.14-7.28 (m, 1H) 8.06-8.12 (m, 1H)
MS ES+: 450
To a stirred solution of sodium hydride (127 mg, 3.18 mmol, 60% dispersion in oil) in anhydrous THF (3 mL) under an atmosphere of nitrogen was added propan-2-ol (CAS 67-63-0; 186 mg, 3.10 mmol). The reaction was stirred at room temperature for 30 min. 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 250 mg, 0.775 mmol) was added and the reaction mixture heated in a sealed tube at 110° C. for 16 h. The reaction was diluted with 5% aq. citric acid solution and EtOAc, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-5% methanol/DCM) followed 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 1.22-1.36 (m, 6H) 2.46 (s, 3H) 5.36-5.49 (m, 1H) 6.52 (s, 2H) 7.49-7.62 (m, 3H) 7.99-8.08 (m, 2H) 11.28 (s, 1H)
MS ES+: 347
To a stirred solution of sodium hydride (95 mg, 2.373 mmol, 60% dispersion in oil) in anhydrous THF (3 mL) under an atmosphere of nitrogen was added 1-cyclopropylpropan-1-ol (CAS 18729-46-9; 230 mg, 2.30 mmol). The reaction was stirred at room temperature for 30 min. 7-(benzenesulfonyl)-4-chloro-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 28; 250 mg, 0.775 mmol) was added and the reaction mixture heated in a sealed tube at 110° C. for 16 h. The reaction was diluted with 5% aq. citric acid solution and EtOAc, dried (H-frit) and concentrated in vacuo. The crude product was purified 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 0.29-0.37 (m, 1H) 0.37-0.46 (m, 2H) 0.49-0.58 (m, 1H) 0.87-0.97 (m, 3H) 1.01-1.13 (m, 1H) 1.68-1.83 (m, 2H) 2.43 (s, 3H) 4.67-4.78 (m, 1H) 6.51 (s, 2H) 7.50-7.61 (m, 3H) 8.00-8.07 (m, 2H) 11.22 (br. s., 1H)
MS ES+: 387
1H NMR (400 MHz, DMSO-d6) δ ppm 0.85-0.94 (m, 3 H) 1.24-1.30 (m, 3 H) 1.58-1.73 (m, 2 H) 2.46 (s, 3 H) 5.21- 5.31 (m, 1 H) 6.52 (s, 2 H) 7.47-7.61 (m, 3 H) 7.98- 8.09 (m, 2 H) 11.27 (s, 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 0.26-0.36 (m, 1 H) 0.49- 0.56 (m, 1 H) 1.02- 1.13 (m, 7 H) 2.46 (s, 3 H) 4.21- 4.30 (m, 1 H) 4.47- 4.55 (m, 1 H) 6.53 (s, 2 H) 7.50-7.61 (m, 3 H) 8.01- 8.07 (m, 2 H) 11.31 (s, 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-0.95 (m, 3 H) 1.22-1.30 (m, 3 H) 1.56-1.74 (m, 2 H) 2.46 (s, 3 H) 5.18- 5.31 (m, 1 H) 6.52 (s, 2 H) 7.47-7.61 (m, 3 H) 7.97- 8.09 (m, 2 H) 11.27 (s, 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.38 (m, 5 H) 1.39-1.63 (m, 4 H) 1.64 -1.79 (m, 2 H) 2.03-2.17 (m, 1 H) 2.46 (s, 3 H) 5.16- 5.27 (m, 1 H) 6.54 (s, 2 H) 7.50-7.62 (m, 3 H) 7.99- 8.08 (m, 2 H) 11.23 (s, 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.93 (m, 6 H) 1.54-1.74 (m, 4 H) 2.45 (s, 3 H) 5.14-5.25 (m, 1 H) 6.54 (s, 2 H) 7.49-7.59 (m, 3 H) 7.99- 8.08 (m, 2 H) 11.31 (s, 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.74-1.95 (m, 4 H) 1.96-2.11 (m, 2 H) 2.47 (s, 3 H) 2.64-2.78 (m, 1 H) 4.36 Hz, 2 H) 6.56 (s, 2 H) 7.46-7.62 (m, 3 H) 7.97-8.10 (m, 2 H) 11.31 (s, 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (s, 9 H) 2.46 (s, 3 H) 4.04 (s, 2 H) 6.59 (s, 2 H) 7.48-7.62 (m, 3 H) 8.04 (d, J = 7 Hz, 2 H) 11.26 (s, 1H)
1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (d, J = 7 Hz, 6 H) 1.96-2.11 (m, 1 H) 2.46 (s, 3 H) 4.14 (d, J = 7 Hz, 2 H) 6.58 (br. s., 2 H) 7.47-7.64 (m, 3 H) 8.04 (d, J = 7 Hz, 2 H) 11.33 (s, 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.56-1.84 (m, 2 H) 2.00-2.14 (m, 2 H) 2.33- 2.46 (m, 5 H) 5.22- 5.33 (m, 1 H) 6.57 (s, 2 H) 7.48- 7.59 (m, 3 H) 7.97- 8.07 (m, 2 H) 11.36 (br.s., 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.23 (m, 6 H) 1.38-1.60 (m, 2 H) 1.93-2.03 (m, 2 H) 2.46 (s, 3 H) 3.60- 3.69 (m, 1 H) 3.72- 3.80 (m, 1 H) 5.41- 5.53 (m, 1 H) 6.56 (s, 2 H) 7.49-7.60 (m, 3 H) 8.00- 8.06 (m, 2 H) 11.25 (br. s., 1H)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.84-1.93 (m, 4 H) 1.93-2.04 (m, 2 H) 2.05-2.23 (m, 2 H) 2.47 (s, 3 H) 5.35- 5.45 (m, 1 H) 6.64 (s, 2 H) 7.48-7.61 (m, 3 H) 7.99- 8.08 (m, 2 H) 11.30 (s, 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 0.94-1.31 (m, 9 H) 1.47-1.86 (m, 5 H) 2.46 (s, 3 H) 5.11-5.21 (m, 1 H) 6.52 (s, 2 H) 7.48- 7.62 (m, 3 H) 8.00- 8.08 (m, 2 H) 11.21 (br. s., 1H)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (d, J = 6 Hz, 3 H) 1.20-1.27 (m, 1 H) 1.57-2.13 (m, 6 H) 2.47 (s, 3 H) 5.28-5.38 (m, 1 H) 6.48-6.57 (m, 2 H) 7.50-7.62 (m, 3 H) 8.00-8.08 (m, 2 H) 11.19 (br. s., 1 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.65 (m, 2 H) 1.66-1.79 (m, 4 H) 1.86-2.01 (m, 2 H) 2.46 (s, 3 H) 5.49- 5.58 (m, 1 H) 6.52 (s, 2 H) 7.49-7.60 (m, 3 H) 7.98- 8.07 (m, 2 H) 11.21 (br. s., 1 H)
1H NMR(400 MHz, DMSO-d6) δ ppm 1.15-1.22 (m, 6 H) 1.88-2.00 (m, l H) 2.43-2.48 (m, 4 H) 3.75-3.91 (m, 2 H) 5.39 (s, 1 H) 6.59 (s, 2 H) 7.51-7.62 (m, 3 H) 7.99-8.09 (m, 2 H) 11.35 (br.s., 1 H)
A stirred mixture of 2-(benzenesulfonyl)-2-[6-(3,3-difluorocyclobutoxy)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 85; 0.37 g, 0.872 mmol), iron (0.243 g, 4.36 mmol) and ammonium chloride (0.466 g, 8.72 mmol) in ethanol (4 mL) and water (1.0 mL) was heated at reflux temperature for 30 minutes. The reaction was filtered through celite, washing with methanol, DCM and ethyl acetate and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the phases were separated and the aqueous phase extracted with ethyl acetate. The combined organics were washed with water and brine, dried (H-frit) and concentrated in vacuo. The material was taken up in ethanol (5 mL) and heated at reflux temperature for 1 hour. The reaction was concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-5% methanol/DCM) followed by trituration with DCM to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.47 (s, 3H) 2.66-2.84 (m, 2H) 3.09-3.24 (m, 2H) 5.20-5.32 (m, 1H) 6.65 (s, 2H) 7.49-7.62 (m, 3H) 8.03 (d, J=7 Hz, 2H) 11.41 (br. s., 1H)
MS ES+: 395
Prepared as described for 7-(benzenesulfonyl)-4-(3,3-difluorocyclobutoxy)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 259) from 2-(6-cyclobutoxy-2-methyl-5-nitropyrimidin-4-yl)-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 87; 250 mg, 615 iμmol). The crude product was purified by column chromatography (C18 silica 5-95% acetonitrile/water (with 0.05% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.57-1.85 (m, 2H) 2.00-2.15 (m, 2H) 2.28-2.44 (m, 5H) 5.21-5.33 (m, 1H) 6.60 (s, 2H) 7.26-7.43 (m, 2H) 7.57-7.68 (m, 1H) 7.95-8.04 (m, 1H) 11.47 (br. s., 1H)
MS ES+: 377
To a stirred suspension of 2-(2-chlorobenzenesulfonyl)-2-{2-methyl-6-[(2S)-2-methylmorpholin-4-yl]-5-nitropyrimidin-4-yl}acetonitrile (Intermediate 90; 480 mg, 1.062 mmol) in AcOH (5 mL) and MeOH (2.5 mL) was added iron (178 mg, 3.19 mmol) and the reaction stirred at 35° C. for 16 h. A second portion of iron (60 mg, 1.07 mmol) was added and the reaction stirred at 45° C. for 3 h. The reaction was allowed to cool and filtered through a pad of celite washing with acetic acid, methanol and ethyl acetate. The filtrate was concentrated in vacuo and the resulting residue taken up in ethyl acetate and washed with water and sat. aq. NaHCO3 solution. The organics were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petroleum ether) followed by recrystallisation from ethanol to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (d, J=6 Hz, 3H) 2.60 (s, 3H) 2.95-3.07 (m, 1H) 3.23-3.34 (m, 1H) 3.55-3.69 (m, 2H) 3.90-3.99 (m, 1H) 4.26-4.40 (m, 2H) 7.56-7.63 (m, 1H) 7.65-7.75 (m, 2H) 8.23-8.32 (m, 1H)
MS ES+: 422
To a solution of 2-(2,4-difluorobenzenesulfonyl)-2-[2-methyl-6-(2-methylmorpholin-4-yl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 92; 222 mg, 0.490 mmol) in acetic acid (2.45 mL) was added zinc (96 mg, 1.469 mmol) and the reaction mixture stirred at room temperature for 3 days. The reaction mixture was heated at 50° C. for 24 h, allowed to cool, filtered through Celite washing with methanol and concentrated in vacuo. The crude product was purified by column chromotography (silica, 25-75% ethyl acetate/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.17 (d, J=6 Hz, 3H) 2.61 (s, 3H) 2.93-3.04 (m, 1H) 3.21-3.33 (m, 1H) 3.51-3.67 (m, 2H) 3.88-3.99 (m, 1H) 4.25-4.39 (m, 2H) 7.30 (br. s., 1H) 7.34-7.42 (m, 1H) 7.50-7.61 (m, 1H) 8.18-8.27 (m, 1H)
MS ES+: 424
To a stirred solution of 2-(2,6-difluorobenzenesulfonyl)-2-[2-methyl-6-(2-methylmorpholin-4-yl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 94; 62 mg, 0.137 mmol) in acetic acid (1 mL) and MeOH (0.5 mL) was added zinc (31.3 mg, 0.479 mmol) and the resulting mixture heated at reflux temperature for 15 min. The reaction mixture was filtered through Celite, washed with methanol and concentrated in vacuo. The crude product was purified by column chromotography (silica, 25-75% ethyl acetate/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.18 (d, J=6 Hz, 3H) 2.61 (s, 3H) 2.95-3.07 (m, 1H) 3.23-3.36 (m, 1H) 3.53-3.71 (m, 2H) 3.90-4.00 (m, 1H) 4.26-4.41 (m, 2H) 7.18-7.40 (m, 3H) 7.69-7.81 (m, 1H)
MS ES+: 424
A mixture of 2-(3-fluorobenzenesulfonyl)-2-[6-(2-methylmorpholin-4-yl)-2-(methylsulfanyl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 95; 195 mg, 0.417 mmol) and zinc powder (250 mg, 3.82 mmol) in acetic acid (5 mL) under nitrogen was stirred at room temperature for 24 h. A second portion of zinc powder (250 mg, 3.82 mmol) was added and the reaction stirred for a further 24 h at room temperature. The mixture was concentrated in vacuo and the resulting residue partitioned between water and ethyl acetate. The organic layer was separated and washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromotography (silica, 0-8% ethyl acetate/petroleum ether) followed by recrystallisation from ethanol and water to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, J=6 Hz, 3H) 2.47 (s, 3H) 2.63-2.72 (m, 1H) 2.95-3.04 (m, 1H) 3.51-3.62 (m, 2H) 3.83-3.90 (m, 1H) 3.90-4.01 (m, 2H) 6.53 (s, 2H) 7.43-7.50 (m, 1H) 7.58-7.65 (m, 1H) 7.84 (d, J=8 Hz, 1H) 7.87-7.92 (m, 1H) 10.75 (s, 1H)
MS ES+: 438
Prepared as described for 7-(3-fluorobenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-2-(methylsulfanyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 264) from 2-(3-fluorobenzenesulfonyl)-2-[6-(2-methylmorpholin-4-yl)-5-nitro-2-(trifluoromethyl)pyrimidin-4-yl]acetonitrile (Intermediate 96; 192 mg, 0.392 mmol). The crude product was purified by column chromotography (silica, 0-10% methanol/DCM) followed by further column chromotography (C18 silica, 10-50% acetonitrile/water (with 0.1% ammonia)) followed by recrystallisation from ethanol to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.73-2.81 (m, 1H) 3.04-3.13 (m, 1H) 3.53-3.65 (m, 2H) 3.87-3.94 (m, 1H) 4.04 (t, J=14 Hz, 2H) 6.72 (s, 2H) 7.44-7.50 (m, 1H) 7.58-7.65 (m, 1H) 7.85 (d, J=8 Hz, 1H) 7.93 (d, J=9 Hz, 1H) 11.15 (s, 1H)
MS ES+: 460
To a stirred solution of 2-(fluoromethyl)morpholine hydrochloride (CAS 144053-94-1; 1.096 g, 7.04 mmol) and ethylbis(propan-2-yl)amine (3.08 mL, 17.61 mmol) in EtOH (12 mL) was added 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 2.00 g, 5.87 mmol) and the reaction mixture heated under microwave irradiation at 150° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organics were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petroleum ether) followed by recrystallisation from ethanol to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 2.56-2.56 (m, 1H) 2.63 (s, 3H) 3.18-3.26 (m, 1H) 3.28-3.37 (m, 1H) 3.61-3.69 (m, 1H) 3.74-3.89 (m, 1H) 3.98-4.04 (m, 1H) 4.29-4.42 (m, 2H) 4.44-4.54 (m, 1H) 4.55-4.68 (m, 1H) 7.41-7.51 (m, 2H) 7.72-7.79 (m, 1H) 8.13-8.18 (m, 1H)
MS ES+: 424
Prepared as described for 7-(2,6-difluorobenzenesulfonyl)-2-methyl-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 263) from 2-(2-fluoro-5-methoxybenzenesulfonyl)-2-[2-methyl-6-(2-methylmorpholin-4-yl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 98; 50.0 mg, 0.107 mmol). The crude product was purified by column chromotography (silica, 20-70% ethyl acetate/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.13 (d, J=1 Hz, 3H) 1.20-1.30 (m, 1H) 2.33 (br. s., 3H) 2.67 (br. s., 1H) 2.99 (br. s., 1H) 3.47-3.66 (m, 2H) 3.82 (s, 3H) 3.85-4.16 (m, 2H) 6.44 (br. s., 2H) 7.11-7.19 (m, 1H) 7.20-7.29 (m, 1H) 7.52-7.58 (m, 1H) 10.75 (br. s, 1H)
MS ES+: 436
Prepared as described for 7-(3-fluorobenzenesulfonyl)-4-(2-methylmorpholin-4-yl)-2-(methylsulfanyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 264) from 2-(2-fluorobenzenesulfonyl)-2-[6-(2-methylmorpholin-4-yl)-5-nitro-2-(trifluoromethyl)pyrimidin-4-yl]acetonitrile (Intermediate 99; 141 mg, 0.288 mmol). The crude product was purified by column chromotography (silica, 0-15% methanol/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (d, J=6 Hz, 3H) 2.73-2.82 (m, 1H) 3.04-3.14 (m, 1H) 3.55-3.65 (m, 2H) 3.87-3.94 (m, 1H) 3.99-4.10 (m, 2H) 6.68 (s, a H) 7.27-7.35 (m, 1H) 7.39 (t, J=8 Hz, 1H) 7.61-7.68 (m, 1H) 8.00-8.06 (m, 1H) 11.18 (s, 1H)
MS ES+: 460
A mixture of 2-(2-fluorobenzenesulfonyl)-2-[6-(2-methylmorpholin-4-yl)-2-(methylsulfanyl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 101; 46 mg, 0.098 mmol) and zinc powder (156 mg, 2.386 mmol) in acetic acid (2 mL) under an atmosphere of nitrogen was sonicated for 2 hour. A further portion of zinc (106 mg, 1.62 mmol) was added and the mixture was sonicated for a further hour. The reaction mixture was partitioned between ethyl acetate and water and the phases separated. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo.
The crude material was purified by column chromatography (preparative HPLC, 20-60% acetonitrile/water (with 0.1% ammonia)) followed by trituration with methanol to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6 Hz, 3H) 2.30 (s, 3H) 2.63-2.72 (m, 1H) 2.95-3.04 (m, 1H) 3.52-3.63 (m, 2H) 3.84-3.90 (m, 1H) 3.91-4.02 (m, 2H) 6.49 (s, 2H) 7.27-7.34 (m, 1H) 7.39 (t, J=7 Hz, 1H) 7.60-7.69 (m, 1H) 8.00-8.07 (m, 1H) 10.77 (s, 1H)
MS ES+: 438
To a stirred solution 2-(2-(dimethylamino)-6-(2-methylmorpholino)-5-nitropyrimidin-4-yl)-2-((2-fluorophenyl)sulfonyl)acetonitrile (55 mg, 0.118 mmol) in a mixture of ethanol (5 mL), acetic acid (1 mL) and water (1 mL) was added zinc powder (103 mg, 1.575 mmol). The reaction mixture was heated at 75° C. for 3 h, allowed to cool, decanted to remove zinc residues and concentrated in vacuo. The resulting residue was partitioned between water and ethyl acetate and the phases separated. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude material was purified by column chromatography (preparative HPLC, 30-70% acetonitrile/water (with 0.1% ammonia)) followed by trituration with 1:1 ethanol/water to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, J=6 Hz, 3H) 2.57-2.64 (m, 1H) 2.87-2.97 (m, 7H) 3.52-3.62 (m, 2H) 3.83-3.98 (m, 3H) 6.29 (s, 2H) 7.24-7.31 (m, 1H) 7.36 (t, J=8 Hz, 1H) 7.58-7.65 (m, 1H) 8.03-8.09 (m, 1H) 10.37 (s, 1H)
MS ES+: 435
Prepared as described for 7-(2-fluorobenzenesulfonyl)-2-N,2-N-dimethyl-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2,6-diamine (Example 270) from 2-(2-fluorobenzenesulfonyl)-2-[2-methoxy-6-(2-methylmorpholin-4-yl)-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 103: 44 mg, 0.097 mmol). The crude material was purified by column chromatography (silica, 0-10% methanol/DCM) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, J=6 Hz, 3H) 2.62-2.71 (m, 1H) 2.95-3.05 (m, 1H) 3.50-3.61 (m, 2H) 3.64 (s, 3H) 3.81-4.05 (m, 3H) 6.43 (s, 2H) 7.26-7.34 (m, 1H) 7.39 (t, J=8 Hz, 1H) 7.59-7.67 (m, 1H) 8.05 (t, J=7 Hz, 1H) 10.68 (br. s., 1H)
MS ES+: 422
Prepared as described for 7-(benzenesulfonyl)-4-(3,3-difluorocyclobutoxy)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 259) from 2-(2-fluorobenzenesulfonyl)-2-[2-methyl-5-nitro-6-(propan-2-yloxy)pyrimidin-4-yl]acetonitrile (Intermediate 104; 0.401 g, 1.017 mmol). The crude product was purified by column chromatography (silica, 0-5% methanol/DCM) followed by recrystallisation from ethanol and water to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.26-1.35 (m, 6H) 2.31-2.37 (m, 3H) 5.35-5.47 (m, 1H) 6.54 (s, 2H) 7.26-7.34 (m, 1H) 7.35-7.42 (m, 1H) 7.59-7.68 (m, 1H) 7.97-8.05 (m, 1H) 11.36 (s, 1H)
MS ES+: 365
Prepared as described for 7-(benzenesulfonyl)-4-(3,3-difluorocyclobutoxy)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 259) from 2-{6-[(2,2-dimethyloxan-4-yl)oxy]-2-methyl-5-nitropyrimidin-4-yl}-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 105; 3.00 g, 6.46 mmol). The crude product was purified by column chromatography (silica, 0-5% methanol/DCM) followed by recrystallisation from ethanol and water to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (s, 6H) 1.39-1.62 (m, 2H) 1.91-2.04 (m, 2H) 2.35 (s, 3H) 3.60-3.71 (m, 1H) 3.74-3.83 (m, 1H) 5.40-5.52 (m, 1H) 6.58 (s, 2H) 7.26-7.35 (m, 1H) 7.35-7.43 (m, 1H) 7.58-7.68 (m, 1H) 7.96-8.05 (m, 1H) 11.34 (br. s., 1H)
MS ES+: 435
Prepared as described for 7-(2,6-difluorobenzenesulfonyl)-2-methyl-4-(2-methylmorpholin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 263) from 2-(2-fluorobenzenesulfonyl)-2-{2-methyl-5-nitro-6-[(1,1,1-trifluoropropan-2-yl)oxy]pyrimidin-4-yl}acetonitrile (Intermediate 106; 150 mg, 0.335 mmol). The crude product was purified by column chromatography (silica, 20-70% ethyl acetate/petroleum ether) followed by column chromatography (preparative HPLC, 20-60% acetonitrile/water (0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (d, J=6 Hz, 3H) 2.39 (s, 3H) 5.94-6.08 (m, 1H) 6.70 (s, 2H) 7.27-7.36 (m, 1H) 7.37-7.45 (m, 1H) 7.59-7.70 (m, 1H) 7.99-8.07 (m, 1H) 11.63 (br. s., 1H)
MS ES+: 419
To a stirred mixture of 2 2-{6-[(RS,SR)-2,3-dimethylmorpholin-4-yl]-2-methyl-5-nitropyrimidin-4-yl}-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 107; 1.56 g, 3.47 mmol) and zinc (0.681 g, 10.41 mmol) in THF (20 mL), ethanol (5 mL) and AcOH (10 mL) was heated at 65° C. for 1 h. A second portion of zinc (0.681 g, 10.41 mmol) was added and the reaction mixture was stir at 65° C. for a further 2 hours. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between water and ethyl acetate and the phases separated. The combined organic phases were washed with sat. aq. NaHCO3 solution, brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petroleum ether) followed by column chromatography (C18 silica, 5-95% methanol/water (with 0.1% formic acid) and recrystallised from ethanol to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.11 (d, J=6 Hz, 3H) 1.19 (d, J=7 Hz, 3H) 2.61 (s, 3H) 3.39-3.49 (m, 1H) 3.53-3.63 (m, 1H) 3.70-379 (m, 1H) 3.89-4.00 (m, 1H) 4.09-4.28 (m, 1H) 4.42-4.60 (m, 1H) 7.39-7.51 (m, 2H) 7.72-7.83 (m, 1H) 8.11-8.21 (m, 1H)
MS ES+: 420
Prepared as described for 4-[(RS,SR)-2,3-dimethylmorpholin-4-yl]-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 275) from 2-{6-[(RR,SS)-2,3-dimethylmorpholin-4-yl]-2-methyl-5-nitropyrimidin-4-yl}-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 108; 1.48 g, 3.29 mmol). The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petroleum ether) followed by recrystallised from ethanol to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.24 (d, J=7 Hz, 3H) 1.33 (d, J=7 Hz, 3H) 2.61 (s, 3H) 3.54-3.74 (m, 2H) 3.81-3.93 (m, 2H) 4.08-4.20 (m, 1H) 4.37-4.50 (m, 1H) 7.40-7.51 (m, 2H) 7.72-7.81 (m, 1H) 8.09-8.19 (m, 1H)
MS ES+: 420
Prepared as described for 7-(benzenesulfonyl)-4-(cyclohex-1-en-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 2) from 2-(benzenesulfonyl)acetonitrile (CAS 7605-25-9; 380 mg, 2.10 mmol) and 2-chloro-4-(2,2-dimethylmorpholin-4-yl)pyridin-3-amine (Intermediate 111; 250 mg, 1.55 mmol). The crude product was purified by column chromatography (C18 silica, 5-95% acetonitrile/water (with 0.1% formic acid) followed by column chromatography (C18 silica, 5-95% acetonitrile/water (with 0.05% ammonia) to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.19 (s, 6H) 3.31-3.47 (m, 2H) 3.49-3.63 (m, 2H) 3.70-3.88 (m, 2H) 6.77-6.94 (m, 1H) 7.54-7.73 (m, 3H) 7.82 (d, J=7 Hz, 1H) 8.02-8.17 (m, 2H)
MS ES+: 387
Prepared as described for 4-[(RS,SR)-2,3-dimethylmorpholin-4-yl]-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 275) from 2-(2,4-difluorobenzenesulfonyl)-2-[6-(2,2-dimethylmorpholin-4-yl)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 113, 2.50 g, 5.35 mmol). The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) followed by recrystallisation from ethanol to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.19 (s, 6H) 2.61 (s, 3H) 3.71 (s, 2H) 3.74-3.86 (m, 4H) 7.34-7.45 (m, 1H) 7.51-7.62 (m, 1H) 8.18-8.29 (m, 1H)
MS ES+: 438
Prepared as described for 4-[(RS,SR)-2,3-dimethylmorpholin-4-yl]-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 275) from 2-(4-chloro-2-fluorobenzenesulfonyl)-2-[6-(2,2-dimethylmorpholin-4-yl)-2-methyl-5-nitropyrimidin-4-yl]acetonitrile (Intermediate 114; 1.8 g, 3.72 mmol). The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) followed by recrystallisation from ethanol to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.18 (s, 6H) 2.60 (s, 3H) 3.71 (s, 2H) 3.74-3.86 (m, 4H) 7.54-7.62 (m, 1H) 7.68-7.79 (m, 1H) 8.09-8.21 (m, 1H)
MS ES+: 454
To a stirred suspension of 2-((2,3-difluorophenyl)sulfonyl)-2-(6-(2,2-dimethylmorpholino)-2-methyl-5-nitropyrimidin-4-yl)acetonitrile (Intermediate 115; 2.13 g, 4.56 mmol) in acetic acid (30 mL) and 2-methyltetrahydrofuran (20 mL) was added zinc (0.6 g, 20 mmol) and the reaction mixture was heated at 70° C. for 3 h. A second portion of zinc (0.3 g, 10 mmol) was added and the reaction heated at reflux for 6 days. The reaction was filtered through Celite, washed with 1:1 EtOAc/methanol and the filtrate concentrated in vacuo. The crude product was purified by column chromatography (silica, 30-70% ethyl acetate/petroleum ether) followed by recrystallisation from EtOH/heptane (5:1) to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.19 (s, 6H) 2.61 (s, 3H) 3.71 (s, 2H) 3.74-3.85 (m, 4H) 7.36 (br. s., 1H) 7.44-7.53 (m, 1H) 7.76-7.86 (m, 1H) 7.91-7.99 (m, 1H)
MS ES+: 438
A stirred mixture of 4-chloro-7-((2-fluorophenyl)sulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 0.94 g, 2.76 mmol), (S)-2-(trifluoromethyl)morpholine hydrochloride (CAS 1394909-69-3; 0.581 g, 3.03 mmol), triethylamine (1.153 mL, 8.28 mmol) and ethanol (4 mL) was heated under microwave irradiation at 180° C. for 2 h. The reaction was concentrated in vacuo then partitioned between 0.2 M aq. NaOH solution and MTBE. The layers were separated and the organic extracted further with 0.2 M aq. NaOH solution. The combined aqueous layers were basified with dilute citric acid solution and extracted EtOAc. The combined organic layers were washed sequentially with sat. aq. NaHCO3 solution and brine, dried (H-frit) and concentrated in vacuo. The crude product was purified by recrystallised from EtOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (br. s., 3H) 2.94-3.08 (m, 1H) 3.08-3.22 (m, 1H) 3.66-3.81 (m, 1H) 3.84-3.98 (m, 1H) 4.01-4.10 (m, 1H) 4.17-4.28 (m, 1H) 4.28-4.38 (m, 1H) 5.29-5.83 (m, 1H) 6.59 (br. s., 2H) 7.27-7.36 (m, 1H) 7.36-7.43 (m, 1H) 7.58-7.69 (m, 1H) 7.97-8.07 (m, 1H) 10.94 (br. s., 1H)
MS ES+: 460
Prepared as described for 4-[(RS,SR)-2,3-dimethylmorpholin-4-yl]-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 275) from 2-(2-fluoro-4-methoxybenzenesulfonyl)-2-{2-methyl-5-nitro-6-[(2S)-2-(trifluoromethyl)morpholin-4-yl]pyrimidin-4-yl}acetonitrile (Intermediate 117; 2.21 g, 4.25 mmol). The crude product was purified by column chromatography (silica, 30-70% ethyl acetate/petroleum ether followed by recrystallisation from EtOH/heptane (2:1) to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 2.64 (s, 3H) 3.35-3.53 (m, 2H) 3.71-3.82 (m, 1H) 3.85 (s, 3H) 4.05-4.15 (m, 1H) 4.22-4.32 (m, 1H) 4.35-4.47 (m, 1H) 4.48-4.58 (m, 1H) 6.94-7.10 (m, 2H) 7.36 (br. s, 1H) 8.05-8.13 (m, 1H)
MS ES+: 490
Prepared as described for 4-[(RS,SR)-2,3-dimethylmorpholin-4-yl]-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 275) from 2-(2,4-difluorobenzenesulfonyl)-2-{2-methyl-5-nitro-6-[(2S)-2-(trifluoromethyl)morpholin-4-yl]pyrimidin-4-yl}acetonitrile (Intermediate 118; 3.52 g, 6.94 mmol). The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) followed by recrystallisation from ethanol to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 2.63 (s, 3H) 3.33-3.52 (m, 2H) 3.71-3.83 (m, 1H) 4.04-4.13 (m, 1H) 4.22-4.29 (m, 1H) 4.31-4.45 (m, 1H) 4.49-4.60 (m, 1H) 7.32-7.39 (m, 1H) 7.47-7.57 (m, 1H) 8.19-8.31 (m, 1H)
MS ES+: 478
Prepared as described for 4-[(RS,SR)-2,3-dimethylmorpholin-4-yl]-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 275) from 2-(4-chloro-2-fluorobenzenesulfonyl)-2-{2-methyl-5-nitro-6-[(2S)-2-(trifluoromethyl)morpholin-4-yl]pyrimidin-4-yl}acetonitrile (Intermediate 119; 3.31 g, 6.32 mmol). The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) followed by recrystallised from ethanol to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.63 (s, 3H) 3.35-3.52 (m, 2H) 3.71-3.82 (m, 1H) 4.06-4.14 (m, 1H) 4.22-4.30 (m, 1H) 4.33-4.44 (m, 1H) 4.49-4.59 (m, 1H) 7.53-7.62 (m, 1H) 7.69-7.78 (m, 1H) 8.10-8.21 (m, 1H)
MS ES+: 494
Prepared as described for 4-[(RS,SR)-2,3-dimethylmorpholin-4-yl]-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 275) from 2-((2,3-difluorophenyl)sulfonyl)-2-(2-methyl-5-nitro-6-((S)-2-(trifluoromethyl)morpholino)pyrimidin-4-yl)acetonitrile (Intermediate 120; 1.30 g, 2.56 mmol). The crude product was purified by column chromatography (silica, 20-70% ethyl acetate/petroleum ether) followed by recrystallisation from EtOH to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 (br. s., 3H) 2.95-3.24 (m, 2H) 3.67-3.81 (m, 1H) 3.83-3.98 (m, 1H) 4.01-4.10 (m, 1H) 4.17-4.39 (m, 2H) 6.62 (br. s., 2H) 7.36-7.46 (m, 1H) 7.64-7.74 (m, 1H) 7.78-7.87 (m, 1H) 10.96 (br. s., 1H)
MS ES+: 478
To a stirred mixture of 2-((2,3-difluorophenyl)sulfonyl)-2-(2-methyl-5-nitro-6-((R)-2-(trifluoromethyl)morpholino)pyrimidin-4-yl)acetonitrile (Intermediate 122; 1.76 g, 3.47 mmol) in acetic acid (2 mL), tetrahydrofuran (10 mL) and methanol (10 mL) was added zinc (0.680 g, 10.41 mmol) and the reaction heated at 60° C. for 20 h. The reaction was filtered through Celite, washed with EtOAc/MeOH and the filtrate concentrated in vacuo. The residue was partitioned between 0.2 M NaOH and MTBE, separated and the organic layer extracted further with 0.2 M NaOH. The aqueous was acidified with citric acid solution until a precipitate formed and extracted with EtOAc. The combined organics (including MTBE phase) were washed sequentially with sat. aq. NaHCO3 solution and brine, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 20-45% ethyl acetate/40-60 petroleum ether) followed by recrystallisation from ethanol to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 (br. s., 3H) 2.95-3.24 (m, 2H) 3.66-3.81 (m, 1H) 3.85-3.97 (m, 1H) 4.01-4.10 (m, 1H) 4.17-4.39 (m, 2H) 6.63 (br. s., 2H) 7.35-7.47 (m, 1H) 7.63-7.74 (m, 1H) 7.78-7.89 (m, 1H) 10.96 (br. s., 1H)
MS ES+: 478
To a solution of 2-((2,6-difluorophenyl)sulfonyl)-2-(6-(2,2-dimethylmorpholino)-2-methyl-5-nitropyrimidin-4-yl)acetonitrile (Intermediate 124; 869 mg, 1.86 mmol) in THF (30 mL), methanol (10 mL) and acetic acid (5 mL) was added zinc (730 mg, 11.16 mmol) and the resulting mixture was heated to 6° C. for 2 h. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with sat. aq. NaHCO3 solution, water, brine, dried (H-frit) and in vacuo. The crude product was purified by column chromatography (silica, 30-70% EtOAc/petroleum ether) followed by recrystallisation from ethanol/heptanes to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.19 (s, 6H) 2.60 (s, 3H) 3.72 (s, 2H) 3.75-3.86 (m, 4H) 7.28-7.36 (m, 2H) 7.70-7.80 (m, 1H)
MS ES+: 438
Prepared as described for 7-(2,6-difluorobenzenesulfonyl)-4-(2,2-dimethylmorpholin-4-yl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 287) from 2-((2,5-difluorophenyl)sulfonyl)-2-(6-(2,2-dimethylmorpholino)-2-methyl-5-nitropyrimidin-4-yl)acetonitrile (Intermediate 26; 1.01 g, 1.79 mmol). The crude product was purified by column chromatography (silica, 30-70% EtOAc/petroleum ether) followed by recrystallisation from ethanol/heptane (1:1) to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.18 (s, 6H) 2.61 (s, 3H) 3.71 (s, 2H) 3.74-3.86 (m, 4H) 7.47-7.57 (m, 1H) 7.58-7.68 (m, 1H) 7.99-8.07 (m, 1H)
MS ES+: 438
To a stirred suspension of (R)-2-(trifluoromethyl)morpholine hydrochloride (CAS 1394909-70-6; 607 mg, 3.17 mmol) and 4-chloro-7-((2-fluorophenyl)sulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 900 mg, 2.64 mmol) in ethanol (14 mL) was added triethylamine (1.104 mL, 7.92 mmol) under an atmosphere of nitrogen. The reaction was heated under microwave irradiation for 4 h at 180° C. then concentrated in vacuo. The mixture was partitioned between ethyl acetate and water, separated and the combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-60% ethyl acetate/petroleum ether) then recrystallised from MeOAc/pentane to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.65 (s, 3H) 3.34-3.54 (m, 2H) 3.71-3.86 (m, 1H) 4.02-4.16 (m, 1H) 4.19-4.34 (m, 1H) 4.34-4.47 (m, 1H) 4.48-4.62 (m, 1H) 7.35-7.54 (m, 2H) 7.67-7.82 (m, 1H) 8.09-8.21 (m, 1H)
MS ES+: 460
Prepared as described for 7-(2,6-difluorobenzenesulfonyl)-4-(2,2-dimethylmorpholin-4-yl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 287) from 2-(2,4-difluorobenzenesulfonyl)-2-{2-methyl-5-nitro-6-[(2R)-2-(trifluoromethyl)morpholin-4-yl]pyrimidin-4-yl}acetonitrile (Intermediate 127; 1.26 g, 2.483 mmol). The crude product was purified by column chromatography (silica, 0-60% ethyl acetate/petroleum ether) followed by recrystallisation from MeOAc/pentane to afford the title compound
1H NMR (400 MHz, DMSO-d6) δ ppm 2.64 (s, 3H) 3.28-3.57 (m, 2H) 3.65-3.87 (m, 1H) 4.00-4.17 (m, 1H) 4.20-4.32 (m, 1H) 4.33-4.47 (m, 1H) 4.48-4.61 (m, 1H) 7.25-7.48 (m, 1H) 7.49-7.63 (m, 1H) 8.09-8.31 (m, 1H)
MS ES+: 478
Prepared as described for 7-(2,6-difluorobenzenesulfonyl)-4-(2,2-dimethylmorpholin-4-yl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 287) from 2-(2,5-Difluorobenzenesulfonyl)-2-{2-methyl-5-nitro-6-[(2R)-2-(trifluoromethyl)morpholin-4-yl]pyrimidin-4-yl}acetonitrile (Intermediate 129; 1.86 g, 3.67 mmol). The crude product was purified by column chromatography (silica, 20-40% EtOAc/petroleum ether) followed by recrystallisation from methyl acetate and pentane to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 2.65 (s, 3H) 3.37-3.53 (m, 2H) 3.72-3.82 (m, 1H) 4.06-4.14 (m, 1H) 4.23-4.32 (m, 1H) 4.35-4.45 (m, 1H) 4.49-4.58 (m, 1H) 7.49-7.58 (m, 1H) 7.59-7.69 (m, 1H) 7.98-8.07 (m, 1H)
MS ES+: 478
Prepared as described for 7-(2,6-difluorobenzenesulfonyl)-4-(2,2-dimethylmorpholin-4-yl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 287) from 2-(2,5-Difluorobenzenesulfonyl)-2-{2-methyl-5-nitro-6-[(2S)-2-(trifluoromethyl)morpholin-4-yl]pyrimidin-4-yl}acetonitrile (Intermediate 130; 1.85 g, 3.65 mmol). The crude product was purified by column chromatography (silica, 20-40% EtOAc/petroleum ether) followed by recrystallisation from methyl acetate and pentane to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 2.65 (s, 3H) 3.36-3.55 (m, 2H) 3.70-3.84 (m, 1H) 4.05-4.15 (m, 1H) 4.22-4.32 (m, 1H) 4.34-4.46 (m, 1H) 4.48-4.59 (m, 1H) 7.49-7.57 (m, 1H) 7.58-7.69 (m, 1H) 7.97-8.07 (m, 1H)
MS ES+: 478
Prepared as described for 7-(2,6-difluorobenzenesulfonyl)-4-(2,2-dimethylmorpholin-4-yl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 287) from 2-((2-fluoro-4-methoxyphenyl)sulfonyl)-2-(2-methyl-5-nitro-6-((R)-2-(trifluoromethyl)morpholino)pyrimidin-4-yl)acetonitrile (Intermediate 131; 2.50 g, 4.81 mmol). The crude product was purified by column chromatography (silica, 20-60% EtOAc/petroleum ether) followed by recrystallisation from ethanol to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 2.64 (s, 3H) 3.36-3.53 (m, 2H) 3.71-3.82 (m, 1H) 3.85 (s, 3H) 4.05-4.15 (m, 1H) 4.20-4.32 (m, 1H) 4.35-4.47 (m, 1H) 4.47-4.58 (m, 1H) 6.94-7.10 (m, 2H) 7.33 (br. s., 1H) 8.04-8.13 (m, 1H)
MS ES+: 490
Prepared as described for 7-(2,6-difluorobenzenesulfonyl)-4-(2,2-dimethylmorpholin-4-yl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 287) from 2-(2,6-Difluorobenzenesulfonyl)-2-{2-methyl-5-nitro-6-[(2S)-2-(trifluoromethyl)morpholin-4-yl]pyrimidin-4-yl}acetonitrile (Intermediate 132; 1.61 g, 3.16 mmol). The crude product was purified by column chromatography (silica, 20-40% EtOAc/petroleum ether) followed by recrystallisation from methyl acetate and pentane to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 2.64 (s, 3H) 3.38-3.56 (m, 2H) 3.72-3.85 (m, 1H) 4.12 (d, J=13 Hz, 1H) 4.28 (d, J=13 Hz, 1H) 4.37-4.49 (m, 1H) 4.55 (d, J=13 Hz, 1H) 7.26-7.38 (m, 2H) 7.70-7.82 (m, 1H)
MS ES+: 478
Prepared as described for 7-(2,6-difluorobenzenesulfonyl)-4-(2,2-dimethylmorpholin-4-yl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 287) from 2-(2,6-Difluorobenzenesulfonyl)-2-{2-methyl-5-nitro-6-[(2R)-2-(trifluoromethyl)morpholin-4-yl]pyrimidin-4-yl}acetonitrile (Intermediate 133; 1.587 g, 3.13 mmol). The crude product was purified by column chromatography (silica, 20-40% EtOAc/petroleum ether) followed by recrystallisation from methyl acetate and pentane to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 2.64 (s, 3H) 3.39-3.56 (m, 2H) 3.74-3.84 (m, 1H) 4.12 (d, J=13 Hz, 1H) 4.28 (d, J=13 Hz, 1H) 4.37-4.48 (m, 1H) 4.56 (d, J=13 Hz, 1H) 7.26-7.36 (m, 2H) 7.70-7.80 (m, 1H)
MS ES+: 478
Prepared as described for 7-(benzenesulfonyl)-4-(3,3-difluorocyclobutoxy)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 259) from 2-{6-[(2,2-dimethyloxan-3-yl)oxy]-2-methyl-5-nitropyrimidin-4-yl}-2-(2-fluorobenzenesulfonyl)acetonitrile (Intermediate 134; 375 mg, 0.807 mmol). The crude product was purified by column chromatography (silica, 0-5% methanol/DCM) followed by column chromatography on (silica, 0-100% ethyl acetate/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (s, 3H) 1.25 (s, 3H) 1.44-1.58 (m, 1H) 1.62-1.78 (m, 2H) 1.94-2.06 (m, 1H) 2.34 (s, 3H) 3.53-3.64 (m, 2H) 4.96-5.05 (m, 1H) 6.58 (s, 2H) 7.25-7.35 (m, 1H) 7.36-7.43 (m, 1H) 7.58-7.69 (m, 1H) 7.97-8.07 (m, 1H) 11.36 (s, 1H)
MS ES+: 435
Prepared as described for 7-(2,6-difluorobenzenesulfonyl)-4-(2,2-dimethylmorpholin-4-yl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Example 287) from 2-(4-chloro-2-fluorobenzenesulfonyl)-2-{2-methyl-5-nitro-6-[(2R)-2-(trifluoromethyl)morpholin-4-yl]pyrimidin-4-yl}acetonitrile (Intermediate 136; 2.72 g, 5.19 mmol). The crude product was purified by column chromatography (silica, 0-60% ethyl acetate/petroleum ether) followed by recrystallisation from methyl acetate/pentane to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.64 (s, 3H) 3.27-3.54 (m, 2H) 3.66-3.86 (m, 1H) 4.02-4.17 (m, 1H) 4.19-4.32 (m, 1H) 4.32-4.46 (m, 1H) 4.47-4.61 (m, 1H) 7.52-7.63 (m, 1H) 7.66-7.79 (m, 1H) 8.07-8.27 (m, 1H)
MS ES+: 494
To a stirred solution of 2-((2-fluorophenyl)sulfonyl)-2-(2-(methylamino)-6-(2-methylmorpholino)-5-nitropyrimidin-4-yl)acetonitrile (Intermediate 137; 127 mg, 0.28 mmol) in a mixture of methanol (5 mL) and acetic acid (1 mL) was added zinc powder (200 mg, 3.06 mmol). The reaction was stirred at room temperature for 24 h, diluted with ethanol and filtered, washing with ethanol. The filtrate was concentration in vacuo. The crude material was purified by column chromatography (silica, 0-15% MeOH/DCM). Further purification by column chromatography (preparative HPLC, 20-60% acetonitrile/water (with 0.1% ammonia)) to afford the title compound.
1H NMR (400 MHz, Methanol-d4) δ ppm 1.19 (d, J=6 Hz, 3H) 2.71-2.80 (m, 1H) 2.86 (s, 3H) 3.04-3.13 (m, 1H) 3.61-3.72 (m, 2H) 3.89-3.95 (m, 1H) 4.54 (br. s, 2H) 7.14-7.21 (m, 1H) 7.31 (t, J=8 Hz, 1H) 7.53-7.61 (m, 1H) 8.06 (t, J=7 Hz, 1H)
MS ES+: 421
To a stirred solution of 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 1 g, 2.93 mmol) and triethylamine (1.2 mL, 8.80 mmol) in EtOH (15 mL) was added (R)-2-(fluoromethyl)morpholine hydrochloride (Intermediate 138; 0.55 g, 3.5 mmol) and the reaction mixture was heated under microwave irradiation at 170° C. for 4 h. The reaction mixture was concentrated in vacuo. The crude product was partitioned between EtOAc and water. The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-10% MeOH/DCM). Product fractions were concentrated and the resulting residue triturated with ethanol. The resulting solid was filtered and further purified by column chromatography (silica, 0-100% EtOAc/Petroleum ether). Product fractions were concentrated and the resulting residue recrystallised from ethanol to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 2.62 (s, 3H), 3.17-3.38 (m, 2H), 3.54-3.70 (m, 1H), 3.75-3.91 (m, 1H), 3.97-4.06 (m, 1H), 4.27-4.69 (m, 4H), 7.38-7.54 (m, 2H), 7.70-7.84 (m, 1H), 8.10-8.21 (m, 1H).
MS ES+: 424
To a stirred solution of 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 750 mg, 2.20 mmol) and triethylamine (982 μL, 7.04 mmol) in EtOH (14 mL) was added 4-chloroaniline (CAS 106-47-8; 365 mg, 2.86 mmol) and the reaction mixture was heated under microwave irradiation at 180° C. for 5 h. The reaction was concentrated in vacuo and the resulting residue partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (C18-silica, 5-95% acetonitrile/water (with 0.1% ammonia)) followed by triturating from hot ethanol to afforded the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (s, 3H) 7.17 (s, 2H) 7.25-7.46 (m, 4H) 7.57-7.69 (m, 1H) 7.75 (d, J=9 Hz, 2H) 7.94-8.09 (m, 1H) 9.04 (s, 1H) 10.55 (s, 1H)
MS ES+: 432
To a solution of 2-(2-fluorobenzenesulfonyl)-2-[2-(methylsulfanyl)-5-nitro-6-[2-(trifluoromethyl)morpholin-4-yl]pyrimidin-4-yl]acetonitrile (Intermediate 139; 1.28 g, 2.26 mmol) in THF (30 mL), methanol (5 mL) and acetic acid (5 mL), heated to 60° C., was added zinc powder (0.88 g, 13.4 mmol), in two portions, 2 h apart. The reaction mixture was heated at 60° C. for 1.5 h, cooled and concentrated in vacuo. The residue was partitioned between EtOAc and water and filtered. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water, sat. aq. NaHCO3 solution, brine, dried (H-frit) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 30-60% EtOAc/petroleum ether) to afford the title compound.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3H) 3.03-3.12 (m, 1H) 3.16-3.25 (m, 1H) 3.68-3.78 (m, 1H) 3.88-3.96 (m, 1H) 4.00-4.08 (m, 1H) 4.19-4.27 (m, 1H) 4.28-4.39 (m, 1H) 6.61 (s, 2H) 7.27-7.36 (m, 1H) 7.36-7.44 (m, 1H) 7.61-7.70 (m, 1H) 8.01-8.09 (m, 1H) 10.93 (s, 1H)
MS ES+: 492
To a suspension of 4-chloro-7-(2-fluorobenzenesulfonyl)-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 21, 152 mg, 0.465 mmol) and 2-(trifluoromethyl)morpholine hydrochloride (CAS 1196152-51-8; 107 mg, 0.558 mmol) in ethanol (2 mL) was added triethylamine (0.19 mL, 1.39 mmol). The reaction mixture was heated under microwave irradiation at 180° C. for 2 h. The reaction mixture was then evaporated and the residue partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water, brine, dried (H-frit) and concentrated in vacuo. The crude product was absorbed onto MgSO4 from a solution in MeOH/DCM and purified by column chromatography (silica, 0-6% MeOH/DCM) followed by recrystallisation from MeOAc/pentane to afford the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 3.40-3.58 (m, 2H) 3.73-3.83 (m, 1H) 4.06-4.16 (m, 1H) 4.21-4.31 (m, 1H) 4.37-4.47 (m, 1H) 4.50-4.59 (m, 1H) 7.40-7.52 (m, 2H) 7.72-7.81 (m, 1H) 8.13-8.21 (m, 1H) 8.46 (s, 1H)
MS ES+: 446
To a stirred solution of 4-chloro-7-(2-fluorobenzenesulfonyl)-2-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-amine (Intermediate 50; 750 mg, 2.20 mmol) and triethylamine (920 μL, 6.60 mmol) in EtOH (14 mL) was added 2-methyl-2-(trifluoromethyl)morpholine hydrochloride (Intermediate 143; 543 mg, 2.64 mmol) and the reaction mixture was heated under microwave irradiation at 180° C. for 4 h. The reaction mixture was concentrated in vacuo. The crude product was partitioned between EtOAc and water. The combined organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (silica, 0-80% EtOAc/petroleum ether) followed by recrystallisation from methyl acetate and pentane afforded the title compound.
1H NMR (400 MHz, DMSO-d6+TFA-d) δ ppm 1.36 (s, 3H) 2.62 (s, 3H) 3.75-3.91 (m, 1H) 3.95-4.11 (m, 4H) 4.24 (m, 1H) 7.33-7.52 (m, 2H) 7.63-7.84 (m, 1H) 8.04-8.25 (m, 1H)
MS ES+: 474
Screening Protocol:
Ca-Flux Functional Assay: Determination of Agonist/Positive Allosteric Modulator (PAM) Activity
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 10 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.
Results:
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 |
|---|---|---|---|
| 1411236.1 | Jun 2014 | GB | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/GB2015/051840 | 6/24/2015 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2015/198045 | 12/30/2015 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 20140018361 | Harriman et al. | Jan 2014 | A1 |
| Number | Date | Country |
|---|---|---|
| 20040060893 | Jul 2004 | WO |
| 20050023818 | Mar 2005 | WO |
| 20110140164 | Nov 2011 | WO |
| 20110153553 | Dec 2011 | WO |
| 20120064897 | May 2012 | WO |
| Entry |
|---|
| Zhou et al, Am J Physiol. Endocrine. Metab., 2008, 295(5), E1120-E1166. |
| Dumoulin et al, Endocrinology, 1988, 139(9), 3780-3786. |
| Brown et al, J Biol chem, 2003, 278(13), 11312-11319. |
| Tazoe et al, Biomed Res. 2009, 30(3), 149-156. |
| Tolhurst et al, Diabetes, 2012, 61, 364-371. |
| Bindels et al, Trends in Pharmacol Sci, 2013, 34(4), 226-32. |
| Macia L et al; Nat Commun 2015, 6, article 6734. |
| Smith, PM et al; Science, 2013, 341 (6145), pp. 569-573. |
| European Patent Office, International Search Report issued in corresponding Application No. PCT/GB2015/051840, dated Sep. 2, 2015. |
| Intellectual Property Office, Search Report issued in corresponding Application No. GB 1411236.1, dated Feb. 23, 2015. |
| European Patent Office, Written Opinion of the International Searching Authority issued in corresponding Application No. PCT/GB2015/051840, dated Sep. 2, 2015. |
| Number | Date | Country | |
|---|---|---|---|
| 20170158700 A1 | Jun 2017 | US |
