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HK1169411B - Methylpyrrolopyrimidinecarboxamides - Google Patents

Methylpyrrolopyrimidinecarboxamides Download PDF

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Publication number
HK1169411B
HK1169411B HK12110218.1A HK12110218A HK1169411B HK 1169411 B HK1169411 B HK 1169411B HK 12110218 A HK12110218 A HK 12110218A HK 1169411 B HK1169411 B HK 1169411B
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HK
Hong Kong
Prior art keywords
methyl
pyrrolo
cyclopropylmethoxy
pyrimidine
carboxamide
Prior art date
Application number
HK12110218.1A
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Chinese (zh)
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HK1169411A1 (en
Inventor
Josef Stadlwieser
Beate Schmidt
Heiko Bernsmann
Torsten Dunkern
Ewald Benediktus
Andreas Pahl
Ragna Hussong
Olaf Nimz
Matthias Müller
Martin Viertelhaus
Original Assignee
Astrazeneca Ab
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Priority claimed from PCT/EP2010/062329 external-priority patent/WO2011023693A1/en
Publication of HK1169411A1 publication Critical patent/HK1169411A1/en
Publication of HK1169411B publication Critical patent/HK1169411B/en

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Description

Methylpyrrolopyrimidinecarboxamides
Field of application of the subject matter of the invention
The present subject matter relates to methylpyrrolidine carboxamide compounds, processes for their preparation, pharmaceutical compositions comprising said compounds and their use in the treatment or prophylaxis of diseases.
Background
Pyrrolopyrimidine carboxamides are described in WO 2009/106531. EP1634883 discloses 2-substituted phenyl-5, 7-dihydrocarbyl-3, 7-dihydropyrrolo [2,3-d ] pyrimidin-4-one derivatives and their use for the treatment and/or prevention of sexual dysfunction and other diseases associated with phospholipase 5. WO01/94350 discloses 6-phenylpyrrolopyrimidine derivatives as selective cyclic GMP-specific phosphodiesterase (PDE 5) inhibitors.
Description of the subject matter of the invention
It has now been found that the methylpyrrolidone carboxamide compounds described in detail below have surprising and advantageous properties.
The present subject matter relates to compounds of the formula (I)
Wherein
R1 is-CH 2-3-6C-cycloalkyl or 1-4C-alkyl, optionally substituted with R11,
r11 is 1-4C-alkoxy or hydroxy,
r2 is hydrogen or 1-4C-alkyl
R21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy or 1-4C-fluoroalkoxy,
or R22 and R23 combine to form a group-O-CH2-O-，
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl which is substituted by R6 and optionally by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, -C (O) -3-6C-cycloalkyl, wherein 3-6C-cycloalkyl is optionally substituted by R42, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r42 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
If two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, -C (O) -NR8R9, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
r8 is a hydrogen atom or a salt thereof,
r9 is 1-4C-alkyl optionally substituted by R91, or 3-6C-cycloalkyl optionally substituted by R92,
r91 is 1-4C-alkoxy or hydroxy,
r92 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
1-4C-alkyl is straight-chain or branched alkyl having 1 to 4 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
2-4C-alkyl is straight-chain or branched alkyl having 2 to 4 carbon atoms. Examples are ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
1-4C-fluoroalkyl is a straight-chain or branched alkyl moiety having 1 to 4 carbon atoms, wherein one or more hydrogen atoms of the alkyl moiety are substituted by fluorine. Examples include, but are not limited to: trifluoromethyl, difluoromethyl, fluoromethyl, perfluoroethyl, 1,1, 1-trifluoro-2-fluoroethyl, 1,1, 1-trifluoroethyl, 1, 1-difluoro-2, 2-difluoroethyl, 1, 1-difluoro-2-fluoroethyl, 1, 1-difluoroethyl, 1-fluoro-2, 2-difluoroethyl, 1-fluoro-2-fluoroethyl, 1-fluoroethyl, 2, 2-difluoroethyl, 2-fluoroethyl, perfluoro-n-propyl and perfluoro-n-butyl.
1-2C-fluoroalkyl is a straight-chain or branched alkyl moiety having 1 to 2 carbon atoms, wherein one or more hydrogen atoms of the alkyl moiety are substituted by fluorine. Examples include, but are not limited to: trifluoromethyl, difluoromethyl, fluoromethyl, perfluoroethyl, 1,1, 1-trifluoro-2-fluoroethyl, 1,1, 1-trifluoroethyl, 1, 1-difluoro-2, 2-difluoroethyl, 1, 1-difluoro-2-fluoroethyl, 1, 1-difluoroethyl, 1-fluoro-2, 2-difluoroethyl, 1-fluoro-2-fluoroethyl, 1-fluoroethyl, 2, 2-difluoroethyl and 2-fluoroethyl.
Halogen includes fluorine, chlorine, bromine and iodine. In case R22 and/or R23 and/or R5 and/or R6 and/or R61 are halogen, fluorine is preferred.
3-6C-cycloalkyl is cycloalkyl having 3 to 6 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In case R3 is 3-6C-cycloalkyl, cyclohexyl and cyclopentyl are preferred.
3-4C-cycloalkyl is cycloalkyl having 3 to 4 carbon atoms, examples of which include cyclopropyl and cyclobutyl.
5-6C-cycloalkyl is cycloalkyl having 5 to 6 carbon atoms, examples of which include cyclopentyl and cyclohexyl.
1-4C-alkoxy represents a group which, in addition to the oxygen atom, contains a straight-chain or branched alkyl moiety of 1 to 4 carbon atoms. Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.
1-2C-alkoxy represents a group which, in addition to the oxygen atom, contains a straight-chain alkyl moiety of 1 to 2 carbon atoms. Examples are the methoxy and ethoxy radical and,
1-4C-fluoroalkoxy represents a group containing, in addition to an oxygen atom, a straight-chain or branched alkyl moiety of 1 to 4 carbon atoms in which one or more hydrogen atoms of the alkyl moiety are replaced by fluorine. Examples include, but are not limited to: trifluoromethoxy, difluoromethoxy, fluoromethoxy, perfluoroethoxy, 1,1, 1-trifluoro-2-fluoroethoxy, 1,1, 1-trifluoroethoxy, 1, 1-difluoro-2, 2-difluoroethoxy, 1, 1-difluoro-2-fluoroethoxy, 1, 1-difluoroethoxy, 1-fluoro-2, 2-difluoroethoxy, 1-fluoro-2-fluoroethoxy, 1-fluoroethoxy, 2, 2-difluoroethoxy, 2-fluoroethoxy, perfluoro-n-propoxy and perfluoro-n-butoxy.
The radical-C (O) -1-4C-alkyl represents a radical which, in addition to the carbonyl group-C (O) -contains a linear or branched alkyl moiety having from 1 to 4 carbon atoms. Examples are methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl and tert-butylcarbonyl.
The radical-C (O) -1-2C-alkyl represents a radical which, in addition to the carbonyl group-C (O) -contains a linear or branched alkyl moiety having from 1 to 2 carbon atoms. Examples are methylcarbonyl and ethylcarbonyl.
The radical-C (O) -3-6C-cycloalkyl denotes a radical of a cycloalkyl group which, in addition to the carbonyl group-C (O) -contains from 3 to 6 carbon atoms. Examples are cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl.
The radical-C (O) -O-1-4C-alkyl represents a radical which, in addition to the oxycarbonyl radical-C (O) -O-, contains a linear or branched alkyl moiety of 1 to 4 carbon atoms. Examples are methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl.
4-to 7-membered saturated heterocyclic rings containing one nitrogen atom and optionally one oxygen atom include, but are not limited to: azetidinyl, oxazacyclobutylalkyl, pyrrolidinyl, Oxazolidinyl, piperidinyl, morpholinyl, azepanyl and oxaazepanyl radicals, especially azetidinyl, 1, 3-oxazepanyl, pyrrolidinyl, 1,3-Oxazolidinyl, piperidinyl, morpholinyl, azepanyl and 1, 3-oxaazepanyl, preferably azetidin-3-yl, pyrrolidin-3-yl, morpholin-2-yl, piperidin-3-yl and piperidin-4-yl.
Containing a nitrogen atom and optionally an oxygen atomThe 4-to 6-membered saturated heterocyclic ring of (a) includes, but is not limited to: azetidinyl, oxazacyclobutylalkyl, pyrrolidinyl,oxazolidinyl, piperidinyl and morpholinyl, especially azetidinyl, 1, 3-oxazacyclobutylalkyl, pyrrolidinyl, 1,3-Oxazolidinyl, piperidinyl, morpholinyl, preferably azetidin-3-yl, pyrrolidin-3-yl, morpholin-2-yl, piperidin-3-yl and piperidin-4-yl.
5-to 6-membered saturated heterocyclic rings containing one nitrogen atom and optionally one oxygen atom include, but are not limited to: a pyrrolidinyl group,oxazolidinyl, piperidinyl and morpholinyl radicals, especially pyrrolidinyl, 1,3-Oxazolidinyl, piperidinyl, morpholinyl, preferably pyrrolidin-3-yl, morpholin-2-yl, piperidin-3-yl and piperidin-4-yl.
In one embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-6C-cycloalkyl or 1-4C-alkyl, optionally substituted with R11,
r11 is 1-4C-alkoxy or hydroxy,
r2 is hydrogen or 1-4C-alkyl
R21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy or 1-4C-fluoroalkoxy,
or R22 and R23 combine to form a group-O-CH2-O-，
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, -C (O) -3-6C-cycloalkyl, wherein 3-6C-cycloalkyl is optionally substituted by R42, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r42 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, -C (O) -NR8R9, halogen, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
R71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
r8 is a hydrogen atom or a salt thereof,
r9 is 1-4C-alkyl optionally substituted by R91, or 3-6C-cycloalkyl optionally substituted by R92,
r91 is 1-4C-alkoxy or hydroxy,
r92 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In one embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-4C-cycloalkyl or 2-4C-alkyl, optionally substituted with R11,
r11 is 1-4C-alkoxy or hydroxy,
r2 is hydrogen or 1-4C-alkyl
R21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy or 1-4C-fluoroalkoxy,
or R22 and R23 combine to form a group-O-CH2-O-，
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl which is substituted by R6 and optionally by R61,
R4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, -C (O) -3-6C-cycloalkyl, wherein 3-6C-cycloalkyl is optionally substituted by R42, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r42 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In one embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-4C-cycloalkyl or 2-4C-alkyl, optionally substituted with R11,
r11 is 1-4C-alkoxy or hydroxy,
r2 is hydrogen or 1-4C-alkyl
R21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy or 1-4C-fluoroalkoxy,
or R22 and R23 combine to form a group-O-CH2-O-，
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, -C (O) -3-6C-cycloalkyl, wherein 3-6C-cycloalkyl is optionally substituted by R42, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r42 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
R71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-4C-cycloalkyl or 2-4C-alkyl,
r2 is hydrogen or 1-4C-alkyl
R21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-fluoroalkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
If two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-4C-cycloalkyl or 2-4C-alkyl,
r2 is hydrogen or 1-4C-alkyl
R21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-fluoroalkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
R4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-4C-cycloalkyl or 2-4C-alkyl,
r2 is hydrogen or 1-4C-alkyl
R21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-fluoroalkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
R4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-4C-cycloalkyl or 2-4C-alkyl,
r2 is hydrogen or 1-4C-alkyl
R21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-fluoroalkoxy,
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, hydroxy, halogen or NH2，
R7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is hydrogen or methyl
R21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-2C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-2C-alkyl or 1-2C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-2C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and on the heterocyclic ring optionally by one or two substituents R5, or cyclohexyl or cyclopentyl substituted by R6 and optionally substituted by R61,
R4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is fluoro, methyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from fluorine or methyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, fluoro, hydroxy or NH2，
R61 is fluoro, methyl or hydroxy,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-2C-alkoxy-1-4C-fluoroalkoxy, -C (O) -1-2C-alkyl or 1-2C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-2C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
R4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7 or hydroxy,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, fluoro, methyl, ethyl, isopropyl, methoxy, -C (O) -methyl, fluoromethyl, difluoromethyl or trifluoromethyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, fluoro or methoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7 or hydroxy,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
A salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-6C-cycloalkyl or 1-4C-alkyl,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or by one substituent R5, or 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
R71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-6C-cycloalkyl or 1-4C-alkyl,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen or 1-4C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one substituent R5, or 5-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
r5 is halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R61 is halogen or 1-4C-alkyl,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen or 1-4C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one substituent R5, or 5-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted with R41,
r41 is 1-4C-alkoxy or hydroxy,
r5 is halogen, hydroxy or 1-4C-alkyl,
r6 is-NH-C (O) -R7,
r61 is halogen or 1-4C-alkyl,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, fluoro, methyl, methoxy, -C (O) -methyl, difluoromethyl or trifluoromethyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, fluoro or methoxy,
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and on the heterocyclic ring optionally by one substituent R5, or cyclohexyl or cyclopentyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted with R41,
r5 is fluorine, hydroxy or methyl,
r6 is-NH-C (O) -R7,
r61 is fluorine or a methyl group,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, fluoro, methyl, methoxy, -C (O) -methyl, difluoromethyl or trifluoromethyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, fluoro or methoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and on the heterocyclic ring optionally by one substituent R5, or cyclohexyl or cyclopentyl substituted by R6 and optionally substituted by R61,
R4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41,
r41 is a methoxy group or a hydroxy group,
r5 is fluorine, hydroxy or methyl,
r6 is-NH-C (O) -R7,
r61 is fluorine or a methyl group,
r7 is methyl or ethyl, optionally substituted with R71, or ethoxy,
r71 is a methoxy group or a hydroxy group,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-6C-cycloalkyl or 1-4C-alkyl,
r2 is a hydrogen atom or a salt thereof,
r21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl which is substituted by R6 and optionally by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, -C (O) -3-6C-cycloalkyl, wherein 3-6C-cycloalkyl is optionally substituted by R42, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
R41 is 1-4C-alkoxy or hydroxy,
r42 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, -C (O) -NR8R9, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
r8 is a hydrogen atom or a salt thereof,
r9 is 1-4C-alkyl optionally substituted by R91, or 3-6C-cycloalkyl optionally substituted by R92,
r91 is 1-4C-alkoxy or hydroxy,
r92 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
R2 is a hydrogen atom or a salt thereof,
r21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl which is substituted by R6 and optionally by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
R71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
R71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is hydrogen or a halogen,
r22 is hydrogen, halogen, 1-4C-alkyl or 1-4C-fluoroalkyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
R6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl or 1-4C-fluoroalkyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is methoxy, fluoro, methyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from fluorine or methyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
R6 is-NH-C (O) -R7, fluoro, hydroxy or NH2，
R61 is fluoro, methyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl or 1-4C-fluoroalkyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or cyclohexyl or cyclopentyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is methoxy, fluoro, methyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from fluorine or methyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
R6 is-NH-C (O) -R7, fluoro, hydroxy or NH2，
R61 is fluoro, methyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl or 1-4C-fluoroalkyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
A salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, fluorine, methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl or trifluoromethyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and on the heterocyclic ring optionally by one or two substituents R5, or cyclohexyl or cyclopentyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is methoxy, fluoro, methyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from fluorine or methyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, fluoro, hydroxy or NH 2，
R61 is fluoro, methyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is halogen, 1-4C-alkyl or 1-4C-fluoroalkyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or by one substituent R5, or 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, -C (O) -3-6C-cycloalkyl, wherein 3-6C-cycloalkyl is optionally substituted by R42, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r42 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, halogen, hydroxy or NH 2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is halogen, 1-4C-alkyl or 1-4C-fluoroalkyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one substituent R5, or 5-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
r5 is halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R61 is halogen or 1-4C-alkyl,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
A salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is halogen, 1-4C-alkyl or 1-4C-fluoroalkyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is 5-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R61 is halogen or 1-4C-alkyl,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is fluorine, methyl, difluoromethyl or trifluoromethyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and on the heterocyclic ring optionally by one substituent R5, or 5-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
R41 is 1-4C-alkoxy or hydroxy,
r5 is halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O)-R7, hydroxy or NH2，
R61 is halogen or 1-4C-alkyl,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is fluorine, methyl, difluoromethyl or trifluoromethyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and on the heterocyclic ring optionally by one substituent R5, or cyclohexyl or cyclopentyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41,
r41 is 1-4C-alkoxy or hydroxy,
r5 is halogen or 1-4C-alkyl,
r6 is-NH-C (O) -R7,
r61 is halogen or 1-4C-alkyl,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is fluorine, methyl, difluoromethyl or trifluoromethyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and on the heterocyclic ring optionally by one substituent R5, or cyclohexyl or cyclopentyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41,
r41 is 1-4C-alkoxy,
r5 is fluorine or a methyl group,
r6 is-NH-C (O) -R7,
r61 is fluorine or a methyl group,
r7 is methyl or ethyl, optionally substituted with R71, or ethoxy,
r71 is a methoxy group or a hydroxy group,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-6C-cycloalkyl or 1-4C-alkyl,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH 2-O-，
R23 is hydrogen, halogen, 1-4C-alkoxy, hydroxy or 1-4C-fluoroalkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl which is substituted by R6 and optionally by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, -C (O) -NR8R9, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
R72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
r8 is a hydrogen atom or a salt thereof,
r9 is 1-4C-alkyl optionally substituted by R91, or 3-6C-cycloalkyl optionally substituted by R92,
r91 is 1-4C-alkoxy or hydroxy,
r92 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkoxy, hydroxy or 1-4C-fluoroalkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl which is substituted by R6 and optionally by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
R43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkoxy, hydroxy or 1-4C-fluoroalkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
R4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen or 1-4C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
R41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, fluorine, methyl, ethyl, isopropyl, methoxy, ethoxy, -C (O) -1-2C-alkyl, fluoromethyl, difluoromethyl or trifluoromethyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, fluoro or methoxy
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH 2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-6C-cycloalkyl or 1-4C-alkyl,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, fluorine, methyl or methoxy,
r23 is hydrogen, fluoro or methoxy
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, -C (O) -NR8R9, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
R71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
r8 is a hydrogen atom or a salt thereof,
r9 is 1-4C-alkyl optionally substituted by R91, or 3-6C-cycloalkyl optionally substituted by R92,
r91 is 1-4C-alkoxy or hydroxy,
r92 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or a methyl group,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, fluorine, methyl or methoxy,
r23 is hydrogen, fluoro or methoxy
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is methoxy, fluoro, methyl or hydroxy,
r6 is-NH-C (O) -R7, hydroxyRadical or NH2，
R7 is 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
R71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is hydrogen or a methyl group,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, fluorine, methyl or methoxy,
r23 is hydrogen, fluoro or methoxy
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R7 is 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
R2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, fluorine, methyl or methoxy,
r23 is hydrogen, fluoro or methoxy
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and on the heterocyclic ring optionally by one or two substituents R5, or cyclohexyl or cyclopentyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is fluoro, methyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from fluorine or methyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, fluoro, hydroxy or NH2，
R61 is fluoro, methyl or hydroxy,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, fluorine, methyl or methoxy,
r23 is hydrogen, fluoro or methoxy
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and on the heterocyclic ring optionally by one substituent R5, or cyclohexyl or cyclopentyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
r5 is fluoro, methyl or hydroxy,
r6 is-NH-C (O) -R7, fluoro, hydroxy or NH2，
R61 is fluoro, methyl or hydroxy,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, fluorine, methyl or methoxy,
r23 is hydrogen, fluoro or methoxy
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and on the heterocyclic ring optionally by one substituent R5, or cyclohexyl or cyclopentyl substituted by R6 and optionally substituted by R61,
R4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
r5 is fluoro, methyl or hydroxy,
r6 is-NH-C (O) -R7,
r61 is fluorine or a methyl group,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is a hydrogen atom or a salt thereof,
r23 is fluorine
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, -C (O) -3-6C-cycloalkyl, wherein 3-6C-cycloalkyl is optionally substituted by R42, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r42 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
R6 is-NH-C (O) -R7, -C (O) -NR8R9, halogen, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
r8 is a hydrogen atom or a salt thereof,
r9 is 1-4C-alkyl optionally substituted by R91, or 3-6C-cycloalkyl optionally substituted by R92,
r91 is 1-4C-alkoxy or hydroxy,
r92 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is a hydrogen atom or a salt thereof,
r23 is fluorine
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is hydrogen or a methyl group,
r21 is a hydrogen atom or a salt thereof,
r22 is a hydrogen atom or a salt thereof,
r23 is fluorine
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7, fluoro, hydroxy or NH2，
R7 is 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is a hydrogen atom or a salt thereof,
r23 is fluorine
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7, fluoro, hydroxy or NH2，
R7 is 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is a hydrogen atom or a salt thereof,
r23 is fluorine
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
R4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41,
r41 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7 or hydroxy,
r7 is 1-4C-alkyl optionally substituted with R71,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is a hydrogen atom or a salt thereof,
r23 is fluorine
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and which heterocyclic ring is optionally substituted by R5, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41,
r41 is 1-4C-alkoxy or hydroxy,
r5 is a hydroxyl group, and R5 is a hydroxyl group,
r6 is-NH-C (O) -R7,
r7 is 1-4C-alkyl optionally substituted with R71,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is fluorine
R23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl which is substituted by R6 and optionally by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, -C (O) -3-6C-cycloalkyl, wherein 3-6C-cycloalkyl is optionally substituted by R42, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r42 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, -C (O) -NR8R9, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
R71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
r8 is a hydrogen atom or a salt thereof,
r9 is 1-4C-alkyl optionally substituted by R91, or 3-6C-cycloalkyl optionally substituted by R92,
r91 is 1-4C-alkoxy or hydroxy,
r92 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is fluorine
R23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
R6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r21 is a hydrogen atom or a salt thereof,
r2 is hydrogen or 1-4C-alkyl,
r22 is fluorine
R23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7 or hydroxy,
r7 is 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is fluorine
R23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7 or hydroxy,
r7 is 1-4C-alkyl, optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is fluorine
R23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and which heterocyclic ring is optionally substituted by R5, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
R41 is 1-4C-alkoxy or hydroxy,
r5 is a hydroxyl group, and R5 is a hydroxyl group,
r6 is-NH-C (O) -R7,
r7 is 1-4C-alkyl, optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is methoxy
R23 is a fluorine atom or a fluorine atom,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, -C (O) -3-6C-cycloalkyl, wherein 3-6C-cycloalkyl is optionally substituted by R42, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r42 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, -C (O) -NR8R9, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
R71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
r8 is a hydrogen atom or a salt thereof,
r9 is 1-4C-alkyl optionally substituted by R91, or 3-6C-cycloalkyl optionally substituted by R92,
r91 is 1-4C-alkoxy or hydroxy,
r92 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is methoxy
R23 is a fluorine atom or a fluorine atom,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
R71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is methoxy
R23 is a fluorine atom or a fluorine atom,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
R21 is a hydrogen atom or a salt thereof,
r22 is methoxy
R23 is a fluorine atom or a fluorine atom,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, or-C (O) -O-1-4C-alkyl,
r6 is-NH-C (O) -R7 or hydroxy,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is a methyl group, and R22 is a methyl group,
r23 is a fluorine atom or a fluorine atom,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, -C (O) -3-6C-cycloalkyl, wherein 3-6C-cycloalkyl is optionally substituted by R42, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
R42 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, -C (O) -NR8R9, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
r8 is a hydrogen atom or a salt thereof,
r9 is 1-4C-alkyl optionally substituted by R91, or 3-6C-cycloalkyl optionally substituted by R92,
r91 is 1-4C-alkoxy or hydroxy,
r92 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is a methyl group, and R22 is a methyl group,
r23 is a fluorine atom or a fluorine atom,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
R41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is a methyl group, and R22 is a methyl group,
r23 is a fluorine atom or a fluorine atom,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
R71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is a methyl group, and R22 is a methyl group,
r23 is a fluorine atom or a fluorine atom,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41,
r41 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7 or hydroxy,
r7 is 1-4C-alkyl optionally substituted with R71,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is a fluorine atom or a fluorine atom,
r23 is a methoxy group, and R23 is a methoxy group,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
R4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, -C (O) -3-6C-cycloalkyl, wherein 3-6C-cycloalkyl is optionally substituted by R42, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r42 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, -C (O) -NR8R9, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
r8 is a hydrogen atom or a salt thereof,
r9 is 1-4C-alkyl optionally substituted by R91, or 3-6C-cycloalkyl optionally substituted by R92,
r91 is 1-4C-alkoxy or hydroxy,
r92 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is a fluorine atom or a fluorine atom,
r23 is a methoxy group, and R23 is a methoxy group,
r24 is a hydrogen atom or a salt thereof,
Y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or 3-6C-cycloalkyl substituted by R6,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is a fluorine atom or a fluorine atom,
r23 is a methoxy group, and R23 is a methoxy group,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
R41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-A 6C-cycloalkyl group, which is,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is a fluorine atom or a fluorine atom,
r23 is a methoxy group, and R23 is a methoxy group,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7 or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is 1-4C-alkyl
R23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl which is substituted by R6 and optionally by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, -C (O) -3-6C-cycloalkyl, wherein 3-6C-cycloalkyl is optionally substituted by R42, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r42 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, -C (O) -NR8R9, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
R71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
r8 is a hydrogen atom or a salt thereof,
r9 is 1-4C-alkyl optionally substituted by R91, or 3-6C-cycloalkyl optionally substituted by R92,
r91 is 1-4C-alkoxy or hydroxy,
r92 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is methyl, ethyl or isopropyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
R6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is methyl, ethyl or isopropyl,
r23 is a hydrogen atom or a salt thereof,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
A salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is methyl, ethyl or isopropyl,
r23 is a hydrogen atom or a salt thereof,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and/or R5, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
r5 is methoxy, fluoro, methyl or hydroxy,
r6 is-NH-C (O) -R7 or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is 1-4C-alkyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and which heterocyclic ring is optionally substituted by R5, or cyclohexyl or cyclopentyl which is substituted by R6 and which is optionally substituted by R61,
R4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is methyl, ethyl or isopropyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and which heterocyclic ring is optionally substituted by R5, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
R5 is a hydroxyl group, and R5 is a hydroxyl group,
r6 is-NH-C (O) -R7 or hydroxy,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is a methyl group, and R22 is a methyl group,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and which heterocyclic ring is optionally substituted by R5, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is a hydroxyl group, and R5 is a hydroxyl group,
r6 is-NH-C (O) -R7 or hydroxy,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is a 1-4C-fluoroalkyl group,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl which is substituted by R6 and optionally by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, -C (O) -3-6C-cycloalkyl, wherein 3-6C-cycloalkyl is optionally substituted by R42, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r42 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, -C (O) -NR8R9, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
r8 is a hydrogen atom or a salt thereof,
r9 is 1-4C-alkyl optionally substituted by R91, or 3-6C-cycloalkyl optionally substituted by R92,
r91 is 1-4C-alkoxy or hydroxy,
r92 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is fluoromethyl, difluoromethyl or trifluoromethyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, -C (O) -3-6C-cycloalkyl, wherein 3-6C-cycloalkyl is optionally substituted by R42, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
R41 is 1-4C-alkoxy or hydroxy,
r42 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, -C (O) -NR8R9, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
r8 is a hydrogen atom or a salt thereof,
r9 is 1-4C-alkyl optionally substituted by R91, or 3-6C-cycloalkyl optionally substituted by R92,
r91 is 1-4C-alkoxy or hydroxy,
r92 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
R2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is fluoromethyl, difluoromethyl or trifluoromethyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is methoxy, fluoro, methyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R61 is fluoro, methyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is fluoromethyl, difluoromethyl or trifluoromethyl,
r23 is a hydrogen atom or a salt thereof,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is a trifluoromethyl group and R is a trifluoromethyl group,
r23 is a hydrogen atom or a salt thereof,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH) 2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7 or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is a 1-4C-fluoroalkyl group,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one substituent R5, or 5-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
r5 is halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
R7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is fluoromethyl, difluoromethyl or trifluoromethyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one substituent R5, or 5-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
r5 is halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
R2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is a difluoromethyl group,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one substituent R5, or 5-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
r5 is halogen, 1-4C-alkyl or hydroxy,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is a difluoromethyl group,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and which heterocyclic ring is optionally substituted by R5, or cyclohexyl or cyclopentyl which is substituted by R6 and which is optionally substituted by R61,
R4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41,
r41 is 1-4C-alkoxy,
r5 is halogen or 1-4C-alkyl,
r6 is-NH-C (O) -R7,
r61 is halogen or 1-4C-alkyl,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is a difluoromethyl group,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and which heterocyclic ring is optionally substituted by R5, or cyclohexyl or cyclopentyl which is substituted by R6 and which is optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41,
r41 is 1-4C-alkoxy,
r5 is fluorine or a methyl group,
r6 is-NH-C (O) -R7,
r61 is fluorine or a methyl group,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is a difluoromethyl group,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and which heterocyclic ring is optionally substituted by R5, or cyclohexyl or cyclopentyl which is substituted by R6 and which is optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41,
r41 is 1-4C-alkoxy,
r5 is fluorine or a methyl group,
r6 is-NH-C (O) -R7,
r61 is fluorine or a methyl group,
r7 is methyl or ethyl, optionally substituted with R71, or ethoxy,
r71 is a methoxy group, and R71 is a methoxy group,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is a 1-4C-fluoroalkyl group,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is 5-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r6 is-NH-C (O) -R7,
r61 is halogen or 1-4C-alkyl,
r7 is 1-4C-alkyl optionally substituted with R71,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is difluoromethyl or trifluoromethyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is cyclohexyl substituted by R6 and optionally substituted by R61,
r6 is-NH-C (O) -R7,
r61 is fluorine or a methyl group,
r7 is methyl or ethyl optionally substituted with R71,
r71 is a methoxy group or a hydroxy group,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is a difluoromethyl group,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is cyclohexyl substituted by R6 and optionally substituted by R61,
r6 is-NH-C (O) -R7,
r61 is fluorine or a methyl group,
r7 is methyl or ethyl optionally substituted with R71,
r71 is a methoxy group or a hydroxy group,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-6C-cycloalkyl or 1-4C-alkyl, optionally substituted with R11,
r11 is 1-4C-alkoxy or hydroxy,
R2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy or 1-4C-fluoroalkoxy,
or R22 and R23 combine to form a group-O-CH2-O-，
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, -C (O) -3-6C-cycloalkyl, wherein 3-6C-cycloalkyl is optionally substituted by R42, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r42 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
A salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-6C-cycloalkyl or 1-4C-alkyl,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy or 1-4C-fluoroalkoxy,
or R22 and R23 combine to form a group-O-CH2-O-，
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is methoxy, fluoro, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
A salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy or 1-4C-fluoroalkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
Or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-fluoroalkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and/or by R5,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
R41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom with R4,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH 2-O-，
R23 is hydrogen, halogen, 1-4C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and/or which heterocyclic ring is optionally substituted by R5,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and/or which heterocyclic ring is optionally substituted by R5,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
R41 is 1-4C-alkoxy or hydroxy,
r5 is halogen or 1-4C-alkyl,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and/or which heterocyclic ring is optionally substituted by R5,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
r5 is halogen or 1-4C-alkyl,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-6C-cycloalkyl or 1-4C-alkyl, optionally substituted with R11,
r11 is 1-4C-alkoxy or hydroxy,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy, 1-4C-fluoroalkoxy or-C (O) -1-4C-alkyl, 1-4C-fluoroalkyl,
Or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy or 1-4C-fluoroalkoxy,
or R22 and R23 combine to form a group-O-CH2-O-，
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r6 is-NH-C (O) -R7, -C (O) -NR8R9, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
r8 is a hydrogen atom or a salt thereof,
r9 is 1-4C-alkyl optionally substituted by R91, or 3-6C-cycloalkyl optionally substituted by R92,
r91 is 1-4C-alkoxy or hydroxy,
r92 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-6C-cycloalkyl or 1-4C-alkyl, optionally substituted with R11,
r11 is 1-4C-alkoxy or hydroxy,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy, 1-4C-fluoroalkoxy or-C (O) -1-4C-alkyl, 1-4C-fluoroalkyl,
Or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy or 1-4C-fluoroalkoxy,
or R22 and R23 combine to form a group-O-CH2-O-，
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is cyclohexyl or cyclopentyl substituted by R6 and optionally substituted by R61,
r6 is-NH-C (O) -R7, -C (O) -NR8R9, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r72 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
r8 is a hydrogen atom or a salt thereof,
r9 is 1-4C-alkyl optionally substituted by R91, or 3-6C-cycloalkyl optionally substituted by R92,
r91 is 1-4C-alkoxy or hydroxy,
r92 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy, 1-4C-fluoroalkoxy or-C (O) -1-4C-alkyl, 1-4C-fluoroalkyl,
Or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy or 1-4C-fluoroalkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-fluoroalkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is cyclohexyl or cyclopentyl substituted by R6 and optionally substituted by R61,
r6 is-NH-C (O) -R7, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
R7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is 3-6C-cycloalkyl substituted by R6,
r6 is-NH-C (O) -R7 or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-6C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
Or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is cyclohexyl or cyclopentyl substituted by R6,
r6 is-NH-C (O) -R7 or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is cyclohexyl or cyclopentyl substituted by R6 and optionally substituted by R61,
r6 is-NH-C (O) -R7,
r61 is halogen or 1-4C-alkyl,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-6C-cycloalkyl or 1-4C-alkyl, optionally substituted with R11,
r11 is 1-4C-alkoxy or hydroxy,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy, 1-4C-fluoroalkoxy or-C (O) -1-4C-alkyl, 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxy or 1-4C-fluoroalkoxy,
or R22 and R23 combine to form a group-O-CH2-O-，
R24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl which is substituted by R6 and optionally by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
R6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-6C-cycloalkyl or 1-4C-alkyl, optionally substituted with R11,
r11 is 1-4C-alkoxy or hydroxy,
r2 is hydrogen or 1-4C-alkyl,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-fluoroalkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0 or 1,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or R5, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41,
r41 is 1-4C-alkoxy or hydroxy,
r5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
R6 is-NH-C (O) -R7 or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the present subject matter relates to compounds of formula (I), wherein
R1 is-CH2-3-6C-cycloalkyl or 1-4C-alkyl,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41,
r41 is 1-4C-alkoxy or hydroxy,
r6 is-NH-C (O) -R7 or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R1 is-CH 2-3-6C-cycloalkyl or1-4C-alkyl, R2, R21, R22, R23, R24, Y, n, R3, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91 and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R1 is-CH2-3-6C-cycloalkyl, R2, R21, R22, R23, R24, Y, n, R3, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91 and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R1 is-CH2-3-4C-cycloalkyl, R2, R21, R22, R23, R24, Y, n, R3, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91 and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R2 is hydrogen, R1, R21, R22, R23, R24, Y, n, R3, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R2 is methyl, R1, R21, R22, R23, R24, Y, n, R3, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R21 is hydrogen, R1, R2, R22, R23, R24, Y, n, R3, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R21 is fluoro, R1, R2, R22, R23, R24, Y, n, R3, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, -C (O) -1-4C-alkyl, 1-4C-fluoroalkyl, or R21 and R22 combine to form a group-O-CH2-O-, R1, R11, R2, R21, R23, R24, Y, n, R3, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91 and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R22 is hydrogen, fluoro, methyl, ethyl, isopropyl, methoxy, -c (O) -methyl, fluoromethyl, difluoromethyl, trifluoromethyl, or R21 and R22 combine to form a group-O-CH 2-O-, R1, R11, R2, R21, R23, R24, Y, n, R3, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91 and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R22 is fluoro, methyl, difluoromethyl, or trifluoromethyl, R1, R11, R2, R21, R23, R24, Y, n, R3, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R23 is hydrogen, halogen or 1-4C-alkoxy, R1, R11, R2, R21, R22, R24, Y, n, R3, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R23 is hydrogen, fluoro, or methoxy, R1, R11, R2, R21, R22, R24, Y, n, R3, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein n is 0, R1, R11, R2, R21, R22, R23, R24, Y, R3, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which is substituted on the nitrogen atom with R4 and optionally substituted on the heterocyclic ring with one or two substituents R5, or cyclohexyl or cyclopentyl substituted with R6 and optionally substituted with R61, R1, R11, R2, R21, R22, R23, R24, Y, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91 and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which is substituted on the nitrogen atom with R4 and optionally substituted on the heterocyclic ring with one substituent R5, or cyclohexyl or cyclopentyl substituted with R6 and optionally substituted with R61, R1, R11, R2, R21, R22, R23, R24, Y, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which is substituted on the nitrogen atom with R4, or cyclohexyl or cyclopentyl substituted with R6, R1, R11, R2, R21, R22, R23, R24, Y, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R3 is piperidine substituted on the nitrogen atom with R4, and is optionally substituted on the piperidine ring with one or two substituents R5, or cyclohexyl or cyclopentyl substituted with R6 and optionally substituted with R61, R1, R11, R2, R21, R22, R23, R24, Y, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91 and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R3 is piperidine substituted on the nitrogen atom with R4, or cyclohexyl or cyclopentyl substituted with R6, R1, R11, R2, R21, R22, R23, R24, Y, R4, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the subject matter of the invention relates to compounds of formula (I) or salts thereof, wherein R4 is-C (o) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted with R41, R1, R11, R2, R21, R22, R23, R24, Y, R3, R41, R42, R43, R5, R6, R61, R7, R71, R72, R73, R8, R9, R91 and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R5 is hydroxy, R1, R11, R21, R2, R22, R23, R24, Y, R3, R4, R41, R42, R43, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R5 is fluoro, R1, R11, R21, R2, R22, R23, R24, Y, R3, R4, R41, R42, R43, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R5 is hydroxy or fluoro, R1, R11, R21, R2, R22, R23, R24, Y, R3, R4, R41, R42, R43, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R5 is methyl, R1, R11, R21, R2, R22, R23, R24, Y, R3, R4, R41, R42, R43, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the subject of the invention is a compound of formula (I) or a salt thereof, wherein two substituents R5 are present, which are identical and bonded to the same carbon atom, and which are fluorine, R1, R11, R21, R2, R22, R23, R24, Y, R3, R4, R41, R42, R43, R6, R61, R7, R71, R72, R73, R8, R9, R91 and R92 are as described above or below.
In another embodiment, the subject of the invention is a compound of formula (I) or a salt thereof, wherein two substituents R5 are present, which are identical and bonded to the same carbon atom, and which are methyl, R1, R11, R21, R2, R22, R23, R24, Y, R3, R4, R41, R42, R43, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein two substituents R5 are present and form together with the carbon atom to which they are bound a spiro-linked cyclopropane ring, R1, R11, R21, R2, R22, R23, R24, Y, R3, R4, R41, R42, R43, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R5 is halogen or 1-4C alkyl, R1, R11, R21, R2, R22, R23, R24, Y, R3, R4, R41, R42, R43, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R5 is fluoro or methyl, R1, R11, R21, R2, R22, R23, R24, Y, R3, R4, R41, R42, R43, R6, R61, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R6 is-NH-C (O) -R7, halogen, hydroxy or NH2，R1、R11. R2, R21, R22, R23, R24, Y, R3, R4, R41, R42, R43, R5, R61, R7, R71, R72 and R73 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R6 is-NH-C (O) -R7, hydroxy or NH2R1, R11, R2, R21, R22, R23, R24, Y, R3, R4, R41, R42, R43, R5, R61, R7, R71, R72, and R73 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R6 is-NH-C (O) -R7 or NH2R1, R11, R2, R21, R22, R23, R24, Y, R3, R4, R41, R42, R43, R5, R61, R7, R71, R72, and R73 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R6 is-NH-c (o) -R7 or hydroxy, R1, R11, R2, R21, R22, R23, R24, Y, R3, R4, R41, R42, R43, R5, R61, R7, R71, R72, and R73 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R6 is-NH-c (o) -R7, R1, R11, R2, R21, R22, R23, R24, Y, R3, R4, R41, R42, R43, R5, R61, R7, R71, R72, and R73 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R6 is hydroxy, R1, R11, R2, R21, R22, R23, R24, Y, R3, R4, R41, R42, R43, R5, and R61 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R6 is halogen, R1, R11, R2, R21, R22, R23, R24, Y, R3, R4, R41, R42, R43, R5, and R61 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R61 is halogen, R1, R11, R2, R21, R22, R23, R24, Y, R3, R4, R41, R42, R43, R5, R6, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R61 is fluoro, R1, R11, R2, R21, R22, R23, R24, Y, R3, R4, R41, R42, R43, R5, R6, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the subject matter of the invention relates to compounds of the formula (I) or salts thereof, wherein R61 is 1-4C-alkyl, R1, R11, R2, R21, R22, R23, R24, Y, R3, R4, R41, R42, R43, R5, R6, R7, R71, R72, R73, R8, R9, R91 and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R61 is methyl, R1, R11, R2, R21, R22, R23, R24, Y, R3, R4, R41, R42, R43, R5, R6, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the subject matter of the invention relates to compounds of formula (I) or salts thereof, wherein R61 is halogen or 1-4C-alkyl, R1, R11, R2, R21, R22, R23, R24, Y, R3, R4, R41, R42, R43, R5, R6, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R61 is fluoro or methyl, R1, R11, R2, R21, R22, R23, R24, Y, R3, R4, R41, R42, R43, R5, R6, R7, R71, R72, R73, R8, R9, R91, and R92 are as described above or below.
In another embodiment, the subject matter of the invention relates to compounds of formula (I) wherein R7 is 1-4C-alkyl (which is optionally substituted by R71) or 1-4C-alkoxy, R1, R11, R21, R2, R22, R23, R24, Y, R3, R4, R41, R42, R43, R5, R6, R61, R71, R8, R9, R91 and R92 are as described above or below, or salts thereof.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R1 is-CH2-3-4C-cycloalkyl, n is 0, R2 is hydrogen, R3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which is substituted on the nitrogen atom with R4 and on which is optionally substituted with one or two substituents R5, or cyclohexyl or cyclopentyl substituted with R6 and optionally substituted with R61, R4 is-C (o) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted with R41, R6 is-NH-C (o) -R7 or hydroxy, R7 is 1-4C-alkyl (which is optionally substituted with R71) or 1-4C-alkoxy, R21, R22, R23, R24, Y, R41, R5, R61 and R71 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R1 is-CH2-3-4C-cycloalkyl, n is 0, R2 is hydrogen, R3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which is substituted on the nitrogen atom with R4 and on which is optionally substituted with one substituent R5, or cyclohexyl or cyclopentyl substituted with R6 and optionally substituted with R61, R4 is-C (o) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted with R41, R6 is-NH-C (o) -R7, R7 is 1-4C-alkyl (which is optionally substituted with R71) or 1-4C-alkoxy, R21, R22, R23, R24, Y, R41, R5, R61 and R71 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R1 is-CH2-3-4C-cycloalkyl, n is 0, R2 is hydrogen, R3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6, R4 is-C (o) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, R6 is-NH-C (o) -R7 or hydroxy, R7 is 1-4C-alkyl (which is optionally substituted by R71) or 1-4C-alkoxy, R21, R22, R23, R24, Y, R41 and R71 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) or salts thereof, wherein R1 is-CH2-3-4C-cycloalkyl, n is 0, R2Is hydrogen, R3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4, or cyclohexyl or cyclopentyl substituted by R6, R4 is-C (o) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, R6 is-NH-C (o) -R7, R7 is 1-4C-alkyl (which is optionally substituted by R71) or 1-4C-alkoxy, R21, R22, R23, R24, Y, R41 and R71 are as described above or below.
In another embodiment, the inventive subject matter relates to compounds of formula (I) selected from the group consisting of:
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester;
n- (trans-4-acetamidocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
Ethyl { trans-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
n- (cis-4-acetamidocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
ethyl { cis-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides；
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
N-[(3S*,4S*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3S*,4S*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3S*,4S*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (1-acetyl-piperidin-4-yl) -amide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid [1- (2-methoxy-acetyl) -piperidin-4-yl ] -amide;
4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
ethyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- (2-ethoxy-5-fluorophenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-ethoxy-5-fluorophenyl) -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-ethoxy-5-fluorophenyl) -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d ]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl ]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
ethyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
N-[(3S*,4S*) -1-acetyl-4-hydroxypiperidin-3-yl]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -4-hydroxy-1-propionylpiperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -4-hydroxy-1- (methoxyacetyl) piperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl radical]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl radical]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
ethyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
N-[(3R*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- (1-acetylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
(3R) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid ethyl ester;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- (1-glycolylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ trans-4- (ethanolamido) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ cis-4- (ethanolamido) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ (3R) -1-ethanoylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- (1-glycolylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ (3R) -1- (hydroxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4R*) -4-hydroxy-1- (hydroxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3S*,4S*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid [1- (2-hydroxy-acetyl) -piperidin-4-yl ] -amide;
4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid [1- ((S) -2-hydroxy-propionyl) -piperidin-4-yl ] -amide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- [ (3R) -1- (hydroxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-ethoxy-5-fluorophenyl) -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-ethoxy-5-fluorophenyl) -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- (1-glycoloylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methylOxy-phenyl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- (1-glycoloylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- (1-glycoloylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac) -3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac) -3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -1-glycolyl-4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac) -3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac) -3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl radical]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- (1-glycoloylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (hydroxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1S,2S) -2-hydroxycyclopentyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1S,2R) -2-hydroxycyclopentyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1R,2R) -2-hydroxycyclopentyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-{(3R*,4R*) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl group]Pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ]-N-{(3R*,4R*) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl group]Pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-{(3R*,4R*) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl group]Pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
(3R) -3- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester;
(3R*,4R*) -3- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
(3R) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester;
(3R*,4R*) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester;
(3S*,4S*) -4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- ({1- [4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl ] -formyloxy } -amino) -piperidine-1-carboxylic acid tert-butyl ester;
Tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
(3R) -3- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester;
(3R*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- ({ [4- (2-ethoxy-5-fluorophenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl ] carbonyl } amino) piperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
(3R) -3- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester;
(3R*,4R*) -3- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
(3R) -3- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester;
(3R*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
Tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
4- [ ({4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
4- [ ({4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
(3R*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
(3S*,4S*) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
(3R*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
(3R*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
(3R*,4R*) -3- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
a salt thereof, or a stereoisomer of the compound or salt thereof.
In another embodiment, the inventive subject matter relates to compounds of formula (I) selected from the group consisting of:
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester;
n- (trans-4-acetamidocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
ethyl { trans-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
n- (cis-4-acetamidocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
ethyl { cis-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
N- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy)1, 3-benzodioxol-4-yl radical]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
N-[(3S*,4S*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3S*,4S*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3S*,4S*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (1-acetyl-piperidin-4-yl) -amide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid [1- (2-methoxy-acetyl) -piperidin-4-yl ] -amide;
4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
ethyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
N- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- (2-ethoxy-5-fluorophenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-ethoxy-5-fluorophenyl) -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-ethoxy-5-fluorophenyl) -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
ethyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
N-[(3S*,4S*) -1-acetyl-4-hydroxypiperidin-3-yl]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -4-hydroxy-1-propionylpiperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ]-N-[(3S*,4S*) -4-hydroxy-1- (methoxyacetyl) piperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl radical]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl radical]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
ethyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
N-[(3R*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- (1-acetylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N- [ trans-4- (acetylamino) cyclohexyl ] -4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
(3R) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid ethyl ester;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl ]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d ]Pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- (1-glycolylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ trans-4- (ethanolamido) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ cis-4- (ethanolamido) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ (3R) -1-ethanoylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- (1-glycolylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ (3R) -1- (hydroxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4R*) -4-hydroxy-1- (hydroxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3S*,4S*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid [1- (2-hydroxy-acetyl) -piperidin-4-yl ] -amide;
4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid [1- ((S) -2-hydroxy-propionyl) -piperidin-4-yl ] -amide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- [ (3R) -1- (hydroxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-ethoxy-5-fluorophenyl) -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-ethoxy-5-fluorophenyl) -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- (1-glycoloylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d ]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- (1-glycoloylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- (1-glycoloylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac) -3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac) -3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -1-glycolyl-4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac) -3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac) -3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl radical]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- (1-glycoloylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (hydroxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1S,2S) -2-hydroxycyclopentyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1S,2R) -2-hydroxycyclopentyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1R,2R) -2-hydroxycyclopentyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-{(3R*,4R*) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl group ]Pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-{(3R*,4R*) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl group]Pyrrolidine-3-6-methyl-5H-pyrrolo [3,2-d ] methyl]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-{(3R*,4R*) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl group]Pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
(3R) -3- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester;
(3R*,4R*) -3- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
(3R) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester;
(3R*,4R*) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester;
(3S*,4S*) -4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- ({1- [4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl ] -formyloxy } -amino) -piperidine-1-carboxylic acid tert-butyl ester;
tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
(3R) -3- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester;
(3R*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl) ]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- ({ [4- (2-ethoxy-5-fluorophenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl ] carbonyl } amino) piperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
(3R) -3- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester;
(3R*,4R*) -3- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
Tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
(3R) -3- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester;
(3R*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl esterAn ester group;
4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
4- [ ({4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
4- [ ({4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
(3R*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
(3S*,4S*) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
(3R*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
(3R*,4R*) -4- [ ({4- [2- (cyclopropyl) amino acid)Methoxymethoxy) -5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
(3R*,4R*) -3- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
N- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (3S,5S) -1-acetyl-5-methylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- [ (3S,5S) -5-methyl-1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -N- [ (3S,5S) -1- (methoxyacetyl) -5-methylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (1S,3S) -3- (acetylamino) cyclopentyl ] -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- [ (1S,3S) -3- (propionylamino) cyclopentyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -N- { (1S,3S) -3- [ (methoxyacetyl) amino ] cyclopentyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(1R*,2R*,4R*) -4- (acetylamino) -2-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-[(1R*,2R*,4R*) -2-fluoro-4- (propionylamino) cyclopentyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1R*,2R*,4R*) -2-fluoro-4- [ (methoxyacetyl) amino]Cyclopentyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamide;
N-[(1S*,2S*,4S*) -4- (acetylamino) -2-methylcyclohexyl radical ]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-N- [ (1S)*,2S*,4S*) -2-methyl-4- (propionylamino) cyclohexyl]-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1S*,2S*,4S*) -4- [ (methoxyacetyl) amino]-2-methylcyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamide;
N-[(1R*,2R*,4R*) -4- (acetylamino) -2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-[(1R*,2R*,4R*) -2-fluoro-4- (propionylamino) cyclohexyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1R*,2R*,4R*) -2-fluoro-4- [ (methoxyacetyl) amino]Cyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamide;
N-[(1S*,3S*,4S*) -4- (acetylamino) -3-methylcyclohexyl radical]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-N- [ (1S)*,3S*,4S*) -3-methyl-4- (propionylamino) cyclohexyl ]-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1S*,3S*,4S*) -4- [ (methoxyacetyl) amino]-3-methylcyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamide;
N-[(1S*,3S*,4S*) -4- (acetylamino) -3-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-methylAn amide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-[(1S*,3S*,4S*) -3-fluoro-4- (propionylamino) cyclohexyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1S*,3S*,4S*) -3-fluoro-4- [ (methoxyacetyl) amino]Cyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamide;
N-[(1R*,3S*,4S*) -3- (acetylamino) -4-methylcyclopentyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-N- [ (1R)*,3S*,4S*) -3-methyl-4- (propionylamino) cyclopentyl]-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1R*,3S*,4S*) -3- [ (methoxyacetyl) amino]-4-methylcyclopentyl } -6-methyl-5H-pyrrolo [3,2-d ]Pyrimidine-7-carboxamide;
N-[(1R*,2R*,4S*) -4- (acetylamino) -2-methylcyclopentyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-N- [ (1R)*,2R*,4S*) -2-methyl-4- (propionylamino) cyclopentyl]-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1R*,2R*,4S*) -4- [ (methoxyacetyl) amino]-2-methylcyclopentyl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
N-[(1S*,3S*,4S*) -3- (acetylamino) -4-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-[(1S*,3S*,4S*) -3-fluoro-4- (propionylamino) cyclopentyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1S*,3S*,4S*) -3-fluoro-4- [ (methoxyacetyl) amino]Cyclopentyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamide;
N-[(1S*,2R*,4S*) -4- (acetylamino) -2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ]-N-[(1S*,2R*,4S*) -2-fluoro-4- (propionylamino) cyclohexyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1S*,2R*,4S*) -2-fluoro-4- [ (methoxyacetyl) amino]Cyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamide;
a salt thereof, or a stereoisomer of the compound or salt thereof.
It is to be understood that the subject matter of the invention includes all combinations of the above mentioned substituent groups. In particular, the subject matter of the invention includes all combinations of the above-described alternative or preferred groups.
The compounds according to the subject of the invention and their stereoisomeric salts include all inorganic and organic acid addition salts and salts with bases, in particular all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases, especially all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases which are customarily used in pharmacy.
Examples of acid addition salts include, but are not limited to: hydrochloride, hydrobromide, phosphate, nitrate, sulphate, acetate, trifluoroacetate, citrate, gluconate (including D-gluconate and L-gluconate), glucuronate (including D-glucuronate and L-glucuronate), benzoate, 2- (4-hydroxybenzoyl) benzoate, butyrate, salicylate, sulphosalicylate, maleate, laurate, malate (including L-malate and D-malate), lactate (including L-lactate and D-lactate), fumarate, succinate, oxalate, tartrate (including L-tartrate, D-tartrate and meso-tartrate), stearate, benzenesulfonate, tosylate, mesylate, lauryl sulfonate, 3-hydroxy-2-naphthoate, lactobionate (salts of 4-O- β -D-galactopyranosyl (galactopyranosyl) -D-gluconic acid), galactarate (galactarates), pamoate (embonate) and ascorbate.
Examples of salts with bases include, but are not limited to: lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine, and guanidinium salts.
Salts include water insoluble salts, especially water soluble salts.
When the compounds, salts thereof, stereoisomers of the compounds and salts thereof according to the inventive subject matter are isolated in crystalline form, they may contain varying amounts of solvent. Accordingly, the compounds of formula (I), their salts, stereoisomers of the compounds and all solvates of their salts are included within the scope of the subject matter of the present invention. Hydrates are preferred examples of such solvates.
Some of the compounds of formula 1, their salts, stereoisomers thereof or salts of the latter may exist in various crystalline forms (polymorphs) which are within the scope of the present invention. The solid obtained of the compound of formula 1, its salt, its stereoisomer or its salt, can be recrystallized in various crystalline forms (polymorphs) with a solvent or a mixture of solvents selected from: water, methanol, ethanol, isopropanol, n-butanol, dichloromethane, methyl tert-butyl ether, acetonitrile, dioxane, methyl ethyl ketone, acetone, glycol ether (glycole), ethylene glycol, methyl isobutyl ketone.
The compounds and salts thereof according to the inventive subject matter include stereoisomers.
Examples of stereoisomers include, but are not limited to: compounds of formula (I) wherein R3 is 3-6C-cycloalkyl substituted by R6. One illustrative stereoisomer of a compound of formula (I) wherein R3 is 3-6C-cycloalkyl substituted with R6 is shown below (cis/trans stereoisomer), with the trans stereoisomer (S1) being preferred.
Furthermore, the inventive subject matter includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Examples of stereoisomers include, but are not limited to: compounds of formula (I) wherein R3 is 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61. An illustrative stereoisomer of a compound of formula (I) (wherein R3 is 3-6C-cycloalkyl substituted with R6 and optionally substituted with R61) includes: pure (S, S) -isomer, (S, R) -isomer, (S, R, S) -isomer and (S, R) -isomer, (R, S) -isomer, (R, S) -isomer and (R, S, R) -isomer and mixtures of two or more thereof in any proportion are preferred, with stereoisomers (S11), (S13), (S15) and (S18) and mixtures of two or more thereof in any proportion being preferred. Examples of such isomers are shown below
In addition, examples of stereoisomers include, but are not limited to: compounds of formula (I) wherein R3 is 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61. An illustrative stereoisomer of a compound of formula (I) (wherein R3 is 3-6C-cycloalkyl substituted with R6 and optionally substituted with R61) includes: pure (S, S) -isomer, (S, R) -isomer, (S, R, S) -isomer and (S, R) -isomer, (R, S) -isomer, (R, S) -isomer and (R, S, R) -isomer and mixtures of two or more thereof in any proportion are preferred, with stereoisomers (S19), (S21), (S23) and (S26) and mixtures of two or more thereof in any proportion being preferred. Examples of such isomers are shown below
Further examples of stereoisomers include, but are not limited to: a compound of formula (I) wherein R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, said heterocyclic ring being optionally substituted with R4, wherein said heterocyclic ring contains a stereocentre. An illustrative stereoisomer of a compound of formula (I) (wherein R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom, said heterocyclic ring being optionally substituted with R4, said heterocyclic ring containing a stereogenic center) is shown below:
Further examples of stereoisomers include, but are not limited to: a compound of formula (I) wherein R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, said heterocyclic ring being optionally substituted with R4 and/or with two substituents R5, wherein said heterocyclic ring contains a stereogenic center. An illustrative stereoisomer of a compound of formula (I) (wherein R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom, said heterocyclic ring being optionally substituted with R4 and/or with two substituents R5, said heterocyclic ring containing a stereogenic center) is shown below:
further examples of stereoisomers include, but are not limited to: a compound of formula (I) wherein R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, said heterocyclic ring being optionally substituted with R4 and/or R5, wherein said heterocyclic ring contains a stereogenic center. The subject of the invention includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any ratio. Examples of such isomers are shown below
Furthermore, the inventive subject matter includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the inventive subject matter includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the inventive subject matter includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Further illustrative are stereoisomers of compounds of formula (I) wherein R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom, said heterocyclic ring being optionally substituted with R4, said heterocyclic ring containing a stereogenic center (stereogenic center) as shown below:
further illustrative are compounds of formula (I) wherein R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom, said heterocyclic ring being optionally substituted with R4 and/or R5, said heterocyclic ring containing a stereoisomer of a stereogenic center. The subject of the invention includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any ratio. Examples of such isomers are shown below
Furthermore, the inventive subject matter includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the inventive subject matter includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the inventive subject matter includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the inventive subject matter includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Further examples of stereoisomers include, but are not limited to: compounds of formula (I) wherein R4 is a group having a stereogenic center, e.g. the group-C (O) -CH (CH)3) -OH. Further examples of stereoisomers include, but are not limited to: compounds of formula (I) wherein R6 is a group having a stereogenic center, e.g. the group-NH-C (O) -CH (CH)3)-OCH3。
Each of the stereogenic centers may have either an absolute configuration R or an absolute configuration S (according to the rules of Cahn, Ingold and Prelog).
The present subject matter relates to mixtures of pure stereoisomers and stereoisomers independent of the ratio, including racemates. Accordingly, the inventive subject matter relates to the pure (cis) -isomer, the pure (trans) -isomer and mixtures thereof, the pure (R) -isomer, the pure (S) -isomer and mixtures thereof, the pure (RS) -isomer, the pure (SS) -isomer, the pure (SR) -isomer, the pure (RR) -isomer and mixtures of two or more thereof in any ratio.
Furthermore, the inventive subject matter includes the pure (trans, R) -isomer, (trans, S) -isomer, (cis, R) -isomer and (cis, S) -isomer and mixtures of two or more thereof in any proportion, with the stereoisomers (S77) and (S78) and mixtures of two or more thereof being preferred. Examples of such isomers are shown below
Furthermore, the inventive subject matter includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the inventive subject matter includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the inventive subject matter includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the inventive subject matter includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the inventive subject matter includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the inventive subject matter includes the pure (R, R) -isomer, (R, S) -isomer, (S, R) -isomer and (S, S) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the subject of the invention includes the pure (S, R, S) -isomer, (R, S) -isomer, (S, R) -isomer, (R, R) -isomer, (S, S) -isomer, (R, S) -isomer and (S, R) -isomer, (R, S, R) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the subject of the invention includes the pure (S, R, S) -isomer, (R, S) -isomer, (S, R) -isomer, (R, R) -isomer, (S, S) -isomer, (R, S) -isomer and (S, R) -isomer, (R, S, R) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the subject of the invention includes the pure (S, R, S) -isomer, (R, S) -isomer, (S, R) -isomer, (R, R) -isomer, (S, S) -isomer, (R, S) -isomer and (S, R) -isomer, (R, S, R) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the subject of the invention includes the pure (S, R, S) -isomer, (R, S) -isomer, (S, R) -isomer, (R, R) -isomer, (S, S) -isomer, (R, S) -isomer and (S, R) -isomer, (R, S, R) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the subject of the invention includes the pure (S, R, S) -isomer, (R, S) -isomer, (S, R) -isomer, (R, R) -isomer, (S, S) -isomer, (R, S) -isomer and (S, R) -isomer, (R, S, R) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the subject of the invention includes the pure (S, R, S) -isomer, (R, S) -isomer, (S, R) -isomer, (R, R) -isomer, (S, S) -isomer, (R, S) -isomer and (S, R) -isomer, (R, S, R) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the subject of the invention includes the pure (S, R, S) -isomer, (R, S) -isomer, (S, R) -isomer, (R, R) -isomer, (S, S) -isomer, (R, S) -isomer and (S, R) -isomer, (R, S, R) -isomer and mixtures of two or more thereof in any proportion. Examples of such isomers are shown below
Furthermore, the subject matter of the invention includes the pure (S, S, S, S) -isomer, (S, S, S, R) -isomer, (R, S, S, S) -isomer and (R, S, S, R) -isomer, (S, R, S, S) -isomer, (S, R, S, R) -isomer, (R, R, S, R) -isomer, (S, S, R, S) -isomer, (S, S, R, R) -isomer, (R, S, R, S) -isomer, (R, S, R, R) -isomer, (S, R, R, S) -isomer and (R, R, S) -isomer, r) -isomers and mixtures of two or more thereof in any proportion, with the stereoisomers (S161), (S162), (S165), (S166), (S171), (S172), (S175) and (S176) and mixtures of two or more thereof in any proportion being preferred. Examples of such isomers are shown below
Furthermore, the subject matter of the invention includes the pure (S, S, S, S) -isomer, (S, S, S, R) -isomer, (R, S, S, S) -isomer and (R, S, S, R) -isomer, (S, R, S, S) -isomer, (S, R, S, R) -isomer, (R, R, S, R) -isomer, (S, S, R, S) -isomer, (S, S, R, R) -isomer, (R, S, R, S) -isomer, (R, S, R, R) -isomer, (S, R, R, S) -isomer and (R, R, S) -isomer, r) -isomers and mixtures of two or more thereof in any proportion, with the stereoisomers (S177), (S178), (S181), (S182), (S187), (S188), (S191) and (S192) and mixtures of two or more thereof in any proportion being preferred. Examples of such isomers are shown below
Furthermore, the subject matter of the invention includes the pure (S, S, S, S) -isomer, (S, S, S, R) -isomer, (R, S, S, S) -isomer and (R, S, S, R) -isomer, (S, R, S, S) -isomer, (S, R, S, R) -isomer, (R, R, S, R) -isomer, (S, S, R, S) -isomer, (S, S, R, R) -isomer, (R, S, R, S) -isomer, (R, S, R, R) -isomer, (S, R, R, S) -isomer and (R, R, S) -isomer, r) -isomers and mixtures of two or more thereof in any proportion, with the stereoisomers (S193), (S194), (S197), (S198), (S203), (S204), (S207) and (S208) and mixtures of two or more thereof in any proportion being preferred. Examples of such isomers are shown below
Furthermore, the subject of the invention includes compounds according to the subject of the invention, salts thereof, stereoisomers of the compounds and derivatives of the salts thereof, which can be converted in a biological system into compounds according to the subject of the invention, salts thereof, stereoisomers of the compounds or salts thereof (bioprecursors or prodrugs). The biological system is, for example, a mammalian organism, especially a human patient. For example, by metabolic processes, the biological precursors are converted into the compounds according to the subject invention, salts thereof, stereoisomers of the compounds or salts thereof.
The compounds according to the invention can be prepared as follows.
Scheme 1.
Compounds of formula (6), wherein R2 is hydrogen, can be obtained according to the procedure described in US 2005/0124623a1, as shown in scheme 1.
Scheme 2.
As shown in reaction scheme 2, synthesis of a compound of formula (25) wherein R2 is methyl can be performed from a compound of formula (17) [ Gangjee, A.; li, W.; yang, j.; kisliuk, r.l.; J. med, chem, 2008, 51, 68]Initially, with a nitrile of formula (18) in the presence of an acid, preferably hydrochloric acid, under anhydrous conditions, and according to, for example, Venugopalan, b.; desai, p.d.; souza, n.j.; J. heterocyclic chem. 1988, 25, 1633, cyclizing the obtained compound of formula (19) or salt thereof to a compound of formula (20) (wherein R2 is methyl). Subsequently, the compound of formula (20) is reacted with pure POCl at reflux temperature 3Or POCl3Is reacted with e.g. bromine or N-bromosuccinimide in an organic solvent such as Dichloromethane (DCM) at a temperature of-40 to 20 ℃ for a period of 0.5 to 4 hours to give a compound of formula (22). Then, as per, for example, mucchowski, j.m.; solas, d.. r.; J. chem. 1984, 49, 203 by reaction with a base such as sodium hydride and (2-chloromethoxy-ethyl-trimethyl-silane in an organic solvent such as dimethoxyethane, dimethylformamide or dimethylsulfoxide at a temperature of from 0 ℃ to 25 ℃ for a period of from 1 hour to 24 hoursThe resulting compound of formula (22) is protected to give a compound of formula (23).
In an additional step, the compound of formula (23) (in an organic solvent such as tetrahydrofuran) may be reacted with n-BuLi (n-butyllithium) (in an organic solvent such as hexane) at a temperature of-78 ℃ for 0.5 to 3 hours. Subsequently, Dimethylformamide (DMF) is added and the reaction is carried out at a temperature of-78 to 0 ℃ for 0.5 to 3 hours according to, for example, the method described in WO2008/30119 to give a compound of formula (24).
Finally, according to, for example, Corey, e.j.; gilman, n.w.; ganem, b.e.; J. am. chem, Soc, 1968, 90, 5616 in the presence of potassium cyanide at room temperature with MnO 2Treating a methanol solution of the compound of formula (24) for 4 hours to 24 hours to obtain the compound of formula (25).
Scheme 3.
As shown in scheme 3, the synthesis of boronic acid derivatives of formula (9) can start from phenols of formula (7), wherein R21, R22, R23 and R24 have the above-mentioned meanings. The phenol of formula (7) is commercially available or can be prepared using methods known to those skilled in the art. In the first step, R1 having the above definition may be introduced by alkylation. For example, alkylation can be carried out as follows: sodium hydride is suspended in an organic solvent such as Dimethylethane (DME) or Dimethylsulfoxide (DMSO) or a mixture thereof at a temperature ranging from 0 to 40 ℃, a solution of the compound (7) in the organic solvent such as DME is added, then the compound R1-halogen, preferably R1-Br or R1-I is added, and the mixture is reacted at a temperature ranging from 20 to 80 ℃ for 1 to 48 hours to obtain the compound of formula (8). In a second step, direct ortho-metallation is carried out, followed by reaction with a boron electrophile to give compounds of formula (9) wherein R1, R21, R22, R23 and R24 have the meaning indicated above, Ra and Rb represent 1-4C-alkyl or hydrogen, preferably, Ra and Rb are combined to form a compound of formulaStraight or branched chain alkylene groups having 2 to 8 carbon atoms such as, but not limited to: -C (CH) 3)2-C(CH3)2-. In particular, a solution of the compound (8) in an organic solvent such as Tetrahydrofuran (THF) may be reacted with n-butyllithium (n-BuLi) in an organic solvent such as hexane at a temperature of-78 to 0 ℃ for 0.5 to 4 hours. Subsequently, for example, commercially available 2-isopropoxy 4,4,5, 5-tetramethyl- [1,3,2 ] is added]Dioxaborolane and the reaction is carried out at a temperature of-78 to 0 ℃ for 0.5 to 3 hours to give the compound of formula (9).
Scheme 4.
Another preparation of the compound of formula (9) is shown in scheme 4. The preparation process can start from phenols of formula (7), wherein R21, R22, R23 and R24 have the meanings defined above or below, which are commercially available or can be prepared by methods known to the person skilled in the art or by methods described, for example, in Yamamoto, Y.; Hattori, K.; Ishii, J. -I.; Nishiyama, H. Tetrahedron, 2006, 62, 4294. For example, the phenol of formula (7) is reacted with bromine or N-bromosuccinimide in an organic solvent such as Dichloromethane (DCM) at a temperature of-40 to 20 ℃ for 0.5 to 4 hours to give the compound of formula (10). In the second step, R1 having the above definition may be introduced by alkylation. For example, alkylation can be carried out as follows: sodium hydride is suspended in an organic solvent such as Dimethylethane (DME) or Dimethylsulfoxide (DMSO) or a mixture thereof, a solution of compound (10) in an organic solvent such as DME is added at a temperature ranging from 0 to 40 ℃, then compound R1-halogen, preferably R1-Br or R1-I is added, and the mixture is reacted at a temperature ranging from 20 to 80 ℃ for 1 to 48 hours to give a compound of formula (11). In the case where R22 is difluoromethyl, in an additional step, the compound of formula 11 (which is a compound of formula 11) is heated at elevated temperature (preferably under microwave heating) in an organic solvent such as dichloromethane Wherein R21, R23, R24 and R1 have the meaning defined above and R22 is CH = O, is reacted with a fluorinating agent, such as tris (2-methoxyethyl) aminosulfur trifluoride. In a next step, a halogen-lithium exchange is carried out, followed by reaction with a boron electrophile to give a compound of formula (9) wherein R1, R21, R22, R23 and R24 have the above-mentioned meanings, Ra and Rb represent 1-4C-alkyl or hydrogen, preferably Ra and Rb combine to form a linear or branched alkylene group having 2 to 8 carbon atoms, such as, but not limited to: -C (CH)3)2-C(CH3)2-. In particular, the compound (11) (a solution in an organic solvent such as methyl t-butyl ether) may be reacted with n-BuLi (n-butyllithium) (in an organic solvent such as hexane) at a temperature of-78 to 0 ℃ for 0.5 to 3 hours. Subsequently, for example, commercially available 2-isopropoxy-4, 4,5, 5-tetramethyl- [1,3,2 ] is added]Dioxaborolane and the reaction is carried out at a temperature of-78 to 0 ℃ for 0.5 to 3 hours to give the compound of formula (9). Compounds of the formula (9) in which R22 is 1-4C-alkyl-1, 3-dioxolane, R1, R21, R23, R24, Ra and Rb have the meanings defined above, can also be prepared starting from phenols of the formula (7) in which R22 is-C (O) -1-4C-alkyl and R1, R21, R23 and R24 have the meanings defined above, by acetalization of compounds (11) in which R22 is-C (O) -1-4C-alkyl and R1, R21, R23 and R24 have the meanings defined above, followed by halogen-lithium replacement reactions as described above. Acetalization can be performed using methods known to those skilled in the art, for example, as described, for example, in Hwu, j.r.; wetzel, j.m.; the method of j, org, chem, 1985, 50, 3946, reacting compound (11) with 1, 2-bis (trimethylsilyloxy) -ethane in an organic solvent such as dichloromethane in the presence of a catalytic amount of trimethylsilyl triflate at a temperature of 0 ℃ to 25 ℃ for 1 to 4 hours.
Scheme 5.
As further shown in scheme 5According to another preparation method, the synthesis of boronic acid derivatives of formula (9) can start from phenols of formula (7) in which R21, R22, R23 and R24 have the meanings defined above, which are commercially available or can be prepared using methods known to those skilled in the art. In the first step, R1 having the meaning defined above can be introduced by alkylation. For example, alkylation can be carried out as follows: sodium hydride is suspended in an organic solvent such as Dimethylethane (DME) or Dimethylsulfoxide (DMSO) or a mixture thereof, and compound (7) (a solution in an organic solvent such as DME) is added at a temperature ranging from 0 to 40 ℃, then compound R1-halogen, preferably R1-Br or R1-I is added, and the mixture is reacted at a temperature ranging from 20 to 80 ℃ for 1 to 48 hours to give a compound of formula (12). In the second step, compound (11) can be prepared as follows: for example, starting from compound (12), with N-bromosuccinimide in an organic solvent (e.g., dimethylformamide) at a temperature of 0 to 60 ℃ for 0.5 to 5 hours. In a third step, a halogen-lithium exchange is carried out followed by reaction with a boron electrophile to give a compound of formula (9) wherein R1, R21, R22, R23 and R24 have the meanings defined above, Ra and Rb represent 1-4C-alkyl or hydrogen, preferably Ra and Rb combine to form a linear or branched alkylene group having 2 to 8 carbon atoms, such as, but not limited to: -C (CH) 3)2-C(CH3)2-. In particular, the compound (11) (a solution in an organic solvent such as methyl t-butyl ether) may be reacted with n-BuLi (n-butyllithium) (in an organic solvent such as hexane) at a temperature of-78 to 0 ℃ for 0.5 to 3 hours. Subsequently, for example, commercially available 2-isopropoxy-4, 4,5, 5-tetramethyl- [1,3,2 ] is added]Dioxaborolane and the reaction is carried out at a temperature of-78 to 0 ℃ for 0.5 to 3 hours to give the compound of formula (9). Alternatively, compounds of formula (9) may be synthesized from compounds of formula (11) and a suitable boron compound (e.g., di (valeryl) diboron): the reaction is carried out in the presence of a Pd catalyst (e.g. 1,1' -bis (diphenyl-phosphino) ferrocene palladium- (II) chloride) and a base (e.g. potassium acetate) in an organic solvent (e.g. dioxane) at a temperature of 20 to 100 ℃ for 1 to 24 hours. This Pd-catalyzed preparation of boronic acid derivatives is described, for example, in (Murata et al) J Org Chem 2000, 65164 and J Org Chem 1997, 62, 6458.
Scheme 6.
Scheme 6 illustrates the synthesis of compounds of formula (15) wherein R2 is hydrogen and R1, R21, R22, R23 and R24 have the meanings defined above. In a first step, compound (6) prepared according to scheme 1 may be reacted with a compound of formula (9) prepared according to any one of schemes 3, 4 or 5, wherein R1, R21, R22, R23, R24, Ra and Rb have the meaning defined above, to obtain a compound of formula (13). In particular, it is preferred that the compound of formula (6), a base (e.g., K) is reacted at a temperature in the range of 60 to 120 ℃ 2CO3、Cs2CO3Or K3PO4) A solvent (e.g. dimethoxyethane, dioxane or dimethylformamide), a compound of formula (9) and a Pd catalyst (e.g. PdCl)2(PCy3)2(Cy = cyclohexyl)) was heated for 1 to 16 hours. The compound of formula (13) thus obtained is then protected by reaction with a base such as sodium hydride and (2-chloromethoxy-ethyl) -trimethyl-silane in an organic solvent (e.g. dimethoxyethane, dimethylformamide or dimethylsulfoxide) at a temperature of 0 to 25 ℃ for 1 to 24 hours, e.g. according to muchwski j.m.; solas, d.r.; J. org, chem. 1984, 49, 203, to give a compound of formula (14). The compound of formula (14) is reacted with an alkali metal hydroxide (e.g. LiOH) in a solvent (preferably a mixture of organic solvents, e.g. dioxane and water) at a temperature in the range of 20 to 100 ℃ for 1 to 48 hours to give the compound of formula (15).
Scheme 7.
Scheme 7 illustrates the synthesis of compounds of formula (15) wherein R2 is methyl and R1, R2, R21, R22, R23 and R24 have the meanings defined above. In a first step, compound (25) prepared according to scheme 2 may be reacted with a compound of formula (9) prepared according to any one of schemes 3, 4 or 5, wherein R1, R21, R22, R23, R24, Ra and Rb have the meaning defined above, to obtain a compound of formula (26). In particular, it is preferred that the compound of formula (25), a base (e.g., K) is reacted at a temperature in the range of 60 to 120 ℃ 2CO3、Cs2CO3Or K3PO4) A solvent (e.g. dimethoxyethane, dioxane or dimethylformamide), a compound of formula (9) and a Pd catalyst (e.g. PdCl)2(PCy3)2(Cy = cyclohexyl)) was heated for 1 to 16 hours. The compound of formula (26) thus obtained is reacted with an alkali metal hydroxide (e.g. LiOH) in a solvent (preferably a mixture of organic solvents, e.g. dioxane and water) at a temperature in the range of 20 to 100 ℃ for 1 to 48 hours to give the compound of formula (15).
Scheme 8.
As shown in scheme 8, compounds of formula (I-1), wherein R1, R2, R21, R22, R23, R24 and Y have the meanings as defined above, R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, said heterocyclic ring being substituted with R4 and optionally substituted with one or two substituents R5, wherein R5 has the meaning as defined above, R4 is-C (O) -1-4C-alkyl (wherein the 1-4C-alkyl is optionally substituted with R41), -C (O) -3-6C-cycloalkyl (wherein the 3-6C-cycloalkyl is optionally substituted with R42) or-C (O) -O-1-4C-alkyl (wherein the 1-4C-alkyl is optionally substituted with R43), R41, R3978 and Y, R42 and R43 have the meanings defined above, can be prepared by reaction with a compound of the formula (16-1), wherein Y has the meanings defined above, R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which is substituted with R4 and optionally with one or two substituents R5, wherein R5 has the meanings defined above, R4 is-C (O) -1-4C-alkyl (wherein the 1-4C-alkyl is optionally substituted with R41), -C (O) -3-6C-cycloalkyl (wherein the 3-6C-cycloalkyl is optionally substituted with R42) or-C (O) -O-1-4C-alkyl (wherein the 1-4C-alkyl is optionally substituted with R41), under standard amide bond forming conditions, starting from a compound of the formula (15) prepared according to either of schemes 6 or 7 Optionally substituted by R43), R41, R42 and R43 have the meanings defined above. Compounds of formula (16-1) are commercially available or can be prepared using methods known to those skilled in the art or as described in scheme 16. In particular, a dehydrating agent (e.g., 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), a base (e.g., triethylamine) and a catalyst (e.g., 1-hydroxybenzotriazole) may be added to the compound of formula (15) (preferably, dissolved or suspended in an organic solvent, e.g., dichloromethane). For example, after stirring the mixture for 0.3 to 2 hours (preferably at room temperature, e.g., 20 to 25 ℃), the compound of formula (16-1) may be added, and preferably, the reaction is carried out at room temperature (e.g., 20 to 25 ℃) for 1 to 48 hours to give the compound of formula (I-1).
Scheme 9.
As shown in scheme 9, compounds of formula (I-2), wherein R1, R2, R21, R22, R23, R24 and Y have the meanings defined above, R3 is 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61, R6 is-NH-C (O) -R7, R7 is 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73, R61, R71, R72 and R73 have the meanings defined above, can be synthesized as follows: a compound of formula (15) prepared according to any one of schemes 6 or 7 is reacted with a compound of formula (16-2) wherein Y has the meaning defined above, R3 is 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61, R6 is-NH-C (O) -R7, R7 is 1-4C-alkyl optionally substituted by R71, 3-6C-cycloalkyl optionally substituted by R72, or 1-4C-alkoxy optionally substituted by R73, R61, R71, R72 and R73 have the meanings defined above. The compound of formula (16-2) is commercially available or can be prepared using methods known to those skilled in the art, or can be prepared using the methods described in the experimental section (see C11, CC22, C33, and C44). In particular, a dehydrating agent (e.g., 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), a base (e.g., triethylamine) and a catalyst (e.g., 1-hydroxybenzotriazole) may be added to the compound of formula (15) (preferably, dissolved or suspended in an organic solvent such as dichloromethane). After stirring the mixture, for example, for 0.3 to 2 hours (preferably at room temperature, e.g., 20 to 25 ℃), the compound of formula (16-2) may be added, and preferably, the reaction is carried out at room temperature (e.g., 20 to 25 ℃) for 1 to 48 hours to give the compound of formula (I-2).
Scheme 10.
Compounds of formula (I-1) prepared according to scheme 8, wherein R1, R2, R21, R22, R23, R24 and Y have the meanings defined above, R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is substituted with R4 and optionally with one or two substituents R5, wherein R5 has the meanings defined above, R4 is-C (O) -O-C (CH 5)3)3Which may be deprotected and converted to a compound of formula (I-4) wherein R1, R2, R21, R22, R23, R24 and Y have the meanings defined above and R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is optionally substituted with one or two substituents R5, wherein R5 has the meanings defined above. In particular, compounds of formula (I-1) are deprotected using methods known to those skilled in the art, for example, by reaction with tetrabutylammonium fluoride and 1, 2-diamino-ethane in an organic solvent (e.g., tetrahydrofuran), for example, as described in muchwoski, j.m.; solas, d.r.; J. org: chem. 1984, 49, 203.
In the following step, HCl (preferably dissolved in an organic solvent such as dioxane) may be added to the compound of formula (I-3) (preferably dissolved in an organic solvent such as an alcohol, e.g. 2-propanol). Then, the reaction mixture is preferably heated at 40 to 80 ℃ for 1 to 4 hours to obtain the hydrochloride of the compound of formula (I-4). The compound of formula (I-4) can be prepared from the hydrochloride salt according to methods known to those skilled in the art, for example, treatment with a base such as aqueous potassium carbonate or aqueous ammonia.
Scheme 11.
As shown in scheme 11, compounds of formula (I-2) prepared according to scheme 9, wherein R1, R2, R21, R22, R23, R24 and Y have the meaning defined above, R3 is 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61, wherein R6 is-NH-C (O) -R7, R7 is-O-C (CH) C3)3R61 has the meaning defined above, can be deprotected and converted into compounds of the formula (I-6) in which R1, R2, R21, R22, R23, R24 and Y have the meanings defined above, R3 is 3-6C-cycloalkyl substituted by R6 and optionally by R61, in which R6 is-NH-2R61 has the meaning defined above. In particular, compounds of formula (I-2) are deprotected using methods known to those skilled in the art, for example, by reaction with tetrabutylammonium fluoride and 1, 2-diamino-ethane in an organic solvent (e.g., tetrahydrofuran), for example, as described in muchwoski, j.m.; solas, d.r.; J. org: chem. 1984, 49, 203.
In the following step, HCl (preferably dissolved in an organic solvent such as dioxane) may be added to the compound of formula (I-5) (preferably dissolved in an organic solvent such as an alcohol, e.g. 2-propanol). The reaction mixture is then preferably heated at 40 to 80 ℃ for 1 to 4 hours to give the hydrochloride salt of the compound of formula (I-6). The compound of formula (I-6) can be prepared from the hydrochloride salt according to methods known to those skilled in the art, for example, by treatment with a base such as aqueous potassium carbonate or aqueous ammonia.
As shown in scheme 11, compounds of formula (I-2) wherein R1, R2, R21, R22, R23, R24 and Y have the meanings defined above, R3 is 3-6C-cycloalkyl substituted by R6 and optionally by R61, wherein R6 is hydroxy and R61 has the meanings defined above, can be deprotected and converted into compounds of formula (I-5) wherein R1, R2, R21, R22, R23, R24 and Y have the meanings defined above, R3 is 3-6C-cycloalkyl substituted by R6 and optionally by R61, wherein R6 is hydroxy and R61 has the meanings defined above, are prepared according to scheme 9. In particular, compounds of formula (I-2) are deprotected using methods known to those skilled in the art, for example, by reaction with tetrabutylammonium fluoride and 1, 2-diamino-ethane in an organic solvent (e.g., tetrahydrofuran), for example, as described in muchwoski, j.m.; solas, d.r.; J. org: chem. 1984, 49, 203.
Scheme 11 a:
compounds of the formula (I-3) (in which R1, R2, R21, R22, R23, R24 and Y have the meanings defined above and R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which heterocyclic ring is substituted by R4 and optionally by one or two substituents R5, in which R5 has the meanings defined above and R4 is-C (O) -O-C (CH 4) 3)3) And compounds of formula (1-5) (wherein R1, R2, R21, R22, R23, R24 and Y have the meanings defined above, R3 is 3-6C-cycloalkyl substituted by R6 and optionally by R61, wherein R6 is-NH-C (O) -R7, R7 is-O-C (CH 2)3)3R61 has the meaning defined above) and compounds of the formula (1-6) (in which R1, R2, R21, R22, R23, R24 and Y have the meaning defined above, R3 is 3-6C-cycloalkyl which is substituted by R6 and optionally by R61, in which R6 is-NH-2R61 has the formulaThe meanings defined above) is shown in scheme 11 a.
The compounds of formula (13) prepared according to scheme 6, wherein R1, R2, R21, R22, R23 and R24 have the meaning defined above, are changed into compounds of formula (13a) by reaction with an alkali metal hydroxide, preferably KOH (formed from potassium tert-butoxide and water), in an organic solvent, preferably tert-BuOH. Similar reactions are described, for example, in Gassman, p.g.; schenk, w.n.j. org. chem. 1977, 42, 918.
Compounds of formula (13a) may be reacted with compounds of formula (16-1), which are commercially available or may be prepared using methods known to those skilled in the art or as described in scheme 16, compounds of formula (16-2), which are commercially available or may be prepared using methods known to those skilled in the art or may be prepared using methods described in the experimental section (see C11, CC22, C33 and C44), or compounds of formula (16-3), which are commercially available or may be prepared using methods known to those skilled in the art or may be prepared using methods described in the experimental section (see C12, C23, C34 and C45).
In particular, a dehydrating agent (e.g., 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), a base (e.g., triethylamine) and a catalyst (e.g., 1-hydroxybenzotriazole) may be added to the compound of formula (13) (preferably, dissolved or suspended in an organic solvent, e.g., dichloromethane). After stirring the mixture for, for example, 0.3 to 2 hours (preferably at room temperature (e.g., 20 to 25 ℃)), the compound of formula (16-1), the compound of formula (16-2) or the compound of formula (16-3) may be added, and the reaction is preferably carried out at room temperature (e.g., 20 to 25 ℃) for 1 to 48 hours to give the corresponding compound of formula (I-3), the compound of formula (I-5) or the compound of formula (13 b). The compound of the formula (I-6) can be obtained as follows: in the presence of a catalyst (e.g., Pd/carbon or Pd (OH)2Carbon) in an organic solvent such as methanol, preferably at room temperature, for example from 20 to 25 ℃, and subjecting the compound of formula (13b) to pressure hydrogenation (for example from 10 to 30 bar).
Scheme 12.
Alternatively, as shown in scheme 12, compounds of formula (I-1), wherein R1, R2, R21, R22, R23, R24 and Y have the meanings as defined above, R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, said heterocyclic ring being substituted with R4 and optionally substituted with one or two substituents R5, wherein R5 has the meaning as defined above, R4 is-C (O) -1-4C-alkyl (wherein the 1-4C-alkyl is optionally substituted with R41), -C (O) -3-6C-cycloalkyl (wherein the 3-6C-cycloalkyl is optionally substituted with R42) or-C (O) -O-1-4C-alkyl (wherein the 1-4C-alkyl is optionally substituted with R43), r41, R42 and R43 are as described above and can be prepared from compounds of formula (I-4) prepared according to scheme 10, wherein R1, R21, R22, R23, R24 and Y have the meanings defined above, R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, said heterocyclic ring being optionally substituted with one or two substituents R5, wherein R5 has the meanings defined above. In particular, compound R4-Cl may be added to a compound of formula (I-4), preferably dissolved in an organic solvent, such as dichloromethane, in the presence of a base, such as Diazabicycloundecene (DBU). Compounds of the formula R4-Cl are commercially available or can be prepared using methods known to those skilled in the art. The addition is preferably carried out at a temperature of from 0 to 20 ℃. After the addition is complete, the reaction is preferably continued at room temperature (e.g., 20 to 25 ℃) for 1 to 24 hours. In the case where R41, R42 or R43 represents a hydroxyl group, known to those skilled in the art are: the hydroxyl group is preferably protected with a suitable protecting group, such as an acetate group or a silyl protecting group, such as tert-butyl-dimethylsilyl or tert-butyl-diphenylsilyl. The protecting group may be removed using methods known to those skilled in the art, with or without prior isolation of the protected intermediate (i.e., the protected form of the compound of formula (I-1)).
Scheme 13.
Alternatively, as shown in scheme 13, compounds of formula (I-2) (wherein R1, R2, R21, R22, R23, R24 and Y have the meanings defined above, R3 is 3-6C-cycloalkyl substituted with R6 and optionally substituted with R61, wherein R6 is-NH-C (O) -R7, R7 is 1-4C-alkyl optionally substituted with R71, 3-6C-cycloalkyl optionally substituted with R72 or 1-4C-alkoxy optionally substituted with R73, R61 and R61 are as described above) can be prepared from compounds of formula (I-6) (wherein R61, R61 and Y have the meanings defined above, R61 is 3-6C-cycloalkyl substituted with R61 and optionally substituted with R61, R61 is NH-C-cycloalkyl optionally substituted with R61, R61 is NH-C-62R61 has the meaning defined above). In particular, compound R7-C (O) -Cl may be added to a compound of formula (I-6), preferably dissolved in an organic solvent, such as dichloromethane, in the presence of a base, such as Diazabicycloundecene (DBU). Compounds of the formula R7-C (O) -Cl are commercially available or can be prepared using methods known to those skilled in the art. The addition is preferably carried out at a temperature of from 0 to 20 ℃. After the addition is complete, the reaction is preferably continued at room temperature (e.g., 20 to 25 ℃) for 1 to 24 hours to give the compound of formula (I-2). In the case where R71, R72 or R73 represents a hydroxyl group, known to those skilled in the art are: the hydroxyl group is preferably protected with a suitable protecting group, such as an acetate group or a silyl protecting group, such as tert-butyl-dimethylsilyl or tert-butyl-diphenylsilyl. The protecting group may be removed using methods known to those skilled in the art, with or without prior isolation of the protected intermediate (i.e., the protected form of the compound of formula (I-2)).
Scheme 14.
Such as the reverseAs shown in scheme 14, compounds of formula (I-1), wherein R1, R2, R21, R22, R23, R24 and Y have the meanings as defined above and R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which is substituted with R4 and optionally substituted with one or two substituents R5, wherein R5 has the meanings as defined above and R4 is-C (O) -H, can be prepared from compounds of formula (I-4) prepared according to scheme 10, wherein R1, R2, R21, R22, R23, R24 and Y have the meanings as defined above and R3 is a 4-to 7-membered saturated heterocyclic ring containing one nitrogen atom and optionally one oxygen atom, which is optionally substituted with one or two substituents R5, wherein R5 has the meanings as defined above. In particular, compound R4-O-C (O) -CH may be reacted in the presence of a base, such as Diazabicycloundecene (DBU)3(which may be prepared by methods known to those skilled in the art) is added to the compound of formula (I-4), preferably dissolved in an organic solvent, for example dichloromethane. The addition is preferably carried out at a temperature of from 0 to 20 ℃. After the addition is complete, the reaction is preferably continued at room temperature (e.g., 20 to 25 ℃) for 1 to 24 hours to give the compound of formula (I-1).
Scheme 15.
As shown in scheme 15, compounds of formula (I-2), wherein R1, R2, R21, R22, R23, R24 and Y have the meanings defined above, R3 is 3-6C-cycloalkyl substituted by R6 and optionally by R61, R6 is-NH-C (O) -R7, R7 is hydrogen, R61 has the meanings defined above, can be prepared from compounds of formula (I-6) obtained according to scheme 11, wherein R1, R2, R21, R22, R23, R24 and Y have the meanings defined above, R3 is 3-6C-cycloalkyl substituted by R6 and optionally by R61, R6 is-NH2. In particular, compound R7-C (O) -O-C (O) -CH can be reacted in the presence of a base, such as Diazabicycloundecene (DBU)3(R7 is hydrogen) (which can be prepared by methods known to those skilled in the art) is added to the reaction of formula (I-6)The compound is preferably dissolved in an organic solvent, such as dichloromethane. The addition is preferably carried out at a temperature of from 0 to 20 ℃. After the addition is complete, the reaction is preferably continued at room temperature (e.g., 20 to 25 ℃) for 1 to 24 hours to give the compound of formula (I-2).
Scheme 16.
As shown in scheme 16, compounds of formula (16a) or (16b) can be prepared from known compounds (18a) or (18b) [ Zhao, s.; ghosh, a.; d' Andrea, s.v.; freeman, P.; von voigtlander, p.f.; carter, d.b.; smith, m.w.; heterocyles, 1994, 39, 163 and Erickson, s.d.; banner, b.; berthel, s.; Conde-Knape, K.; faliconii, F.; hakimi, i.; hennessy, b.; kester, r.f.; kim, k.; ma, Ch.; McComas, w.; mennon, f.; mischke, s.; orzechowski, l.; qian, y.; salari, h.; tengi, j.; thakkar, k.; taub, r.; tilley, j.w.; wang, h.; bioorg. med. chem. lett. 2008, 18, 1402] prepared, for example, by catalytic hydrogenation in an organic solvent such as ethanol or methanol in the presence of a noble metal catalyst (e.g. palladium on carbon or platinum oxide) at a temperature of from 20 to 50 ℃ under standard atmospheric pressure (101,325 kPa) to 1050 kPa for from 1 hour to 48 hours.
Known to the person skilled in the art are: if there are many reaction centers present on the starting or intermediate compounds, it may be necessary to temporarily block one or more reaction centers with protecting groups in order to allow the reaction to proceed specifically at the desired reaction center.
The compounds according to the subject matter of the invention are isolated and purified in a manner known per se, for example by distilling off the solvent in vacuo, recrystallizing the residue obtained from a suitable solvent and subjecting it to a customary purification process, for example column chromatography (on a suitable support material).
The compounds of formula (I) and the salts of stereoisomers thereof may be obtained as follows: the free compound is dissolved in a suitable solvent (e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as dichloromethane or chloroform, a low molecular weight aliphatic alcohol, such as methanol, ethanol or isopropanol, a low molecular weight aliphatic ester, such as ethyl acetate or isopropyl acetate, or water) containing or to which the desired acid or base is subsequently added. The acid or base can be used for the preparation of the salt in equimolar quantitative ratios or ratios different from them, depending on whether a mono-or polybasic acid or base is involved and on which salt is desired. The salt is obtained by filtration, reprecipitation with a solvent incapable of dissolving the salt, precipitation, or evaporation of the solvent. The obtained salt can be converted into a free compound, and the free compound can also be converted into a salt. In this manner, pharmaceutically unacceptable salts (which may be obtained, for example, as process products in industrial scale manufacture) may be converted into pharmaceutically acceptable salts using methods known to those skilled in the art.
Pure diastereomers and pure enantiomers of the compounds of formula (I) and salts thereof may be obtained as follows: for example by asymmetric synthesis, using chiral starting compounds in the synthesis, and/or separating mixtures of enantiomers and diastereomers obtained in the synthesis. Preferably, the pure diastereomeric and pure enantiomeric compounds, which are the subject of the invention, can be obtained as follows: chiral starting compounds are used in the synthesis and/or the enantiomeric and diastereomeric mixtures obtained in the synthesis are separated.
Enantiomeric and diastereomeric mixtures can be separated into the pure enantiomers and pure diastereomers using methods known to those skilled in the art. Preferably, the separation of the mixture of diastereomers is carried out by crystallization (especially fractional crystallization) or chromatography. For example, mixtures of enantiomers can be separated by forming diastereomers with a chiral auxiliary, resolving the obtained diastereomers and removing the chiral auxiliary. As chiral auxiliary, for example, a chiral acid can be used to separate the enantiomeric bases and a chiral base can be used to separate the enantiomeric acids by forming diastereomeric salts. Furthermore, using a chiral acid or a chiral alcohol, respectively, as chiral auxiliary, diastereomeric derivatives (e.g. diastereomeric esters) may be formed from a mixture of enantiomers of the alcohol or of the acid, respectively. In addition, diastereomeric complexes or diastereomeric complexes may be used to separate mixtures of enantiomers. Alternatively, chiral separation columns in chromatography may be used to separate mixtures of enantiomers. Another suitable method for separating enantiomers is an enzymatic separation method.
All patents, patent applications, publications, test methods, and other materials cited herein are hereby incorporated by reference in their entirety.
The following examples illustrate the subject matter of the invention in more detail, without limiting it. Other compounds according to the inventive subject matter may be prepared in a similar manner (methods for their preparation are not explicitly described).
The compounds, salts and stereoisomers mentioned in the examples and the salts of the compounds mentioned in the examples and the stereoisomers of the compounds mentioned in the examples, the stereoisomers of the salts mentioned in the examples and the stereoisomers of the salts of the compounds mentioned in the examples represent preferred embodiments of the subject matter of the present invention.
Examples
The abbreviations min: min, h: h, DCM: dichloromethane, DCE: dichloroethane, THF: tetrahydrofuran, EA: ethyl acetate, sesamol (sesamol) to 3, 4-methylenedioxyphenol, brine: saturated sodium chloride solution, DBU: 1, 8-diazabicyclo [5.4.0]Undec-7-ene, Huenigs base: N-ethyl-diisopropylamine, mp.: melting point, bp: boiling point, RT: room temperature (20 to 25 ℃), ambient temperature: 20 to 25 ℃, TLC: thin layer chromatography, GC-MS (EI) gas chromatography coupled to mass spectrometry (electron impact ionization), MS (ESI) electrospray ionization Mass spectrometry, HR-MM (ESI) to electrospray ionization high resolution mass spectrometry,1H-NMR∶1h NMR spectra (chemical shifts are reported in ppm, tetramethylsilane as internal standard, coupling constant J is reported in Hz). Epimers and/or racemates are designated herein with an "at the center of the corresponding stereo structure (stereogenic center) of the chemical name.
Example A1 (E/Z) -2-cyano-3-ethoxy-but-2-enoic acid ethyl ester
A round bottom flask equipped with a magnetic stir bar, a short Vigreux column and a cooler was charged with commercially available triethyl orthoacetate (973.4 g; 6.0 mol), commercially available ethyl cyanoacetate (452.5 g; 4.0 mol) and commercially available acetic anhydride (816.7 g; 8.0 mol). The stirred reaction mixture was heated to about 100 ℃ and the ethyl acetate formed was distilled off. As the reaction proceeded, the temperature was gradually increased to 150 ℃.
The reaction mixture was cooled to room temperature. The semi-solid crude product was distilled under high vacuum. Collecting at 110 deg.C and 120 deg.C (4X 10)-3mbar) and redistilled to give the title compound as a pale yellow solid.
GC-MS(EI): m/z=183(M+); 127(100 %)。
1H-NMR(300 MHz, DMSO-d6): 4.35(qu, J=7.0, 2H); 4.15(qu, J=7.1, 2H); 2.63(s, 3H); 1.29(t, J=7.0, 3H); 1.22(t, J=7.1, 3H)。
Example A2: 3-amino-5-methyl-1H-pyrrole-2, 4-dicarboxylic acid diethyl ester
A reaction flask equipped with mechanical stirrer, dropping funnel, reflux condenser and nitrogen bubbler was charged with anhydrous EtOH (700 ml), the (E/Z) -2-cyano-3-ethoxy-but-2-enoic acid ethyl ester of example 1 (128.25 g; 0.70 mol) and commercial 2-amino-malonic acid diethyl ester hydrochloride (148.15 g; 0.70 mol). NaOEt (. about.21% solution in EtOH; 1150 mL;. about.2.45 mol) was added to the well stirred reaction mixture over 15 minutes (slightly exothermic). After the addition was complete, the reaction mixture was heated to gentle reflux under nitrogen atmosphere and mechanically stirred for 18 hours.
The reaction mixture was cooled to room temperature and neutralized to pH =7 by slow addition of a sufficient amount of 1M citric acid. EtOH was removed under reduced pressure at 50 deg.C (rotary evaporator). The remaining solid was partitioned between water (1500 mL) and dichloromethane (500 mL). The organic layer was separated. The aqueous layer was extracted with dichloromethane (2 × 500 ml). In the presence of decolorizing charcoal, with MgSO4The combined organic layers were dried. The solution was filtered through a plug of neutral alumina (act 2-3) followed by a plug of silica. The solvent was removed under reduced pressure until the product started to precipitate. Precipitation of the product was completed by the addition of cyclohexane (1000 ml) and cooling to 0 ℃ for three hours. The solid was collected by suction filtration, washed with several portions of hexane and dried under vacuum at 50 ℃ overnight to give the title compound as an off-white solid.
MS(ESI): m/z=241(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.26(br.s, 1H,-NH); 5.62(br.s, 2H,-NH2); 4.20(qu, J=7.1, 2H); 4.18(qu, J=7.1, 2H); 2.34(s, 3H); 1.27(t, J=7.1, 3H); 1.26(t, J=7.1, 3H)。
Example A3 Ethyl-4-hydroxy-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate
A reaction flask equipped with mechanical stirrer, reflux condenser and nitrogen bubbler was charged with EtOH (5000 mL), diethyl 3-amino-5-methyl-1H-pyrrole-2, 4-carboxylate from example A2 (565.57 g; 2.50 mol) and formamidine acetate (1041.10 g; 10.00 mol). The well stirred reaction mixture was heated to gentle reflux under nitrogen atmosphere and held for 5 days.
The reaction mixture was cooled to room temperature. The precipitated crude product was collected by suction filtration, washed with several small portions of EtOH and suction dried for one hour. The solid was suspended in water (2500 mL), stirred at room temperature for two hours, collected by suction filtration, washed with a few small portions of water, and drained for one hour. The solid was resuspended in EtOH (2500 mL). The suspension was stirred at room temperature for three hours. The solid was collected by suction filtration, washed with several small portions of EtOH, drained for one hour and finally dried under vacuum at 50 ℃ overnight to give the title compound 7 as a white solid containing 15 mol% of isomer 8.
A mixture of 7 and 8(50.0 g, 0.23 mol) was suspended in EtOH (1000 mL). The stirred suspension was refluxed for one hour, filtered while it was still hot, and washed with several small portions of boiling EtOH. The remaining solid was resuspended in EtOH (500 mL). The stirred suspension was refluxed for one hour, filtered while still hot, washed with a few small portions of boiling EtOH and dried under vacuum at 50 ℃ overnight to afford the title compound as a colorless solid.
MS(ESI): m/z=222(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 12.56(s, 1H,-NH); 12.04(s, 1H,-OH); 7.88(s, 1H); 4.24(qu, J=6.9, 2H); 2.55(s, 3H); 1.28(t, J=6.9, 3H)。
After crystallization from EtOH, pure isomer 8 was obtained as a colorless solid from the evaporated filtrate.
MS(ESI): m/z=222(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 12.64(s, 1H,-NH); 11.41(s, 1H,-OH); 7.77(s, 1H); 4.28(qu, J=7.1, 2H); 2.56(s, 3H); 1.30(t, J=7.1, 3H)。
Example A4 Ethyl-4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate
Reaction flask equipped with mechanical stirrer, reflux condenser and nitrogen bubbler was charged with POCl3(1200 mL). Adding in portions4-hydroxy-6-methyl-5H-pyrrolo [3,2-d ] of example A3]Pyrimidine-7-carboxylic acid ethyl ester (207.19 g; 1.00 mol). The carefully stirred suspension was heated to gentle reflux for 5 hours.
The resulting black solution was cooled to room temperature. Removing POCl by reduced pressure distillation3Until the precipitated crude product prevents further stirring. Co-distillation with dry toluene (3X1000 mL) was repeated to remove the remaining POCl3. Finally, the resulting solid was suspended in toluene and stirred at room temperature under nitrogen overnight. The black precipitate was collected by suction filtration, washed with several small portions of toluene and diethyl ether and dried under nitrogen.
The anhydrous solid was suspended in ice-cold water (1000 mL). By careful addition of 2M KHCO3Solution, the pH of the well-stirred suspension was adjusted to 8. The suspension was stirred for several hours until the pH remained at 8.0 (the pH had to be maintained by adding 2M KHCO)3The solution was readjusted to 8.0 from time to time). The product was isolated by suction filtration, washed with a few small portions of water and suction dried for two hours.
For further purification, the product was suspended in acetonitrile (1000 mL). The suspension was stirred at 60 ℃ for one hour and at room temperature for an additional hour. The product was collected by suction filtration, washed with a few small portions of acetonitrile and suction dried for one hour. After concentration under reduced pressure, a second crop of product was obtained from the mother liquor. The solids were combined and dried under vacuum at 50 ℃ overnight to give the title compound as an off-white solid.
MS(ESI): m/z=240(MH+); 226(100 %); 212。
1H-NMR(300 MHz, DMSO-d6): 12.76(br.s, 1H,-NH); 8.64(s, 1H); 4.29(qu, J=7.1, 2H); 1.32(t, J=7.1, 3H)。
Example A.5: 3- (Ethylimidinoylamino) -5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride
Will be according to the literature [ Gangjee A.; li W.; yang J.; kisliuk r.l.; J. ethyl-3-amino-5-methyl-1H-pyrrole-2-carboxylate (58.87 g; 0.35 mol), prepared by med, chem, 2008, 51, 68], was suspended in acetonitrile (1750 mL). To the suspension was added dropwise 4M HCl/dioxane (473 mL; 1.89 mol) over 15 minutes. After the addition was complete, the reaction mixture was heated to 50 ℃ for 18 hours. The reaction mixture was cooled to 10 ℃, the solid collected by suction filtration and washed with cold acetonitrile (400 mL). After concentration under reduced pressure, a second crop of product was obtained from the mother liquor. The residue was collected with methyl tert-butyl ether. After suction filtration, the solids were combined and dried under vacuum at 50 ℃ to give the title compound as an off-white solid.
MS(ESI): m/z=210(MH+)
1H-NMR(300 MHz, DMSO-d6): 11.96(s, 1H,-NH); 10.93(s, 1H,-NH); 9.45(s, 1H,-NH); 8.22(s, 1H,-NH); 5.92(m, 1H); 4.19(qu, J=7.1, 2H); 2.29(s, 3H); 2.23(s, 3H); 1.26(t, J=7.1, 3H)。
Example A.6: 2, 6-dimethyl-3, 5-dihydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
A reaction flask equipped with a mechanical stirrer and a reflux condenser was charged with EtOH (900 mL), ethyl-3- (ethanimidoylamino) -5-methyl-1H-pyrrole-2-carboxylate hydrochloride of example A5 (82.79 g; 0.34 mol) and 6M NaOH (226 mL; 1.36 mol). The well stirred reaction mixture was heated to gentle reflux for 4 hours and cooled to room temperature. The resulting solution was diluted with water (1000 mL) and 2M citric acid was carefully added to adjust the pH to 6.5. The precipitate was collected by suction filtration, washed with several portions of water and dried under vacuum at 50 ℃ to give the title compound as an off-white precipitate.
MS(ESI): m/z=164(MH+)
1H-NMR(300 MHz, DMSO-d6): 11.63(s, 1H,-NH); 11.58(s, 1H,-OH); 5.98(m, 1H); 2.29(s, 3H); 2.26(s, 3H)。
Example A.7: 4-chloro-2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine
The 2, 6-dimethyl-3, 5-dihydro-4H-pyrrolo [3,2-d ] of example A6]Pyrimidin-4-one (87.00 g; 0.53 mol) was suspended in anhydrous acetonitrile (870 mL). Adding POCl3(122 mL; 1.33 mol), the stirred reaction mixture was heated to gentle reflux for 18 hours.
The volatiles were removed by distillation under reduced pressure. The residue was diluted with ice-cold water (1500 mL) and the well-stirred suspension was adjusted to pH =8 by addition of 5M KOH. The suspension was stirred for several hours until the pH remained at 8.0 (the pH had to be readjusted from time to 8.0 by the addition of 5M KOH). The solid was isolated by suction filtration, dissolved in dichloromethane and MgSO4Dried and filtered through a plug of neutral alumina (act. 2-3). The solvent was removed under reduced pressure. The product was resuspended in methyl tert-butyl ether, filtered and dried under vacuum at 50 ℃ overnight to give the title compound as an off-white solid.
MS(ESI): m/z=182(MH+)
1H-NMR(300 MHz, DMSO-d6): 11.99(s, 1H,-NH); 6.33(m, 1H); 2.57(s, 3H); 2.48(s, 3H)。
Example A.8: 7-bromo-4-chloro-2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine
4-chloro-2, 6-dimethyl-5H-pyrrolo [3,2-d ] from example A7]Pyrimidine (10.90 g; 60.00 mmol) was dissolved in dichloromethane (120 mL). The stirred mixture was cooled to-10 ℃. Br dissolved in dichloromethane (20 mL) was added dropwise over 25 minutes 2(3.08 mL; 60.00 mmol). The resulting precipitate was collected by suction filtration and suspended in Na2SO3(5% solution) (100 mL) and stirred at room temperature for 30 minutes. After filtration, the product is dissolved in acetonitrile (1000 mL), refluxed for one hour while it is still hotAnd (5) filtering. The solvent was removed under reduced pressure until the product started to precipitate. Precipitation of the product was completed by adding cyclohexane and cooling to 0 ℃ for several hours. The solid was collected by suction filtration, washed with cyclohexane and dried under vacuum at 50 ℃ overnight to give the title compound as a white solid.
MS(ESI): m/z=262(MH+)
1H-NMR(300 MHz, DMSO-d6): 12.61(s, 1H,-NH); 2.62(s, 3H); 2.48(s, 3H)。
Example A.9: 7-bromo-4-chloro-2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine
Sodium hydride (1.82 g; 45.60 mmol; 60% in oil, washed with hexane) was suspended in anhydrous DMF (125 mL) and anhydrous DMSO (25 mL). To this stirred suspension was added 7-bromo-4-chloro-2, 6-dimethyl-5H-pyrrolo [3,2-d ] of example A8 dissolved in anhydrous DMF (125 mL) dropwise over 30 minutes at room temperature]Pyrimidine (10.00 g; 38.00 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for one hour. To the resulting solution was added 2- (trimethylsilyl) ethoxymethyl chloride (8.74 mL; 49.40 mmol) dropwise, and the reaction mixture was stirred at room temperature for one hour. After dilution with water/ice and dichloromethane, the organic layer was separated and the aqueous layer was extracted with dichloromethane (2 × 400 mL). With MgSO 4The combined organic layers were dried and filtered through a plug of neutral alumina (act. 2-3). The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (cyclohexane: ethyl acetate/9: 1) to give the title compound as a white solid.
MS(ESI): m/z=392(MH+)
1H-NMR(300 MHz, DMSO-d6): 5.81(s, 2H); 3.57(t, J=7.9, 2H); 2.63(s, 3H); 2.58(s, 3H); 0.83(m, 2H);-0.09(s, 9H)。
Example A.10: 4-chloro-2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carbaldehyde
7-bromo-4-chloro-2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] of example A9]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidine (12.41 g; 31.76 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). N-butyllithium (12.7 mL; 31.76 mmol; 2.5M solution in n-hexane) was injected into the stirred reaction mixture at-78 ℃. After 30 minutes DMF (12.4 mL; 158.80 mmol) was added by syringe and the mixture was stirred at-78 ℃ for an additional 2 hours and at 0 ℃ for 30 minutes. The reaction was quenched by the addition of 1M citric acid (32 mL) and brine (32 mL). After dilution with methyl tert-butyl ether, the aqueous layer was separated and extracted with methyl tert-butyl ether (3 × 50 mL). With MgSO4The combined organic layers were dried and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (cyclohexane: ethyl acetate/7: 3) to give the title compound as a white solid.
MS(ESI): m/z=340(MH+)
1H-NMR(300 MHz, DMSO-d6): 10.35(s, 1H); 5.85(s, 1H); 3.61(t. .J=7.9, 2H); 2.87(s, 3H); 2.67(s, 3H); 0.85(m, 2H);-0.08(s, 9H)。
Example A.11: 4-chloro-2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid methyl ester
To a well stirred solution of 4-chloro-2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] of example A10 at room temperature]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidine-7-carbaldehyde (9.49 g; 27.90 mmol), MeOH (50 mL), KCN (6.00 g; 92.10 mmol), and MnO2(35.60 g, 383.30 mmol) to a mixture was added acetic acid (1.68 g; 27.90 mmol). After 4 hours, the black mixture was filtered through celite and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (cyclohexane: ethyl acetate/9: 1)) The title compound was obtained as a pale yellow oil.
MS(ESI): m/z=370(MH+)
1H-NMR(300 MHz, DMSO-d6): 5.85(s, 2H); 3.84(s, 3H); 3.59(t, J=7.9, 2H); 2.84(s, 3H); 2.64(s, 3H); 0.84(m, 2H);-0.09(s, 9H)。
Example B.a 1: 2-bromo-5-fluoro-4-methoxy-phenol
Will be according to the literature [ Freedman, j.; stewart, k.t.; J. heterocyclic chem. 1989, 26, 1547-1554]The prepared 3-fluoro-4-methoxy-phenol (21.32 g; 0.15 mol) was dissolved in anhydrous dichloromethane (300 mL). The well stirred reaction mixture was cooled to-15 ℃ (ice/salt). A solution of bromine (23.97 g; 0.15 mol) in anhydrous dichloromethane (75 mL) was dropped into the reaction mixture. After the addition was complete, stirring was continued for one hour. Water (150 mL) containing sodium sulfite (3.0 g) was added to the reaction mixture. Stirring was continued for 30 minutes at room temperature. The organic layer was separated, washed with water (100 mL), and MgSO 4 in the presence of decolorizing charcoal 4And (5) drying. After filtration, the solvent was completely removed under reduced pressure. The residue was crystallized from methyl tert-butyl ether/hexane to give the title compound as a colorless solid.
GC-MS(EI): m/z=222, 220(M+); 207, 205(M+-CH3, 100%); 179, 177。
1H-NMR(300 MHz, DMSO-d6): 10.06(s, 1H,-OH); 7.28(d, J=9.2, 1H); 6.81(d, J=12.6, 1H); 3.76(s, 3H)。
In a manner analogous to that described in example b.a1 above, the following compounds were obtained.
Example B.a 2: 2-bromo-4-fluoro-5-methoxy-phenol
From the following literature [ Belanger, p.c.; lau, c.k.; williams, h.w.r.; dufresne, c.; starting from 4-fluoro-3-methoxy-phenol prepared by Scheigetz, J. Can. chem. 1988, 66, 1479-acid 1482], the title compound was obtained as a colorless solid.
GC-MS(EI): m/z=222, 220(M+, 100%); 207, 205(M-CH3 +); 179, 177。
1H-NMR(300 MHz, CDCl3): 7.16(d, J=10.2, 1H); 6.67(d, J=7.7, 1H); 5.29(s, 1H,-OH); 3.85(s, 3H)
Example B.a 3: 2-bromo-5-fluoro-4-methylphenol
Starting from commercial 3-fluoro-4-cresol, the title compound was obtained as a colorless solid.
GC-MS(EI): m/z=206, 204(M+); 125(100%)。
1H-NMR(300 MHz, DMSO-d6): 10.38(br.s, 1H,-OH); 7.39(d, J=8.2, 1H); 6.70(d, J=11.1, 1H); 2.11(s, 3H)。
Example B.a4: 1- (3-bromo-4-hydroxy-phenyl) -ethanone
Starting from commercially available 1- (4-hydroxy-phenyl) -ethanone, the title compound was obtained as a colorless solid.
GC-MS(EI): m/z=214, 212(M+); 199,197(100%)。
1H-NMR(300 MHz, DMSO-d6): 11.19(s, 1H,-OH); 8.06(d, J=2.2, 1H); 7.82(dd, J=8.4, 2.2, 1H); 7.03(d, J=8.4, 1H); 2.49(s, 3H)。
Example B.a 5: 2-bromo-4-ethylphenol
Starting from commercial 4-ethylphenol, the title compound was obtained as a colorless oil after short-path distillation at 10 mbar.
GC-MS(EI): m/z=202, 200(M+); 187,195(100%)。
1H-NMR(300 MHz, DMSO-d6): 9.88(s, 1H,-OH); 7.29(d, J=2.0, 1H); 7.00(dd, J=8.2, 2.0, 1H); 6.85(d, J=8.2, 1H); 2.49(qu, J=7.7, 2H); 1.12(t, J=7.7, 3H)。
Example B.a 6: 2-bromo-4-isopropylphenol
Starting from commercially available 4-isopropylphenol, the title compound was obtained as a colorless oil after short-path distillation at 10 mbar.
GC-MS(EI): m/z=216, 214(M+); 201, 199; 120(100%)。
1H-NMR(300 MHz, DMSO-d6): 9.88(s, 1H,-OH); 7.30(d, J=2.2, 1H); 7.04(dd, J=8.4, 2.2, 1H); 6.86(d, J=8.4, 1H); 2.78(sept, J=6.9, 1H); 1.14(d, J=6.9, 6H)。
Example B.b. 1: 5-Cyclopropylmethoxy-benzo [1,3] dioxole
Sodium hydride (60 wt% dispersion in mineral oil; 11.0 g; 275.0 mmol) was freed from the oil by washing with hexane (2X 50 mL) and suspended in anhydrous DME (375 mL) and anhydrous DMSO (37.5 mL). A solution of commercially available sesamol (3, 4-methylenedioxy-phenol) (34.53 g; 250.0 mmol) in dry DME (250 mL) was added dropwise to the well-stirred suspension under nitrogen at a rate that maintained the internal temperature below 40 ℃. After the addition was complete, stirring was continued at room temperature for one hour. Pure, commercially available bromomethyl-cyclopropane (37.13 g; 275.0 mmol) was added in one portion and the reaction mixture was stirred at 80 ℃ overnight. Ice water (125 mL) was added dropwise and the reaction mixture was stirred at room temperature for 30 minutes. After addition of brine (125 mL), the organic layer was separated and concentrated in vacuo. The aqueous layer was washed with methyl tert-butyl ether (3)x 200 mL). All organic phases were combined, washed with brine (200 mL), MgSO4Dried and filtered through a plug of neutral alumina (containing 5 wt% water). The product was eluted thoroughly with several portions of methyl tert-butyl ether. The solvent was removed under reduced pressure. At 3 x 10-3The remaining crude product is purified by short path distillation at mbar (117 ℃) to give the title compound as a colourless oil which solidifies at room temperature.
GC-MS(EI): m/z=192(M+); 138(M+-C4H6, 100 %)。
1H-NMR(200 MHz, DMSO-d6): 6.77(d, J=8.5, 1H); 6.59(d, J=2.5, 1H); 6.32(dd, J=8.5, 2.5, 1H); 5.93(s, 2H); 3.71(d, J=6.9, 2H); 1.15(m, 1H); 0.53(m, 2H); 0.27(m, 2H)。
In a manner analogous to that described in example b.b. 1 above, the following compounds are obtained.
Example B. b 2: 1-bromo-2-cyclopropylmethoxy-4-fluoro-benzene
Starting from commercially available 2-bromo-5-fluoro-phenol and commercially available bromomethyl-cyclopropane at 5x10-3After distillation at mbar the title compound was obtained as a colourless oil.
GC-MS(EI): m/z=244, 246(M+); 190, 192(M+-C4H6); 55(100%). 。
1H-NMR(300 MHz, DMSO-d6): 7.58(dd, J=8.7, 6.4, 1H); 7.02(dd, J=11.2, 2.8, 1H); 6.75(ddd, J=8.7, 2.8, 1H); 3.93(d, J=6.8, 2H); 1.24(m, 1H); 0.56(m, 2H); 0.38(m, 2H)。
Example B. b 3: 1-bromo-2-cyclopropylmethoxy-5-fluoro-benzene
Starting from commercially available 2-bromo-4-fluoro-phenol and commercially available bromomethyl-cyclopropane at 5x10-3 mbar after distillation, the title compound was obtained as a colorless oil.
GC-MS(EI): m/z=244, 246(M+); 190, 192;(M+-C4H6); 55(100%)。
1H-NMR(400 MHz, DMSO-d6): 7.52(dd, J1=8.2, J2=3.1, 1H); 7.19(ddd, J1=9.1, J2=8.2, J3=3.1, 1H); 7.10(dd, J1=9.1, J2=5.0, 1H); 3.89(d, J=6.8, 2H); 1.22(m, 2H); 0.57(m, 2H); 0.35(m, 2H)。
Example B. b 5: 1-bromo-2-cyclopropylmethoxy-4-methoxy-benzene
Starting from commercially available 2-bromo-5-methoxy-phenol and bromomethyl-cyclopropane, the title compound was obtained as a colorless solid.
GC-MS(EI): m/z=258, 256(M+)。
1H-NMR(200 MHz, DMSO-d6): 7.41(d, J=7.9, 1H); 6.48(dd, J1=7.9, J2=2.2, 1H); 6.45(d, J=2.2, 1H); 3.87(d, J=5.6, 2H); 3.76(s, 3H); 1.26(m, 1H); 0.63(m, 2H); 0.36(m, 2H)。
Example B. b 6: 1-bromo-2-cyclopropylmethoxy-5-methoxy-benzene
Starting from commercially available 2-bromo-4-methoxy-phenol and commercially available bromomethyl-cyclopropane at 5x10-3After distillation at mbar the title compound was obtained as a colourless oil.
GC-MS(EI): m/z=256, 258(M+); 202, 204(100 %). 。
1H-NMR(200 MHz, CDCl3): 7.11(d, J=2.8, 1H); 6.86(d, J=8.9, 1H); 6.78(dd, J1=8.9, J2=2.8, 1H); 3.82(d, J=6.8, 2H); 3.75(s, 3H); 1.16(m, 1H); 0.51(m, 2H); 0.44(m, 2H)。
Example B. b 7: 2-bromo-1-cyclopropylmethoxy-4-methyl-benzene
Starting from commercially available 2-bromo-4-methyl-phenol and bromomethyl-cyclopropane at 5x10-3After distillation at mbar the title compound was obtained as a colourless oil.
GC-MS(EI): m/z=242,240(M+); 188,186(M+-C4H6); 107; 80, 78; 55(100%)。
1H-NMR(300 MHz, DMSO-d6):.7.38(dd, J=2.2, 0.7, 1H); 7.10(ddd, J=8.4, 2.2, 0.7, 1H); 6.96(d, J=8.4, 1H); 3.86(d, J=6.8, 2H); 2.22(s, 3H); 1.21(m, 1H); 0.56(m, 2H); 0.33(m, 2H)。
Example B. b 8: 2-bromo-1-cyclopropylmethoxy-4-trifluoromethyl-benzene
Starting from commercially available 2-bromo-4-trifluoromethyl-phenol and bromomethyl-cyclopropane at 5x10-3After distillation at mbar the title compound was obtained as a colourless oil.
GC-MS(EI): m/z=296,294(M+); 268, 266; 242, 240(M+-C4H6); 132; 55(100%)。
1H-NMR(300 MHz, DMSO-d6):.7.93(dd, J=2.3, 0.5, 1H); 7.70(ddd, J=8.8, 2.3, 0.5, 1H); 7.26(d, J=8.8, 1H); 4.03(d, J=6.9, 2H); 1.27(m, 1H); 0.60(m, 2H); 0.38(m, 2H)。
Example B. b9: 2-bromo-1-ethoxy-4-trifluoromethyl-benzene
Starting from commercially available 2-bromo-4-trifluoromethyl-phenol and ethyl iodide at 5x10-3After distillation at mbar the title compound was obtained as a colourless oil.
GC-MS(EI): m/z=270, 268(M+); 242, 240(M+-C2H4, 100%); 132。
1H-NMR(300 MHz, DMSO-d6):.7.93(dd, J=2.3, 0.7, 1H); 7.71(ddd, J=8.8, 2.3, 0.7, 1H); 7.27(d, J=8.8, 1H); 4.21(qu, J=6.9, 2H); 1.38(t, J=6.9, 3H)。
Example B. b 10: 1-bromo-2-cyclopropylmethoxy-4-fluoro-5-methoxy-benzene
Starting from 2-bromo-5-fluoro-4-methoxy-phenol (example b.a1) and a commercially available bromomethyl-cyclopropane, the title compound was obtained as a colorless solid.
GC-MS(EI): m/z=276, 274(M+); 222, 220(M+-C4H6, 100%); 206, 204。
1H-NMR(400 MHz, DMSO-d6): 7.38(d, J=9.2, 1H); 7.13(d, J=13.1, 1H); 3.85(d, J=6.9, 2H); 3.80(s, 3H); 1.20(m, 1H); 0.57(m, 2H); 0.33(m, 2H)。
Example B. b 11: 1-bromo-2-cyclopropylmethoxy-4-fluoro-5-methyl-benzene
Starting from commercially available 2-bromo-5-fluoro-4-methyl-phenol (example b.a3) and commercially available bromomethyl-cyclopropane at 5x10-3After distillation at mbar the title compound was obtained as a colourless oil.
GC-MS(EI): m/z=260, 258(M+); 206, 204(M+-C4H6); 179; 125; 96; 55(100%)。
1H-NMR(400 MHz, DMSO-d6): 7.49(d, J=8.2, 1H); 6.97(d, J=11.7, 1H); 3.89(d, J=6.9, 2H); 2.14(d, J=1.8, 3H); 1.22(m, 1H); 0.57(m, 2H); 0.34(m, 2H)。
Example B. b 12: 1-bromo-2-cyclopropylmethoxy-5-fluoro-4-methoxy-benzene
Starting from 2-bromo-4-fluoro-5-methoxy-phenol (example b.a2) and a commercially available bromomethyl-cyclopropane, the title compound was obtained as a colorless solid.
GC-MS(EI): m/z=276, 274(M+); 222, 220(M+-C4H6, 100 %)。
1H-NMR(400 MHz, DMSO-d6): 7.48(d, J=10.8, 1H); 6.90(d, J=7.9, 1H); 3.93(d, J=6.8, 2H); 3.85(s, 3H); 1.24(m, 1H); 0.58(m, 2H); 0.36(m, 2H)。
Example B. b 13: 1- (3-bromo-4-cyclopropylmethoxy-phenyl) -ethanone
Starting from 1- (3-bromo-4-hydroxy-phenyl) -ethanone (example b.a4) and commercially available bromomethyl-cyclopropane, the title compound was obtained as a colorless solid.
GC-MS(EI): m/z=270, 268(M+); 242, 240; 216, 214(M+-C4H6); 201, 199; 55(100%)。
1H-NMR(400 MHz, DMSO-d6): 8.11(d, J=2.1, 1H); 7.94(dd, J=8.7, 2.1, 1H); 7.19(d, J=8.7, 1H); 4.03(d, J=6.9, 2H); 2.53(s, 3H); 1.27(m, 1H); 0.60(m, 2H); 0.38(m, 2H)。
Example B. b 14: 2- [ 3-bromo-4- (cyclopropylmethoxy) phenyl ] -2-methyl-1, 3-dioxolane
A solution of 1- (3-bromo-4-cyclopropylmethoxy-phenyl) -ethanone from example B.b. 13 (14.0 g; 52.0 mmol) in dry dichloromethane (250 mL) was cooled in an ice bath, then trimethylsilyl trifluoro-mesylate (0.23 g; 1.04 mmol) was added and 1, 2-bis (trimethylsilyl) was added dropwiseOxy) -ethane (13.15 g; 62.4 mmol). The reaction mixture was stirred for two hours with 1M NaHCO3Extracting with aqueous solution (100 mL) over MgSO4And (5) drying. The crude product was purified by silica gel column chromatography (ethyl acetate/cyclohexane-9: 1) to give the title compound as a pale yellow oil.
GC-MS(EI): m/z=314, 314(M+); 299, 297(M+-CH3, 100 %); 245, 243(M+-CH3,-C4H6); 201, 199; 87; 55。
1H-NMR(400 MHz, DMSO-d6): 7.53(d, J=2.2, 1H); 7.33(dd, J=8.6, 2.2, 1H); 7.05(d, J=8.6, 1H); 3.96(m, 2H); 3.91(d, J=6.9, 2H); 3.69(m, 2H); 1.53(s, 3H); 1.23(m, 1H); 0.58(m, 2H); 0.35(m, 2H)。
Example B. b15: 1-bromo-2-cyclopropylmethoxy-5-ethyl-benzene
Starting from 2-bromo-4-ethylphenol (example b.a5) and commercially available bromomethyl-cyclopropane, after distillation at 10 mbar, the title compound was obtained as a colorless oil.
GC-MS(EI): m/z=256, 254(M+); 228, 226(M+-C2H4); 202, 200(M+-C4H6); 187, 185(M+-C4H6,-CH3); 55(100 %)。
1H-NMR(300 MHz, DMSO-d6): 7.39(d, J=2.0, 1H); 7.13(dd, J=8.4, 2.0, 1H); 6.98(d, J=8.4, 1H); 3.87(d, J=6.8, 2H); 3.53(qu, J=7.7, 2H); 1.22(m, 1H); 1.13(t, J=7.7, 3H); 0.56(m, 2H); 0.33(m, 2H)。
Example B. b 16: 2-bromo-1-cyclopropylmethoxy-4- (prop-2-yl) benzene
Starting from 2-bromo-4-isopropylphenol (example B.a6) and commercially available bromomethyl-cyclopropane, 2X10-3After short-path distillation at mbar the title compound is obtained as a colourless solid.
GC-MS(EI): m/z=270, 268(M+); 201, 199; 120; 91; 55(100 %)。
1H-NMR(300 MHz, DMSO-d6): 7.41(d, J=2.2, 1H); 7.17(dd, J=8.4, 2.2, 1H); 6.99(d, J=8.4, 1H); 3.87(d, J=6.8, 2H); 2.38(sept, J=6.9, 1H); 1.22(m, 1H); 1.16(d, J=6.9, 6H); 0.56(m, 2H); 0.34(m, 2H)。
Example B. b 17: 3-bromo-4- (cyclopropylmethoxy) benzaldehyde
Commercial 3-bromo-4-hydroxy-benzaldehyde (40.2 g; 220 mmol), anhydrous K, well stirred in anhydrous DMF (200 mL)2CO3A mixture of (30.4 g; 220 mmol) and commercial bromomethyl-cyclopropane (32.4 g; 240 mmol) was heated to 60 ℃ overnight. The reaction mixture was filtered, concentrated under reduced pressure, diluted with water and extracted with tert-BuOMe. The combined organic extracts were washed with brine, MgSO4Drying, and concentrating under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/AcOEt: 100:0 to 85:15) to yield 47.5 g of the title compound as a pale yellow oil.
1H-NMR(300 MHz, DMSO-d6): 9.85 8s, 1H); 8.10(d, J=2.0, 1H); 7.89(dd, J=8.6, 2.0, 1H); 7.28(d, J=8.6, 1H); 4.06(d, J=6.9, 2H); 1.28(m, 1H); 0.61(m, 2H); 0.39(m, 2H)。
Example B. b 18: 2-bromo-1- (cyclopropylmethoxy) -4- (difluoromethyl) benzene
A pressurized vial was charged with dichloromethane (10.0 mL), 3-bromo-4-cyclopropylmethoxy-benzaldehyde (example B.b 17; 2.55 g; 10.0 mmol) and commercial bis (2-methoxyethyl) aminosulfur trifluoride (5.53 g; 25.0 mmol). After capping, the reaction mixture was heated to 70 ℃ in a microwave oven for 15 minutes and poured slowlyWell stirred ice cold 2M NaHCO was added3In solution (50 mL). After extraction with dichloromethane, MgSO4The combined organic layers were dried and concentrated under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/AcOEt: 90:10 to 80:20) to give 2.3 g of the title compound as a pale yellow oil.
1H-NMR(300 MHz, DMSO-d6): 7.77(~t, J=0.9, 1H); 7.54(~dt, J=8.6, 0.9, 1H); 7.20(d, J=8.6, 1H); 6.95(t, J=55.9, 1H); 3.98(d, J 0 6.9, 2H); 1.26(m, 1H), 0.59(m, 2H); 0.37(m, 2H)。
Example B.c. 1: 5-Cyclopropylmethoxy-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzo [1,3] dioxole
The reaction was carried out in direct fire dried glassware under argon atmosphere.
A stirred solution of 5-cyclopropylmethoxy-benzo [1,3] dioxol from example B.b. 1 (38.44 g; 200.0 mmol) in dry THF (500 mL) was cooled to-40 ℃ and n-butyllithium (138.0 mL; 1.6M solution in hexane; 220 mmol) was added slowly via syringe. After the addition was complete, stirring was continued for two more hours at-40 ℃. Pure 2-isopropoxy-4, 4,5, 5-tetramethyl- [1,3,2] dioxaborolan (40.95 g; 220.0 mmol) was added via syringe at-78 ℃ and stirring was continued for two hours at-78 ℃.
At-15 ℃ with saturated NH4The reaction mixture was quenched with Cl solution (200 mL) and stirred at room temperature for 30 min. The organic layer was separated and concentrated under reduced pressure. The aqueous layer was extracted with methyl tert-butyl ether (3 × 200 mL). All organic phases were combined, washed with saturated NaCl solution (200 mL), MgSO4Dried and filtered through a plug of neutral alumina (containing 5 wt% water). The product was eluted thoroughly with a few small portions of methyl tert-butyl ether.
The solvent was removed under reduced pressure. Treatment of the crude with ice cold methanol (50 mL) provided the title compound as a colorless solid.
GC-MS(EI): m/z=318(M+); 264(M+-C4H6); 207; 164(100 %)。
1H-NMR(200 MHz, DMSO-d6): 6.78(d, J=8.4, 1H); 6.29(d, J=8.4; 1H); 5.92(s, 2H); 3.71(d, J=6.3, 2H); 1.29(s, 12H); 1.14(m, 1H); 0.50(m, 2H); 0.34(m, 2H)。
Example B.c. 2: 2- (2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane
The reaction was carried out in direct fire dried glassware under argon atmosphere.
A stirred solution of 1-bromo-2-cyclopropylmethoxy-4-fluoro-5-methoxy-benzene from example B.b. 10 (27.51 g; 0.10 mol) in dry methyl tert-butyl ether (500 mL) was cooled to-20 ℃ and n-butyllithium (1.6M in hexane; 68.8 mL; 0.11 mol) was added via syringe. After the addition was complete, stirring was continued for one hour. Pure 2-isopropoxy-4, 4,5, 5-tetramethyl- [1,3,2] is injected via syringe at-40 ℃]Dioxaborolane was added to the reaction mixture. After 30 minutes, the reaction was quenched with 1M citric acid (200 mL) at 0 ℃ and stirred at room temperature for one hour. The organic layer was separated. The aqueous layer was extracted with methyl tert-butyl ether (100 mL). The combined organic layers were washed with brine (200 mL) and MgSO4Dried and filtered through a plug of neutral alumina (containing 5 wt% water). The product was eluted thoroughly with a few small portions of methyl tert-butyl ether. The solvent was removed under reduced pressure. At 3 x 10 -3The crude product is purified by short path distillation at mbar (160 ℃ C.) to give the title compound as a colourless oil which solidifies at room temperature.
GC-MS(EI): m/z=322(M+, 100%); 211, 168。
1H-NMR(300 MHz, DMSO-d6): 7.14(d, J=10.5, 1H); 6.91(d, J=13.6, 1H); 3.81(d, J=6.0, 2H); 3.77(s, 3H); 1.28(s, 12H); 1.16(m, 1H); 0.48(m, 2H); 0.38(m, 2H)。
Using a procedure similar to that described in example b.c. 2 above, the following compounds were obtained.
Example B.c. 3: 2- (2-Cyclopropylmethoxy-4-fluoro-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane
Starting from 1-bromo-2-cyclopropylmethoxy-4-fluoro-benzene (example B.b. 2) at 3X10-3 After short path distillation at mbar (130 ℃ C.), the title compound is obtained as a colorless solid.
GC-MS(EI): m/z=292(M+); 181, 55(100%)。
1H-NMR(300 MHz, DMSO-d6): 7.48(dd, J1=J2=8.0, 1H); 6.80(dd, J1=12.0, J2=2.2, 1H); 6.71(ddd, J1=8.4, J2=8.0, J3=2.2, 1H); 3.89(d, J=5.8, 2H); 1.27(s, 12H); 1.17(m, 1H); 0.51(m, 2H); 0.46(m, 2H)。
Example B.c. 4: 2- (2-Cyclopropylmethoxy-5-fluoro-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane
Starting from 1-bromo-2-cyclopropylmethoxy-5-fluoro-benzene (example B.b. 3) at 3X10-3After short-path distillation at mbar (100 ℃ C.), the title compound is obtained as a colorless solid.
GC-MS(EI): m/z=292(M+); 181(100%); 55. 。
1H-NMR(300 MHz, DMSO-d6): 7.22-7.13(m, 2H); 6.95(dd, J1=8.9, J2=4.2, 1H); 3.85(d, J=6.4, 2H); 1.28(s, 12H); 1.17(m, 1H); 0.52(m, 2H); 0.46(m, 2H)。
Example B.c. 6: 2- (2-Cyclopropylmethoxy-4-methoxy-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane
The title compound was prepared as a colorless solid after crystallization from 1-bromo-2-cyclopropylmethoxy-4-methoxy-benzene (example b. b5) with hexane.
GC-MS(EI): m/z=304(M+); 276 ; 250; 193; 164(100%); 150。
1H-NMR(200 MHz, DMSO-d6): 7.41(d, J=7.9, 1H); 6.48(dd, J1=7.9, J2=2.2, 1H); 6.45(d, J=2.2, 1H); 3.87(d, J=5.6, 2H); 3.75(s, 3H); 1.25(s, 12H); 1.16(m, 1H); 0.49(m, 2H); 0.44(m, 2H)。
Example B.c. 7: 2- (2-Cyclopropylmethoxy-5-methoxy-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane
Starting from 1-bromo-2-cyclopropylmethoxy-5-methoxy-benzene (example B.b. 6) at 3X10-3After short-path distillation at mbar (160 ℃ C.), the title compound is obtained as a colorless oil.
GC-MS(EI): m/z=304(M+); 276; 250; 193(100%); 150。
1H-NMR(200 MHz, CDCl3): 7.15(d, J=3.1, 1H); 6.90(dd, J1=9.0, J2=3.1, 1H); 6.81(d, J=9.0, 1H); 3.80(d, J=6.3, 2H); 3.78(s, 3H); 1.35(s, 12H); 1.17(m, 1H); 0.55(m, 2H); 0.38(m, 2H)。
Example B.c. 8: 2- (2-Cyclopropylmethoxy-5-methyl-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane
Starting from 1-bromo-2-cyclopropylmethoxy-5-methyl-benzene (example b. b7), the title compound was obtained as a colorless solid.
GC-MS(EI): m/z=288(M+); 177(100%)。
1H-NMR 400 MHz, DMSO-d6): 7.26(d, J=2.1, 1H); 7.16(dd, J=8.3, 2.1, 1H); 6.81(d, J=8.3, 1H); 3.81(d, J=5.9, 2H); 2.21(s, 3H); 1.27(s, 12H); 1.15(m, 1H); 0.47(m, 2H); 0.40(m, 2H)。
Example B.c. 9: 2- (2-Cyclopropylmethoxy-5-trifluoromethyl-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane
Starting from 2-bromo-1-cyclopropylmethoxy-4-trifluoromethyl-benzene (example b. b8), the title compound was obtained as a colorless solid.
GC-MS(EI): m/z=342(M+); 231(100%)。
1H-NMR 300 MHz, DMSO-d6): 7.74(ddd, J=8.8, 2.6, 0.7, 1H); 7.69(d, J=2.6, 1H); 7.12(d, J=8.8, 1H); 3.98(d, J=5.8, 2H); 1.30(s, 12H); 1.20(m, 1H); 0.59(m, 2H); 0.43(m, 2H)。
Example B.c. 10: 2- (2-ethoxy-5-trifluoromethyl-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan
Starting from 2-bromo-1-ethoxy-4-trifluoromethyl-benzene (example b. b9), the title compound was obtained as a colorless solid.
GC-MS(EI): m/z=316(M+); 216(100%)。
1H-NMR 300 MHz, DMSO-d6): 7.75(ddd, J=8.8, 2.4, 0.6, 1H); 7.70(d, J=2.4, 1H); 7.13(d, J=8.8, 1H); 4.09(qu, J=6.9, 2H); 1.33(t, j=6.9, 3H); 1.29(s, 12H)。
Example B.c. 11: 2- (2-Cyclopropylmethoxy-4-fluoro-5-methyl-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane
Starting from 1-bromo-2-cyclopropylmethoxy-4-fluoro-5-methyl-benzene (example b. b11), the title compound was obtained as a colorless oil.
GC-MS(EI): m/z=306(M+); 195(100 %); 55。
1H-NMR(300 MHz, DMSO-d6): 7.35(dd, J=10.0, 0.5, 1H); 6.76(d, J=12.4, 1H); 3.85(d, J=5.8, 2H); 2.13(d, J=0.5, 3H); 1.27(s, 12H); 1.15(m, 1H); 0.49(m, 2H); 0.41(m, 2H)。
Example B.c. 12: 2- (2-Cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane
Starting from 1-bromo-2-cyclopropylmethoxy-5-fluoro-4-methoxy-benzene (example b. b12), the title compound was obtained after crystallization from methanol as a colorless solid.
GC-MS(EI): m/z=322(M+); 211; 182; 168(100 %); 55。
1H-NMR(300 MHz, DMSO-d6): 7.15(d, J=11.7, 1H); 6.73(d, J=7.0, 1H); 3.88(d, J=6.0, 2H); 3.85(s, 3H); 1.26(s, 12H); 1.16(m, 1H); 0.50(m, 2H); 0.30(m, 2H)。
Example B.c 13: 2- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan
Starting from 2- [ 3-bromo-4- (cyclopropylmethoxy) phenyl ] -2-methyl-1, 3-dioxolane (example b. b14), the title compound is obtained as a colorless solid.
GC-MS(EI): m/z=360(M+); 345(100 %)。
1H-NMR(300 MHz, DMSO-d6): 7.49(d, J=2.5, 1H); 7.40(dd, J=8.6, 2.5, 1H); 6.89(d, J=8.6, 1H); 3.95(m, 2H); 3.86(d, J=5.7, 2H); 3.67(m, 2H); 1.50(s, 3H); 1.28(s, 12H); 1.17(m, 1H); 0.48(m, 2H); 0.41(m, 2H)。
Example B.c. 14: 2- (2-Cyclopropylmethoxy-5-ethyl-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane
Starting from 1-bromo-2-cyclopropylmethoxy-5-ethyl-benzene (example b. b15), the title compound was obtained as a pale yellow oil.
GC-MS(EI): m/z=302(M+); 274; 191(100 %); 55。
1H-NMR(300 MHz, DMSO-d6): 7.27(d, J=2.0, 1H); 7.20(dd, J=8.4, 2.0, 1H); 6.83(d, J=8.4, 1H); 3.82(d, J=5.8, 2H); 2.50(qu, J=7.7, 2H); 1.28(s, 12H); 1.13(t, J=7.7, 3H); 1.12(m, 1H); 0.48(m, 2H); 0.39(m, 2H)。
Example B.c 15: 2- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan
Starting from 2-bromo-1-cyclopropylmethoxy-4- (prop-2-yl) benzene (example b. b16), the title compound was obtained as a colorless solid.
GC-MS(EI): m/z=316(M+); 301; 288; 247; 205; 147(100 %); 103; 83; 55。
1H-NMR(300 MHz, DMSO-d6) 7.29(d, J =2.4, 1H), 7.23(dd, J =8.4, 2.2, 1H), 6.84(d, J =8.4, 1H), 3.82(d, J =5.9, 2H), 2.81(sept, J =6.9, 1H), 1.28(s, 12H), 1.15(d, J =6.9, 6H and m, 1H), 0.48(m, 2H), 0.40(m, 2H).
Example B.c 16: 2- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane
2-bromo-1-cyclopropylmethoxy-4-difluoromethyl-benzene (example B.b. 18; 24.35 g; 87.9 mmol) was dissolved in anhydrous tert BuOMe (440 mL). n-BuLi (1.6M in hexane; 60.0 mL; 96.0 mmol) was slowly injected into the well-stirred reaction mixture at-40 ℃. After one hour, commercial 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (17.86 g; 96.0 mmol) was added at-40 ℃ and stirred for an additional hour at 0 ℃. The reaction mixture was quenched by addition of 2M aqueous citric acid (90.0 mL). The organic layer was separated, washed with brine, and MgSO4Dried and filtered through a pad of neutral alumina (act.2-3). The solvent was removed under reduced pressure to give 28.1 g of the title compound as a pale yellow oil.
Note that the compound tends to decompose violently when heated above 80 ℃.
1H-NMR(300 MHz, DMSO-d6): 7.63(~t, J=1.1, 1H); 7.58(~dt, J=8.4, 1.1, 1H); 7.05(d, J=8.4, 1H); 6.95(t, J=56.2, 1H); 3.94(d, J=5.8, 2H); 1.29(s, 12 H); 1.19(m, 1H), 0.51(m, 2H); 0.43(m, 2H)。
Example C1: (3R)*,4R*) -4-azido-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (23f) and (3S)*,4S*) -3-azido-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (23g)
Will be according to the literature [ Zhao, s.; ghosh, a.; d' Andrea, s.v.; freeman, P.; von voigtlander, p.f.; carter, d.b.; smith, m.w.; heterocycles, 1994, 39, 163]Preparation of 7-oxa-3-azabicyclo [4.1.0 ]A mixture of tert-butyl heptane-3-carboxylate (60 g, 0.30 mol), sodium azide (25,4 g, 0.39 mol), and ammonium chloride (21 g, 0.39 mol) in ethanol (150 mL) and water (150 mL) was heated to gentle reflux overnight. The ethanol was evaporated in vacuo. The residue was partitioned between dichloromethane and water. The aqueous layer was separated and extracted with dichloromethane. The combined organic layers were washed with water and brine, and Na2SO4Dried and concentrated in vacuo to yield 67.3 g of crude 23f and 23g of a 4:1 mixture1H-NMR, consistent with literature data[Erickson, S.D.; Banner, B.; Berthel, S.; Conde-Knape, K.; Falicioni, F.; Hakimi, I.; Hennessy, B.; Kester, R.F.; Kim, K.; Ma, Ch.; McComas, W.; Mennona, F.; Mischke, S.; Orzechowski, L.; Qian, Y.; Salari, H.; Tengi, J.; Thakkar, K.; Taub, R.; Tilley, J.W.; Wang, H.; Bioorg. .Med. .Chem. Lett. .2008, 18, 1402]。
Chromatography on a silica gel column (heptane: ethyl acetate-4: 1) gave the faster eluting 23f, the slower eluting 23g and the unseparated 23f and 23 g.
(3R*,4R*) -4-azido-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (23f)
MS(ESI): m/z=217(MH+, 100%)。
1H-NMR(400 MHz, CDCl3): 4.12(m, 1H); 3.95(br.m, 1H); 3.50(m,1H); 3.38(m, 1H); 2.89(m, 1H); 2.78(m, 1H); 2.71-2.32(m 1H); 2.00(m, 1H); 1.52(m, 1H); 1.44(s, 9H)。
(3S*,4S*) -3-azido-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (23g)
MS(ESI): m/z=217(MH+, 100%)。
1H-NMR(400 MHz, CDCl3): 4.23(m, 1H); 4.00(m, 1H); 3.54(m, 1H); 3.30(m, 1H); 2.82(m, 1H); 2.66(m, 1H); 2.24(m, 1H); 1.97(m, 1H); 1.59(m, 1H); 1.46(s, 9H)。
Example C2: (3R)*,4R*) -4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (21f)
Under a nitrogen atmosphere, (3S) of example C1*,4S*) Tert-butyl (47 g, 194 mmol) 4-azido-3-hydroxypiperidine-1-carboxylate is dissolved in methanol (1200 mL). Palladium hydroxide (20% on carbon; 4.7 g) was added. The atmosphere was changed to a hydrogen atmosphere and the stirred reaction mixture was brought to room temperature at 70 psi Hydrogenation for 72 hours. The mixture was filtered through celite. The filtrate was evaporated. By CH2Cl2The residue was recrystallized (with a small amount of MeOH) to obtain the title compound as a white solid.
HR-MS(ESI): m/z=217.1539([MH]+, C10H21N2O3 +Calculating the value: 217.1547).
Example C3: (3S)*,4S*) -3-amino-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (21g)
Following the procedure outlined in example C2 above, from (3S)*,4S*) Starting from tert-butyl (3-azido-4-hydroxy-piperidine-1-carboxylate (example C1), the title compound was obtained as a white solid.
HR-MS(ESI): m/z=217.1541([MH]+, C10H21N2O3 +Calculating the value: 217.1547).
Example C4: (1R,3S) -3- [ (tert-butoxycarbonyl) amino ] cyclopentyl methanesulfonate
Methanesulfonyl chloride (8.2 g; 72.0 mmol) was slowly added to the commercial [ (1S,3R) -3-hydroxycyclopentyl group]Tert-butyl carbamate (12.1 g; 60.0 mmol) and 2, 6-lutidine (9.6 g; 90.0 mmol) in dry dichloromethane (300 mL) were dissolved in ice. The stirred reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was extracted with water, ice-cold 1N HCl, half-saturated brine and MgSO4And (5) drying. After filtration through a pad of neutral alumina (act. 2-3), the solvent was removed under reduced pressure to give the crude title compound as a yellow oil, which was used without additional purification.
Example C5 [ (1S,3S) -3-azidocyclopentyl ] carbamic acid tert-butyl ester
The crude product of example C4 was dissolved in anhydrous DMF (180 mL). After addition of sodium azide (11.7 g; 180.0 mmol), the reaction mixture was stirred at 60 ℃ for three days. After filtration, the reaction mixture was concentrated under reduced pressure, diluted with dichloromethane, extracted with water, half-saturated brine, and extracted with MgSO4And (5) drying. After column chromatography on silica gel (cyclohexane/AcOEt-9: 1), 11.8 g of the title compound are obtained as a pale yellow oil.
1H-NMR(300 MHz, DMSO-d6) 6.90(d, J =6.2, 1H, -NH), 4.11(m, 1H), 3.88(m, 1H), 2.08-1.77(m, 3H), 1.70(m, 1H), 1.60-1.31(m, 2H and s, 9H).
Example C6 [ (1S,3S) -3-Aminocyclopentyl ] carbamic acid tert-butyl ester hydrochloride
Reacting [ (1S,3S) -3-azido cyclopentyl]Tert-butyl carbamate (example C5; 11.3 g; 50.0 mmol) was dissolved in MeOH (250 mL) and washed with Pd (OH) at room temperature and 20 bar2(20% on charcoal; 0.45 g) was hydrogenated under pressure overnight. After filtration through a celite pad, the solvent was removed under reduced pressure. The residue was dissolved in tert. -BuOMe (250 mL) cooled to 0 ℃ and treated with HCl (4N in dioxane; 13.5 mL). The precipitate was collected by suction filtration, washed with several aliquots of tert. -BuOMe and dried under reduced pressure to yield 11.1 g of the title compound as an off-white solid.
1H-NMR(300 MHz, DMSO-d6): 8.26-7.08(br.s, 3H,-NH3 +); 6,95(d, J=6,9, 1H,-NH); 3,95(m, 1H); 3,52(m, 1H); 1,98(m, 2H); 1,77(m, 2H); 1,43(m, 2H); 1,38(s, 9H)。
Example C7 [ (1R) *,3S*,4R*) -4- (benzyloxy) -3-methylcyclohexyl]Carbamic acid tert-butyl ester
Will be known as (1R)*,2S*,4R*) -4-azido-2-methylcyclohexylbenzyl ether (12.0 g; 48.9 mmol) [ Aicher,T.；Chicarelli，M.J.；Hinklin，R.J.；Tian，H.；Wallace，O.B.；Chen，Z.；Mabry，T.E.；McCowan，J.R.；Snyder，N.J.；Winneroski，L.L.；Allen，J.G.；WO 2006/049952(2009)]dissolved in MeOH (500.0 mL) and hydrogenated under pressure over Pd (10% on charcoal; 1.2 g) at 20 bar and room temperature for two hours. The catalyst was removed by filtration through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in dioxane (100 mL). After addition of 2N NaOH (25.0 mL; 50.0 mmol) and di-tert-butyl dicarbonate (11.4 g; 51.3 mmol), the mixture was stirred at room temperature for one hour and concentrated under reduced pressure. After addition of water, extraction with tert-BuOMe and MgSO4The organic layer was dried. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel (cyclohexane/AcOEt-9: 1) to give 14.4 g of the title compound as a colourless oil.
1H-NMR(300 MHz, CDCl3) 7.35-7.21(m, 5H), 4.59(d, J =12.1, 1H), 4.36(d, J =12.1, 1H and br.s, 1H, -NH), 3.55-3.35(m, 2H), 2.08(m, 1H), 1.79-1.57(m, 3H), 1.44(s, 9H), 1.42-1.21(m, 3H), 0.99(d, J =6.6, 3H).
Example C8 [ (1R)*,3R*,4S*) -4-hydroxy-3-methylcyclohexyl]Carbamic acid tert-butyl ester
Dissolve [ (1R) in MeOH (440 mL)*,3S*,4R*) -4- (benzyloxy) -3-methylcyclohexyl]Tert-butyl carbamate (example C7; 14.0 g; 43.8 mmol) was hydrogenated under pressure over Pd (10% on charcoal; 1.4 g) at 50 bar and room temperature for 72 h. The catalyst was removed by filtration through a pad of celite. The filtrate was concentrated under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/AcOEt-70: 30 to 50:50) to give 8.5 g of the title compound as a colourless oil.
1H-NMR(300 MHz, CDCl3): 4.42(br.s, 1H,-NH); 3.76(m, 1H); 3.46(m, 1H); 1.89(m, 1H); 1.80-1.33(m, 6H); 1.45(s, 9H); 1.23(m, 1H); 0.98(d, J=6.8, 3H)。
Example C9: (1S)*,2R*,4R*) -4- [ (tert-butoxycarbonyl) amino group]-2-methylcyclohexylmethanesulfonate
From [ (1R)*,3R*,4S*) -4-hydroxy-3-methylcyclohexyl]Starting from tert-butyl carbamate (example C8; 10.2 g; 44.3 mmol), 12.3 g of the title compound are obtained as a colorless oil after chromatography on a silica gel column (cyclohexane/AcOEt-70: 30) as described in example C4.
1H-NMR(300 MHz, CDCl3) 4.74(br.s, 1H), 4.42(br.s, 1H, -NH), 3.51(m, 1H), 3.01(s, 3H), 2.24(m, 1H), 1.93-1.56(m, 4H), 1.44(s, 9H and m, 1H), 1.20(m, 1H), 1.03(d, J =6.6, 3H).
Example C10 [ (1R)*,3R*,4R*) -4-azido-3-methylcyclohexyl]Carbamic acid tert-butyl ester
From (1S)*,2R*,4R*) -4- [ (tert-butoxycarbonyl) amino group]Starting from 2-methylcyclohexylmethylsulphonate (example C9; 2.4 g; 7.8 mmol), 1.4 g of the title compound are obtained after chromatography on a silica gel column (cyclohexane/AcOEt-95: 05 to 85:15) as described in example C5 as a colourless solid.
1H-NMR(300 MHz, CDCl3) 4.35(br.s, 1H, -NH), 3.46(m, 1H), 2.782.78 (m, 1H), 2.18-1.95(m, 3H), 1.63-1.33(s, 9H and m, 2H), 1.17(m, 1H), 1.03(d, J =6.6, 3H), 0.90(m, 1H).
Example C11 [ (1R)*,3R*,4R*) -4-amino-3-methylcyclohexyl group]Carbamic acid tert-butyl ester
Will [ (1R) *,3R*,4R*) -4-azido-3-methylcyclohexyl]Carbamic acid tert-butyl ester (examples)Example C10; 1.2 g; 4.7 mmol) in MeOH (20.0 mL) and purified over Pd (10% on charcoal at 20 bar and room temperature; 0.1 g) was hydrogenated under pressure overnight. After filtration through a celite pad, the solvent was removed under reduced pressure to obtain 1.0 g of the title compound as a white solid.
1H-NMR(300 MHz, CDCl3, MeOH-d4): 3.41(m, 1H); 2.20(m, 1H); 2.03-1.81(m, 3H); 1.44(s, 9H); 1.34-1.07(m, 3H); 0.98(d, J=6.6, 3H); 0.91(m, 1H)。
HR-MS(ESI): m/z=229.1899([MH]+, C12H25N2O2 +Calculating the value: 229.1911).
Example C12: (1R)*,3R*,4R*) -4-azido-3-methylcyclohexylamine hydrochloride
Will [ (1R)*,3R*,4R*) -4-azido-3-methylcyclohexyl]Tert-butyl carbamate (example C10; 2.5 g; 10.0 mmol) was dissolved in THF (25.0 mL). After addition of HCl (4M solution in dioxane; 10.0 mL; 40.0 mmol), the reaction mixture was stirred at room temperature overnight and refluxed gently for an additional 6 hours. tert-BuOMe was added at room temperature and the precipitated product was collected by suction filtration, washed with several small portions of tert-BuOMe and dried under reduced pressure to give 1.8 g of the title compound as a colorless solid.
1H-NMR(400 MHz, MeOH-d4): 3.16(m, 1H); 2.95(m, 1H); 2.19(m, 1H); 2.11(m, 1H); 2.03(m, 1H); 1.60-1.44(m, 3H); 1.23(m, 1H); 1.10(d, J=6.5, 3H)。
HR-MS(ESI): m/z=155.1284([MH]+, C7H15N4 +Calculating the value: 155.1291).
Example C13 tert-butyl (diphenyl) ({4- [ (trimethylsilyl) oxy ] cyclohex-3-en-1-yl } oxy) silane
Trimethylsilyltriflate (45.0 g; 198.8 mmol) was added dropwise to the known 4{ [ tert-butyl (diphenyl) silyl ester at-78 ℃ under a nitrogen atmosphere ]Oxy } cyclohexanone [ Okamura, w.h.; elnagar, h.y.; ruther, m.; chem. 1993, 58, 600, Dobreff, s.j. org.chem.](58.4 g, 165.5 mmol) and triethylamine (55.4 mL; 397.6 mmol) in dichloromethane (500 mL). After one hour, the reaction mixture was warmed to 0 ℃ and saturated NaHCO was used3The solution (120 mL) was quenched. Separating the organic layer with MgSO4Drying, and concentrating under reduced pressure. A1: 1 mixture of tert-BuOMe and hexane was added to the biphasic residue. The organic layer was separated and washed with saturated NaHCO3The solution was washed and MgSO4And (5) drying. The solvent was removed under reduced pressure to give 69.0 g of the title compound as a colorless oil.
1H-NMR(300 MHz, CDCl3): 7.64(m, 4H); 7.45-7.32(m, 6H); 4.64(m, 1H); 3.93(m, 1H); 2.23-2.05(m, 3H); 1.99-1.85(m, 1H); 1.81-1.62(m, 2H); 1.05(s, 9H); 0.16(s, 9H)。
Example C14: (2S)*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Oxy } -2-fluorocyclohexanone and (2R)*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Oxy } -2-fluorocyclohexanone
To tert-butyl (diphenyl) ({4- [ (trimethylsilyl) oxy) at 5 ℃ C]Cyclohex-3-en-1-yl } oxy) silane (example C13; 69.0 g; 162 mmol) of anhydrous acetonitrile (750 mL) into a small portion of a stirred solution of Selectfluor (68.6 g; 184 mmol). After the addition was complete, the reaction mixture was stirred at room temperature overnight. Adding saturated NaHCO3The solution (200 mL) was filtered to remove the precipitate, and the filtrate was concentrated under reduced pressure. The residue was taken up in tert-BuOMe and saturated NaHCO 3The solutions were partitioned. The organic layer was separated, washed with brine, and MgSO4And (5) drying. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel (cyclohexane/AcOEt-10: 0 to 9:1) to give 44.9 g of (2S*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Oxy } -2-fluorocyclohexanone as a white solid
1H-NMR(300 MHz, CDCl3): 7.67(m, 4H); 7.50-7.34(m, 6H); 5.41(ddd, J=48.7, 12.2, 6.8, 1H); 4.33(m, 1H); 2.93(td, J=13.9, 6.0, 1H); 2.56-2.34(m, 2H); 2.05-1.93(m, 1H); 1.81(m, 1H); 1.69(tdd, J=13.9, 4.6, 2.4, 1H); 1.12(s, 9H)
And 9.3 g (2R)*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Oxy } -2-fluorocyclohexanone as a white solid
1H-NMR(300 MHz, CDCl3): 7.68(m, 4H); 7.49-7.36(m, 6H); 4.68(ddd, J=48.0, 12.4, 7.3, 1H); 4.08(m, 1H); 2.54(m, 1H); 2.40(m, 1H); 2.16-1.96(m, 3H); 1.89-1.73(m, 1H); 1.06(s, 9H)。
Example C15: (1R)*,2S*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Oxy } -2-fluorocyclohexanol
L-Selectride (1M in THF; 69.0 mL; 69.0 mm0L) was added dropwise to (2S) at-15 ℃*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Oxy } -2-fluorocyclohexanone (example C14; 23.3 g; 62.8 mmol) in dry THF (230 mL) was stirred. The reaction mixture was stirred overnight and cooled to 0 ℃, then ice-cold water (100 mL) was carefully added, followed by dropwise addition of H2O2(30% aqueous solution; 39.0 mL). After 30 minutes, saturated Na was added dropwise at 0 deg.C2SO3Solution (80 mL). tert-BuOMe (300 mL) was added, the organic layer was separated and concentrated under reduced pressure. The aqueous layer was extracted with tert-BuOMe. All combined organic phases were washed with brine, over MgSO4And (5) drying. The solvent was removed under reduced pressure. Chromatography of the residue on silica gel (cyclohexane/AcOEt-10: 0 to 9:1) gave 15.5 g of the title compound as a colorless liquid.
1H-NMR(300 MHz, DMSO-d6): 7.59(m, 4H); 7.44(m, 6H); 4.77(d, J=4.7, 1H,-OH); 4.70(tdd, J=49.5, 7.1, 2.7, 1H); 3.97(m, 1H); 3.70(m, 1H); 1.98(m, 1H); 1.75-1.53(m, 3H); 1.40(m, 2H); 1.01(s, 9H)。
Example C16: (1R)*,2S*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Oxy } -2-fluorocyclohexylmethanesulfonate
From (1R)*,2S*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Starting from oxy } -2-fluorocyclohexanol (example C15; 10.4 g; 27.8 mmol), 12.2g of the title compound are obtained as a pale yellow oil after chromatography on a silica gel column (cyclohexane/AcOEt-90: 10 to 80:20) as described in example C4.
1H-NMR(300 MHz, CDCl3): 7.62(m, 4H); 7.43(m, 6H); 5.16-4.91(m, 2H); 4.20(m, 1H); 3.02(s, 3H); 2.17-1.-84(m, 4H); 1.69(m, 1H); 1.49(m, 1H); 1.07(s, 9H)。
Example C17: { [ (1R)*,3S*,4S*) -4-azido-3-fluorocyclohexyl]Oxy } (tert-butyl) diphenylsilane
From (1R)*,2S*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Starting from oxy } -2-fluorocyclohexylmethanesulfonate (example C16; 12.1 g; 26.8 mmol), 9.4g of the title compound are obtained as a colorless oil after chromatography on a silica gel column (cyclohexane/AcOEt-95: 05) as described in example C5.
1H-NMR(300 MHz, CDCl3): 7.63(m, 4H); 7.39(m, 6H); 4.84(dm, J=50.3, 1H); 4.15(m, 1H); 3.45(m, 1H); 2.16(m, 1H); 1.99-1.75(m, 2H); 1.65(m, 1H); 1.49(m, 1H); 1.33(m, 1H); 1.07(s, 9H)。
Example C18 [ (1S)*,2S*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Oxy } -2-fluorocyclohexyl radical]Carbamic acid tert-butyl ester
From { [ (1R)*,3S*,4S*) -4-azido-3-fluorocyclohexyl]Starting from oxy } (tert-butyl) diphenylsilane (example C17; 9.4 g; 23.6 mmol), 8.7g of the title compound are obtained as a colorless solid after chromatography on a silica gel column (cyclohexane/AcOEt-95: 05) as described in example C7.
1H-NMR(300 MHz, DMSO-d6) 7.60(m, 4H), 7.46(m, 6H), 7.11(d, J =8.4, 1H, -NH), 4.73(tdd, J =50.4, 10.4, 4.6, 1H), 4.09(m, 1H), 3.44(m, 1H), 1.98(m, 1H), 1.76(m, 1H), 1.67-1.46(m, 3H), 1.39(s, 9H and m, 1H), 1.03(s, 9H).
Example C19 [ (1S)*,2S*,4R*) -2-fluoro-4-hydroxycyclohexyl]Carbamic acid tert-butyl ester
Tetrabutylammonium fluoride trihydrate (11.9 g; 36.7 mmol) is added to [ (1S)*,2S*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Oxy } -2-fluorocyclohexyl radical]Tert-butyl carbamate (example C18; 8.7 g; 18.3 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/AcOEt-60: 40 to 40:60) to give 4.2 g of the title compound as a colourless oil.
1H-NMR(300 MHz, DMSO-d6) 6.91(d, J =8.0, 1H, -NH), 4.57(d, J =2.7, 1H, -OH), 4.56(dm, J =50.4, 1H), 3.94(m, 1H), 3.41(m, 1H), 2.03(m, 1H), 1.64-1.50(m, 4H), 1.50-1.32(s, 9H and m, 1H).
Example C20: (1R)*,3S*,4S*) -4- [ (tert-butoxycarbonyl) amino group]-3-fluorocyclohexylmethanesulfonate
From [ (1S)*,2S*,4R*) -2-fluoro-4-hydroxycyclohexyl]Starting from tert-butyl carbamate (example C19; 5.9 g; 25.5 mmol), 6.6 g of the title compound are obtained as a colorless solid after chromatography on silica gel (cyclohexane/AcOEt-60: 40 to 50:50) as described in example C4.
1H-NMR(300 MHz, CDCl3) 5.05(m, 1H), 4.61(br.s, 1H, -NH and dm, J =48.9, 1H), 3.72(m, 1H), 3.02(s, 3H), 2.40(m, 1H), 2.09(m, 1H), 1.96(m, 2H), 1.79(m, 1H), 1.64(m, 1H), 1.45(s, 9H).
Example C21 [ (1S)*,2S*,4S*) -4-azido-2-fluorocyclohexyl]Carbamic acid tert-butyl ester
From (1R)*,3S*,4S*) -4- [ (tert-butoxycarbonyl) amino group]Starting from 3-fluorocyclohexylmethanesulfonate (example C20; 5.3 g; 17.0 mmol), 4.0 g of the title compound are obtained as a colorless solid after chromatography on silica gel (cyclohexane/AcOEt-60: 40) as described in example C5.
1H-NMR(300 MHz, CDCl3) 4.45(br.s, 1H, -NH), 4.25(dm, J =49.7, 1H), 3.55(m, 1H), 3.35(m, 1H), 2.46(m, 1H), 2.21(m, 1H), 1.99(m, 1H), 1.64(m, 1H), 1.45(s, 9H and m, 1H), 1.23(m, 1H).
Example C22 [ (1S)*,2S*,4S*) -4-amino-2-fluorocyclohexyl]Carbamic acid tert-butyl ester
From [ (1S)*,2S*,4S*) -4-azido-2-fluorocyclohexyl]Starting from tert-butyl carbamate (example C21; 2.0 g; 7.7 mmol) the method described in example C11 is followed to yield 1.7 g of the title compound as a colorless solid.
HR-MS(ESI): m/z=233.1651([MH]+, C11H22FN2O2 +Calculating the value: 233.1659).
Example C23: (1S)*,2S*,4S*) -4-azido-2-fluorocyclohexylamine hydrochloride
From [ (1S)*,2S*,4S*) -4-azido-2-fluorocyclohexyl]Starting from tert-butyl carbamate (example C21; 1.9 g; 7.5 mmol) the method described in example C12 is followed to yield 1.4 g of the title compound as a colorless solid.
HR-MS(ESI): m/z=159.1038([MH]+, C6H13FN4 +Calculating the value: 159.1040).
Example C24: (1S) *,2S*,4S*) -4- (benzyloxy) -2-methylcyclopentanol
A stirred suspension of CuCN (8.9 g; 100.0 mmol) in dry THF (100.0 mL) was cooled to-78 deg.C, after which MeLi (1.6M solution in Et) was added2O is in; 125.0 mL; 200.0 mmol). The mixture was warmed to room temperature and re-cooled to-78 ℃ before the known cis-3- (benzyloxy) -6-oxabicyclo [3.1.0 ] was added dropwise]Hexane (9.5 g; 50.0 mmol) [ Snider, B.B.; liu, t.j. org. chem. 2000, 65, 8490; mille, d.; murphy, P.J.J.chem.Soc. Chemical Communication 1993, 884]]Is then added dropwise to a solution of anhydrous THF (100 mL) followed by the addition of BF dropwise3Ether compound (6.8 mL; 55.0 mmol). The cooled reaction mixture was stirred overnight, warmed to 0 ℃ and quenched with 25% NH containing 10% (v/v)4Saturated NH of aqueous OH solution4Cl solution (250 mL). The organic layer was separated and concentrated under reduced pressure. The aqueous layer was extracted with tert-BuOMe. All organic phases were combined, washed with brine, and MgSO4Drying, and concentrating under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/tert-BuOMe-80: 20 to 50:50) to give 7.6 g of the title compound as a pale yellow oil.
1H-NMR(300 MHz, DMSO-d6): 7.31(m, 5H); 4.62(d, J=5.3, 1H,-OH); 4.38(s, 2H); 3.87(m, 1H); 3.39(m, 1H); 2.26(m, 1H); 1.84(m, 2H); 1.47(m, 1H); 1.30(m, 1H); 0.93(d, J=6.2, 3H)。
Example C25: (1R)*,2S*,4S*) -4- (benzyloxy) -2-methylcyclopentyl 3-nitrobenzoate
To cold (1S) *,2S*,4S*) -4- (benzyloxy) -2-methylcyclopentanol (example C24; 7.5 g; 36.5 mmol), 3-nitrobenzoic acid (18.4 g; 110.0 mmol) and triphenylphosphine (23.0 g; 87.6 mmol) was added dropwise to a stirred solution of diethyl azodicarboxylate (40% solution in toluene; 38.1 g; 87.6 mmol). The reaction mixture was stirred at room temperature for two hours and concentrated under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/tert-BuOMe-100: 0 to 80:20) to give 11.5 g of the title compound as a pale yellow oil.
1H-NMR(300 MHz, DMSO-d6): 8.61(~s, 1H); 8.49(m, 1H); 8.37(m, 1H); 7.84(t, J=8.0, 1H); 7.33(m, 5H); 5.41(m, 1H); 4.44(d, J=1.5, 2H); 4.20(m, 1H); 2.43(m, 1H); 2.18(m, 2H); 2.00(m, 1H); 1.73(m, 1H); 1.00(d, J=6.7, 3H)。
Example C26: (1R)*,2S*,4S*) -4- (benzyloxy) -2-methylcyclopentanol
To (1R)*,2S*,4S*) -4- (benzyloxy) -2-methylcyclopentyl 3-nitrobenzoate (example 25; 11.5 g; 32.5 mmol) in THF (80.0 mL) and MeOH (40.0 mL) was added LiOH (1.17 g; 48.7 mmol). The reaction mixture was stirred at room temperature for one hour and concentrated under reduced pressure. The residue was diluted with water and extracted with dichloromethane. With MgSO4The organic layer was dried and concentrated under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/tert-BuOMe-80: 20 to 50:50),5.9 g of the title compound are obtained as a pale yellow oil.
1H-NMR(300 MHz, DMSO-d6): 7.30(m, 5H); 4.37(s, 2H); 4.28(d, J=4.2, 1H,-OH); 4.07(m, 1H); 3.97(m, 1H); 2.08-1.86(m, 2H); 1.84-1.68(m, 2H); 1.54(m, 1H); 0.90(d, J=6.8, 3H)。
Example C27: (1R)*,2S*,4S*) -4- (benzyloxy) -2-methylcyclopentyl methanesulfonate
From (1R)*,2S*,4S*) -4- (benzyloxy) -2-methylcyclopentanol (example C26; 5.9 g; 28.4 mmol) were obtained following silica gel column chromatography (cyclohexane/tert-BuOMe-90: 10 to 65:35) as described in example C4 to yield 7.5g of the title compound as a pale yellow oil.
1H-NMR(300 MHz, DMSO-d6): 7.32(m, 5H); 5.02(m, 1H); 4.40(d, J=2.2, 2H); 4.14(m, 1H); 3.14(s, 3H); 2.39-2.24(m, 2H); 2.08(m, 1H); 1.91(m, 1H); 1.52(m, 1H); 0.99(d, J=6.7, 3H)。
Example C28: (1S)*,2S*,4S*) -1-azido-4- (benzyloxy) -2-methylcyclopentane
From (1R)*,2S* ,4S*) -4- (benzyloxy) -2-methylcyclopentyl methanesulfonate (example C27; 7.4 g; 26.5 mmol) and following column chromatography on silica gel (cyclohexane/tert-BuOMe-90: 10 to 65:35) as described in example C5, 5.6 g of the title compound are obtained as a pale yellow oil.
1H-NMR(300 MHz, DMSO-d6): 7.32(m, 5H); 4.41(s, 2H); 3.97(m, 1H); 3.38(m, 1H); 2.40(m, 1H); 2.11-1.90(m, 2H); 1.65(m, 1H); 1.39(m, 1H); 1.02(d, J=6.4, 3H)。
Example C29 [ (1S)*,2S*,4S*) -4- (benzyloxy) -2-methylcyclopentyl]Carbamic acid tert-butyl ester
From (1S)*,2S*,4S*) -1-azido-4- (benzyloxy) -2-methylcyclopentane (example C28; 4.9 g; 24.0 mmol) and following column chromatography on silica gel (cyclohexane/tert-BuOMe-95: 05 to 70:30) as described in example C7, 5.5 g of the title compound are obtained as a pale yellow oil.
1H-NMR(300 MHz, DMSO-d6) 7.31(m, 5H), 6.74(d, J =8.2, 1H, -NH), 4.37(s, 2H), 3.90(m, 1H), 3.26(m, 1H), 2.27(m, 1H), 1.87(m, 2H), 1.46(m, 1H), 1.37(s, 9H and m, 1H), 0.90(d, J =6.0, 3H).
Example C30 [ (1S)*,2S*,4S*) -4-hydroxy-2-methylcyclopentyl ]Carbamic acid tert-butyl ester
From [ (1S)*,2S*,4S*) -4- (benzyloxy) -2-methylcyclopentyl]Starting from tert-butyl carbamate (example C29; 5.4 g; 18.1 mmol) according to the method described in example C8, 3.9 g of the title compound are obtained as a pale yellow oil.
1H-NMR(300 MHz, DMSO-d6): 6.64(d, J=8.0, 1H,-NH); 4.47(d, J=4.0, 1H,-OH); 4.03(m, 1H); 3.21(m, 1H); 2.15(m, 1H); 1.89(m, 1H); 1.64(m, 1H); 1.37(s, 9H); 1.31(m, 2H); 0.89(d, J=6.6, 3H)。
Example C31: (1S)*,3S*,4S*) -3- [ (tert-butoxycarbonyl) amino group]-4-methylcyclopentyl methanesulfonate
From [ (1S)*,2S*,4S*) -4-hydroxy-2-methylcyclopentyl]Starting from tert-butyl carbamate (example C30; 3.9 g; 18.0 mmol), chromatography on silica gel column as described in example C4After this time (cyclohexane/tert-BuOMe-90: 10 to 60:40), 4.8 g of the title compound are obtained as a colorless solid.
1H-NMR(300 MHz, DMSO-d6): 6.89(d, J=7.9, 1H,-NH); 4.99(m, 1H); 3.29(m, 1H); 3.12(s, 3H); 2.45(m, 1H); 2.09-1.84(m, 2H); 1.69-1.50(m, 2H); 1.38(s, 9H); 0.93(d, J=6.2, 3H)。
Example C32 [ (1S)*,2S*,4R*) -4-azido-2-methylcyclopentyl]Carbamic acid tert-butyl ester
From (1S)*,3S*,4S*) -3- [ (tert-butoxycarbonyl) amino group]Starting from 4-methylcyclopentyl methanesulfonate (example C31; 4.8 g; 16.0 mmol), 3.7 g of the title compound were obtained as a colorless oil after chromatography on a silica gel column (cyclohexane/tert-BuOMe-90: 10 to 80:20) as described in example C5.
1H-NMR(300 MHz, DMSO-d6): 6.82(d, J=8.0, 1H,-NH); 4.03(m, 1H); 3.42(m, 1H); 2.22(m, 1H); 1.87(m, 1H); 1.79-1.64(m, 2H); 1.38(s, 9H); 1.15(m, 1H); 0.96(d, J=6.2, 3H)。
Example C33 [ (1S)*,2S*,4R*) -4-amino-2-methylcyclopentyl]Carbamic acid tert-butyl ester
From [ (1S)*,2S*,4R*) -4-azido-2-methylcyclopentyl]Starting from tert-butyl carbamate (example C32; 1.6 g; 6.8 mmol) according to the method described in example C11, 1.4 g of the title compound are obtained as colorless oil.
1H-NMR(300 MHz, DMSO-d6): 6.64(d, J=7.7, 1H,-NH); 3.45(m, 1H); 3.29(br.s, 2H,-NH2); 3.21(m, 1H); 1.99(m, 1H); 1.71-1.50(m, 3H); 1.37(s, 9H); 0.93(d, J=6.6, 3H); 0.83(m, 1H)。
Example C34: (1S)*,2S*,4R*) -4-azido-2-methylcyclopentylamine hydrochloride
From [ (1S)*,2S*,4R*) -4-azido-2-methylcyclopentyl]Starting from tert-butyl carbamate (example C32; 3.6 g; 15.0 mmol) according to the method described in example C12, 2.4 g of the title compound are obtained as a colorless solid.
1H-NMR(300 MHz, DMSO-d6): 8.27(br.s, 3H,-NH3 +); 4.20(m, 1H); 3.12(m, 1H); 2.29(m, 1H); 2.13-1.94(m, 3H); 1.26(m, 1H); 1.10(d, J=6.8, 3H)。
HR-MS(ESI): m/z=141.1136([MH]+, C6H13N4 +Calculating the value: 141.1135)
Example C35: (1S)*,2S*,4R*) -4- (benzyloxy) -2-fluorocyclopentanol
The known cis-3- (benzyloxy) -6-oxabicyclo [3.1.0 ]]Hexane (6.1 g; 32.1 mmol) [ Snider, b.b.; liu, t.j. org. chem. 2000, 65, 8490; mille, d.; murphy, P.J.J.chem.Soc. Chemical Communication 1993, 884]And tetrabutylammonium trifluorodihydride (16.3 g; 54.1 mmol) were heated to 150 deg.C overnight. The mixture was diluted with AcOEt and saturated NaHCO3And (4) solution extraction. With MgSO4The organic layer was dried and concentrated under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/AcOEt-10: 0 to 80:29) to give 5.5 g of the title compound as a pale yellow oil.
1H-NMR(300 MHz, DMSO-d6): 7.32(m, 5H); 5.13(d, J=4.6, 1H,-OH); 4.81(dm, J=53.1, 1H); 4.43(s, 2H); 4.11-3.93(m, 2H); 2.32(m, 1H); 2.18-1.88(m, 2H); 1.51(m, 1H)。
Example C36: (1S)*,2R*,4S*) -4- (benzyloxy) -2-fluorocyclopentyl 3-nitrobenzoate
From (1S)*,2S*,4R*) -4- (benzyloxy) -2-fluorocyclopentanol (example C35; 6.5 g; 30.9 mmol) was carried out as described in example C25 to obtain 7.3 g of the title compound as a pale yellow oil.
1H-NMR(300 MHz, DMSO-d6): 8.63(m, 1H); 8.52(m, 1H); 8.39(m, 1H); 7.86(t, J=8.0, 1H); 7.40-7.24(m, 5H); 5.50-5.21(m, 2H); 4.48(s, 2H); 4.30(m, 1H); 2.46-2.04(m, 4H)。
Example C37: (1S)*,2R*,4S*) -4- (benzyloxy) -2-fluorocyclopentanol
From (1S)*,2R*,4S*) -4- (benzyloxy) -2-fluorocyclopentyl 3-nitrobenzoate (example C36; 7.3 g; 20.0 mmol) of the title compound were obtained as a colorless oil in the manner described in example C26.
1H-NMR(300 MHz, DMSO-d6): 7.31(m, 5H); 4.91(d, J=5.8, 1H,-OH); 4.83(dm, J=54.7, 1H); 4.39(s, 2H); 4.18-3.99(m, 2H); 2.20(m, 1H); 2.00-1.75(m, 3H)。
Example C38: (1S)*,2R*,4S*) -4- (benzyloxy) -2-fluorocyclopentyl methanesulfonate
From (1S)*,2R*,4S*) -4- (benzyloxy) -2-fluorocyclopentanol (example C37; 3.8 g; 17.9 mmol) was carried out as described in example C4 to obtain 5.1 g of the title compound as a pale yellow oil.
1H-NMR(300 MHz, DMSO-d6): 7.33(m, 5H); 5.32-5.01(m, 2H); 4.43(d, J=1.8, 2H); 4.22(m, 1H); 3.24(s, 3H); 2.40-1.91(m, 4H)。
Example C39: (1S)*,3R*,4R*) -3-azido-4-fluorocyclopentylbenzyl ether
From (1S)*,2R*,4S*) -4- (benzyloxy) -2-fluorocyclopentyl methanesulfonate (example C38; 5.1 g; 17.7 mmol) was carried out as described in example C5 to obtain 3.5 g of the title compound as a colorless oil.
1H-NMR(300 MHz, DMSO-d6): 7.32(m, 5H); 5.03(dm, J=53.1, 1H); 4.44(s, 2H); 4.22-4.07(m, 2H); 2.44(m, 1H); 2.16(m, 1H); 2.08(m, 1H); 1.72(m, 1H)。
Example C40 [ (1R)*,2R*,4S*) -4- (benzyloxy) -2-fluorocyclopentyl group]Carbamic acid tert-butyl ester
From (1S)*,3R*,4R*) -3-azido-4-fluorocyclopentylbenzyl ether (example C39; 4.5 g; 19.0 mmol) was carried out as described in example C7 to obtain 5.2 g of the title compound as a colorless solid.
1H-NMR(300 MHz, DMSO-d6): 7.32(m, 5H); 6.95(br.d, J=6.8, 1H,-NH); 4.87(dm, J=53.3, 1H); 4.43(s, 2H); 4.05(m, 1H); 3.83(m, 1H); 2.32(m, 1H); 2.18-1.89(m, 2H); 1.53(m, 1H); 1.38(s, 9H)。
Example C41 [ (1R)*,2R*,4S*) -2-fluoro-4-hydroxycyclopentyl radical]Carbamic acid tert-butyl ester
From [ (1R)*,2R*,4S*) -4- (benzyloxy) -2-fluorocyclopentyl group ]Starting from tert-butyl carbamate (example C40; 5.2 g; 16.9 mmol) according to the method described in example C8, there are obtained3.5 g of the title compound are obtained as a colorless solid.
1H-NMR(300 MHz, DMSO-d6) 6.86(br.d, J =7.1, 1H, -NH), 4.86(d, J =3.7, 1H, -OH), 4.84(dm; J =53.1, 1H), 4.15(m, 1H), 3.79(m, 1H), 2.19(m, 1H), 2.07-1.71(m, 2H), 1.38(s, 9H and m, 1H).
Example C42: (1S)*,3R*,4R*) -3- [ (tert-butoxycarbonyl) amino group]-4-fluorocyclopentyl methanesulfonate
From [ (1R)*,2R*,4S*) -2-fluoro-4-hydroxycyclopentyl radical]Starting from tert-butyl carbamate (example C41; 3.5 g; 16.0 mmol) according to the method described in example C4, 4.4 g of the title compound are obtained as a colorless solid.
1H-NMR(300 MHz, DMSO-d6): 7.13(br.d, J=6.6, 1H,-NH); 5.09(m, 1H); 4.93(dm; J=52.8, 1H); 3.87(m, 1H); 3.18(s, 3H); 2.52(m, 1H); 2.38-2.10(m, 2H); 1.74(m, 1H); 1.39(s, 9H)。
Example C43 [ (1R)*,2R*,4R*) -4-azido-2-fluorocyclopentyl group]Carbamic acid tert-butyl ester
From (1S)*,3R*,4R*) -3- [ (tert-butoxycarbonyl) amino group]Starting from-4-fluorocyclopentyl methanesulfonate (example C42; 4.4 g; 14.8 mmol), following the method described in example C5, 3.5 g of the title compound are obtained as a colorless solid.
1H-NMR(300 MHz, DMSO-d6): 7.07(br.d, J=5.8, 1H,-NH); 4.85(dm; J=52.8, 1H); 4.20(m, 1H); 3.98(m, 1H); 2.36(m, 1H); 1.97(m, 1H); 1.92-1.73(m, 2H); 1.39(s, 9H)。
Example C44 [ (1R)*,2R*,4R*) -4-amino-2-fluorocyclopentyl group]Carbamic acid tert-butyl ester
From [ (1R)*,2R*,4R*) -4-azido-2-fluorocyclopentyl group]Starting from tert-butyl carbamate (example C43; 1.7 g; 7.0 mmol) according to the method described in example C11, 1.5 g of the title compound are obtained as a colorless solid.
1H-NMR(300 MHz, DMSO-d6, MeOH-d4): 4.76(dm; J=52.8, 1H); 4.04(m, 1H); 3.31(m, 1H); 2.23(m, 1H); 1.67(m, 2H); 1.48(m, 1H); 1.39(s, 9H)。
HR-MS(ESI): m/z=219.1495([MH]+, C10H20FN2O2 +Calculating the value: 219.1503).
Example C45: (1R)*,2R*,4R*) -4-azido-2-fluorocyclopentamine hydrochloride
From [ (1R)*,2R*,4R*) -4-azido-2-fluorocyclopentyl group]Starting from tert-butyl carbamate (example C43; 1.8 g; 7.5 mmol), following the method described in example C12, 1.3 g of the title compound are obtained as a colorless solid.
1H-NMR(300 MHz, DMSO-d6): 8.54(br.s, 3H,-NH3 +); 5.19(dm; J=52.4, 1H); 4.34(m, 1H); 3.75(m, 1H); 2.49(m, 1H); 2.17(m, 1H); 2.06-1.88(m, 2H)。
HR-MS(ESI): m/z=145.0888([MH]+, C5H10FN4 +Calculating the value: 145.0884).
Example C46: (1S)*,2R*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Oxy } -2-fluorocyclohexanol
From ((2R)*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Starting from oxy } -2-fluorocyclohexanone (example C14; 18.7 g; 50.4 mmol), 17.9 g of the title compound are obtained as a colorless oil after chromatography on a silica gel column (cyclohexane/AcOEt-100: 0 to 85:15) as described in example C15.
1H-NMR(300 MHz, CDCl3) 7.67(m, 4H), 7.38(m, 6H), 4.31(dddd, J =47.1, 10.7, 4.8, 2.9, 1H), 3.94(m, 1H), 3.61(m, 1H), 2.14-1.67(m, 4H and 1H, -OH), 2.92(m, 1H), 1.20(m, 1H), 1.05(s, 9H).
Example C47: (1R)*,2R*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Oxy } -2-fluorocyclohexyl 3-nitrobenzoate
From (1S)*,2R*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Starting from oxy } -2-fluorocyclohexanol (example C46; 17.8 g; 47.9 mmol), 15.8 g of the title compound are obtained as a pale yellow oil after chromatography on a silica gel column (cyclohexane/AcOEt-100: 0 to 85:15) as described in example C25.
1H-NMR(300 MHz, DMSO-d6): 8.60(m, 1H); 8.49(m, 1H); 8.34(m, 1H); 7.83(t, J=8.2, 1H); 7.64(m, 4H); 7.46(m, 6H); 5.09(m, 1H); 4.65(dm, J=50.6, 1H); 3.87(m, 1H); 2.24(m, 1H); 1.97(m, 1H); 1.87-1.50(m, 3H); 1.35(m, 1H); 1.02(s, 9H)。
Example C48: (1R)*,2R*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Oxy } -2-fluorocyclohexanol
From (1R)*,2R*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Starting from oxy } -2-fluorocyclohexyl 3-nitrobenzoate (example C47; 15.8 g; 30.3 mmol), according to the method described in example C26, after chromatography on a silica gel column (cyclohexane/AcOEt-100: 0 to 85:15), 10.9 g of the titled compound are obtainedThe compound was a colorless oil.
1H-NMR(300 MHz, DMSO-d6) 7.61(m, 4H), 7.45(m, 6H), 4.97(d, J =4.7, 1H, -OH), 4.01(dm, J =50.4, 1H), 3.71(m, 1H), 3.40(m, 1H), 2.09(m, 1H), 1.67(m, 2H), 1.53(m, 1H), 1.37(m, 1H), 1.00(s, 9H and m, 1H).
Example C49: (1R)*,2R*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Oxy } -2-fluorocyclohexylmethanesulfonate
From (1R)*,2R*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Starting from oxy } -2-fluorocyclohexanol (example C48; 13.1 g; 35.2 mmol), 14.8 g of the title compound are obtained as a pale yellow oil after chromatography on a silica gel column (cyclohexane/AcOEt-100: 0 to 80:20) as described in example C4.
1H-NMR(400 MHz, DMSO-d6): 7.62(m, 4H); 7.45(m, 6H); 4.63(m, 1H); 4.45(dm, J=50.3, 1H); 3.83(m, 1H); 3.13(s, 3H); 2.19(m, 1H); 1.97(m, 1H); 1.72(m, 2H); 1.51(m, 1H); 1.35(m, 1H); 1.00(s, 9H)。
Example C50: { [ (1R)*,3R*,4S*) -4-azido-3-fluorocyclohexyl]Oxy } (tert-butyl) diphenylsilane
From (1R)*,2R*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Starting from oxy } -2-fluorocyclohexylmethanesulfonate (example C49; 14.7 g; 32.7 mmol), 10.2 g of the title compound are obtained as a colorless oil after chromatography on a silica gel column (cyclohexane/AcOEt-100: 0 to 95:05) as described in example C5.
1H-NMR(300 MHz, CDCl3): 7.66(m, 4H); 7.39(m, 6H); 4.41(dm, J=46.4, 1H); 3.79(m, 1H); 3.60(m, 1H); 2.13-1.81(m, 3H); 1.71-1.46(m, 2H); 1.22(m, 1H); 1.05(s, 9H)。
Example C51 [ (1S)*,2R*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Oxy } -2-fluorocyclohexyl radical]Carbamic acid tert-butyl ester
From { [ (1R)*,3R*,4S*) -4-azido-3-fluorocyclohexyl]Starting from oxy } (tert-butyl) diphenylsilane (example C50; 10.1 g; 25.6 mmol), 10.5 g of the title compound are obtained as a colorless solid after chromatography on a silica gel column (cyclohexane/AcOEt-100: 0 to 95:05) as described in example C7.
1H-NMR(300 MHz, CDCl3): 7.66(m, 4H); 7.39(m, 6H); 4.92(br.s, 1H,-NH); 4.64(dm, J=46.7, 1H); 3.89(m, 1H); 3.66(m, 1H); 2.08(m, 2H); 1.87-1.37(m, 4H); 1.45(s, 9H); 1.06(s, 9H)。
Example C52 [ (1R)*,2S*,4S*) -2-fluoro-4-hydroxycyclohexyl]Carbamic acid tert-butyl ester
From [ (1S)*,2R*,4R*) -4- { [ tert-butyl (diphenyl) silyl]Oxy } -2-fluorocyclohexyl radical]Starting from tert-butyl carbamate (example C51; 10.4 g; 22.0 mmol), according to the method described in example C19, after column chromatography on silica gel (cyclohexane/AcOEt-50: 50), 4.5 g of the title compound are obtained as a colorless oil.
1H-NMR(300 MHz, CDCl3) 4.89(dm, J =48.9, 1H), 4.87(br.s, 1H, -NH), 3.97(m, 1H), 3.66(m, 1H), 2.31(m, 1H), 2.19(m, 1H), 2.01-1.80(m, 2H), 1.78-1.54(m, 2H and 1H, -OH), 1.45(s, 9H).
Example C53: (1S)*,3S*,4R*) -4- [ (tert-butoxycarbonyl) amino group]-3-fluorocyclohexylmethanesulfonate
From [ (1R)*,2S*,4S*) -2-fluoro-4-hydroxycyclohexyl]Starting from tert-butyl carbamate (example C52; 4.4 g; 18.7 mmol), 5.1 g of the title compound are obtained as a pale yellow solid after chromatography on a silica gel column (cyclohexane/AcOEt-50: 50) as described in example C4.
1H-NMR(300 MHz, CDCl3): 4.97(m, 1H); 4.88(br.s, 1H,-NH); 4.80(dm, J=48.9, 1H); 3.68(m, 1H); 3.03(s, 3H); 2.56(m, 1H); 2.19(m, 1H); 2.01-1.63(m, 4H); 1.45(s, 9H)。
Example C54 [ (1R)*,2S*,4R*) -4-azido-2-fluorocyclohexyl]Carbamic acid tert-butyl ester
From (1S)*,3S*,4R*) -4- [ (tert-butoxycarbonyl) amino group]Starting from 3-fluorocyclohexylmethanesulfonate (example C53; 5.0 g; 16.1 mmol), 3.0 g of the title compound are obtained as a colorless solid after chromatography on a silica gel column (cyclohexane/tert-BuOMe-80: 20) as described in example C5.
1H-NMR(300 MHz, CDCl3): 4.86(dm, J=49.5, 1H); 4.77(br.s, 1H,-NH); 3.75-3.51(m, 2H); 2.38(m, 1H); 2.08(m, 1H); 1.90(m, 1H); 1.70-1.37(m, 3H); 1.44(m, 9H)。
Example C55 [ (1R)*,2S*,4R*) -4-amino-2-fluorocyclohexyl]Carbamic acid tert-butyl ester
From [ (1R)*,2S*,4R*) -4-azido-2-fluorocyclohexyl]Starting from tert-butyl carbamate (example C54; 0.72 g; 2.8 mmol) according to the method described in example C11, 0.65 g of the title compound are obtained as off-white solid.
HR-MS(ESI): m/z=233.1665([MH]+, C11H22FN2O2 +Calculating the value: 233.1660).
Example C56: (1R)*,2S*,4R*) -4-azido-2-fluorocyclohexylamine hydrochloride
From [ (1R)*,2S*,4R*) -4-azido-2-fluorocyclohexyl]Starting from tert-butyl carbamate (example C54; 1.29 g; 5.0 mmol) according to the method described in example C12, 0.92 g of the title compound are obtained as off-white solid.
HR-MS(ESI): m/z=159.1036([MH]+, C6H12FN4 +Calculating the value: 159.1041).
Example D.a 1: 4- (5-Cyclopropylmethoxy-benzo [1,3] dioxol-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Ethyl-4-chloro-6-methyl-5H-pyrrolo [3,2-d ] from example A4 under a nitrogen atmosphere ]Pyrimidine-7-carboxylate (11.98 g; 50.0 mmol), dioxane (200 mL) and Cs2CO3(2M aqueous solution; 75.0 mL; 150.0 mmol) is heated to 80 ℃ and Pd (OAc) is added2(247 mg; 1.1 mmol) and tricyclohexylphosphine (617 mg; 2.2 mmol). After 30 minutes, 5-cyclopropylmethoxy-4- (4,4,5, 5-tetramethyl- [1,3,2] of example B.c1 was added]Dioxaborolan-2-yl) -benzo [1,3]A solution of dioxole (17.50 g; 55.0 mmol) in dioxane (50.0 mL) and the reaction mixture was heated to 100 ℃ until the starting material was consumed (according to LC-MS).
The cooled reaction mixture was diluted with water (250 mL), and acidified to pH =6 with careful addition of 2M aqueous citric acid. The precipitated crude product was filtered, dissolved in dioxane and filtered through a short column of neutral alumina containing 5 wt% water. The column was flushed with several portions of dioxane. The filtrate was concentrated under reduced pressure and the product was collected with methyl tert-butyl ether to give the title compound as an off-white solid.
MS(ESI): m/z=396(MH+, 100%); 382。
1H-NMR(300 MHz, DMSO-d6): 12.09(br.s, 1H,-NH); 8.92(s, 1H); 7.00(d, J=8.6, 1H); 6.55(d, J=8.6, 1H); 5.99(s, 2H); 4.31(qu, J=7.1, 2H); 3.75(d, J=6.7, 2H); 2.72(s, 3H); 1.33(t, J=7.1, 3H); 0.88(m, 1H); 0.30(m, 2H); 0.11(m, 2H)。
The following compounds were prepared using a procedure similar to that described in example d.a1 above.
Example D.a 2: 4- (2-Cyclopropylmethoxy-4-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example a4) and 2- (2-cyclopropylmethoxy-4-fluoro-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan (example b. c3), the title compound was obtained as a white solid.
MS(ESI): m/z=392(MNa+); 370(MH+); 356(100 %); 314; 302。
1H-NMR(400 MHz, DMSO-d6): 11.89(br.s, 1H,-NH); 9.19(s, 1H); 7.64(dd, J=8.4, 7.4, 1H); 7.08(dd, J=11.6, 2.1, 1H); 6.95(ddd; J=8.4, 8.4, 2.1, 1H); 4.31(qu, J=6.9, 2H); 3.90(d, J=6.9, 2H); 2.74(s, 3H); 1.34(t, J=6.9, 3H); 0.94(m, 1H); 0.38(m, 2H); 0.24(m, 2H)。
Example D.a 3: 4- (2-Cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example a4) and 2- (2-cyclopropylmethoxy-5-fluoro-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan (example b. c4), the title compound was obtained as a white solid.
MS(ESI): m/z=424(MH+, 100%); 356。
1H-NMR(300 MHz, DMSO-d6): 11.92(br.s, 1H,-NH); 8.96(s, 1H); 7.41(dd, J=9.0, 3.2, 1H); 7.37(ddd, J=9.1, 8.3, 3.2, 1H); 7.18(dd, J=9.1, 4.4, 1H); 4.32(qu, J=7.1, 2H); 3.87(d, J=6.9, 2H); 2.74(s, 3H); 1.34(t, J=7.1, 3H); 0.93(m, 1H); 0.36(m, 2H); 0.21(m, 2H)。
Example D.a 4: 4- (2-ethoxy-5-fluorophenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example a4) and commercially available 2-ethoxy-5-fluoro-phenyl-boronic acid, the title compound was obtained as a light yellow solid.
MS(ESI): m/z=344(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.95(s, 1H,-NH); 8.95(s, 1H); 7.41(ddd, J=8.9, 8.9, 3.3, 1H); 7.37(dd, J=8.2, 3.3, 1H); 7.22(dd, J=8.9, 4.4, 1H); 4.31(qu, J=7.1, 2H); 4.08(qu, J=6.9, 2H); 2.74(s, 3H); 1.34(t, J=7.1, 3H); 1.10(t, J=6.9, 3H)。
Example D.a 5: 4- (2-Cyclopropylmethoxy-4-methoxy-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example a4) and 2- (2-cyclopropylmethoxy-4-methoxy-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan (example b.c. 6), the title compound was obtained as a white solid.
MS(ESI): m/z=404(MNa+); 382(MH+, 100%); 368; 314。
1H-NMR(300 MHz, DMSO-d6): 11.76(br.s, 1H,-NH); 8.90(s, 1H); 7.56(d, J=8.4, 1H); 6.71(dd, J=8.4, 2.2, 2H); 6.68(d, J=2.2, 1H); 4.30(qu, J=7.0, 2H); 3.90(d, J=6.9, 2H); 3.85(s, 3H); 2.73(s, 3H); 1.33(t, J=7.1, 3H); 0.95(m, 1H); 0.37(m, 2H); 0.25(m, 2H)。
Example D.a 6: 4- (2-Cyclopropylmethoxy-5-methoxy-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example a4) and 2- (2-cyclopropylmethoxy-5-methoxy-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan (example b.c. 7), the title compound was obtained as a yellow solid.
MS(ESI): m/z=404(MNa+); 382(MH+, 100%); 368; 298。
1H-NMR(300 MHz, DMSO-d6): 11.84(br.s, 1H,-NH); 8.94(s, 1H); 7.15(t, J=1.8, 1H); 7.09(d, J=1.8, 2H); 4.31(qu, J=7.1, 2H); 3.81(d, J=6.9, 2H); 3.76(s, 3H); 2.73(s, 3H); 1.34(t, J=7.1, 3H); 0.91(m, 1H); 0.34(m, 2H); 0.18(m, 2H)。
Example D.a 7: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example a4) and 2- (2-cyclopropylmethoxy-5-methyl-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan (example b.c. 8), the title compound was obtained as a light yellow solid.
MS(ESI): m/z=366(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.82(s, 1H,-NH); 8.93(s, 1H); 7.41(d, J=2.1, 1H); 7.32(dd, J=8.4, 2.1, 1H); 7.05(d, J=8.4, 1H); 4.31(qu, J=7.1, 2H); 3.85(d, J=6.8, 2H); 2.72(s, 3H); 2.33(s, 3H); 1.34(t, J=7.1, 3H); 0.93(m, 1H); 0.35(m, 2H); 0.21(m, 2H)。
Example D.a 8: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example a4) and 2- (2-cyclopropylmethoxy-5-trifluoromethyl-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan (example b. c9), the title compound was obtained as a white solid.
MS(ESI): m/z=420(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.98(s, 1H,-NH); 8.98(s, 1H); 7.93-7.85(m, 2H); 7.37(m, 1H); 4.32(qu, J=7.1, 2H); 3.99(d, J=6.9, 2H); 2.74(s, 3H); 1.34(t, J=7.1, 3H); 0.89(m, 1H); 0.39(m, 2H); 0.26(m, 2H)。
Example D.a 9: 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example a4) and 2- (2-ethoxy-5-trifluoromethyl-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane (example b.c. 10), the title compound was obtained as a white solid.
MS(ESI): m/z=394(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.01(s, 1H,-NH); 8.97(s, 1H); 7.91(dd, J=8.9, 2.1, 1H); 7.89(d, J=2.1, 1H); 7.41(d, J=8.9, 1H); 4.32(qu, J=7.1, 2H); 4.20(qu, J=6.9, 2H); 2.74(s, 3H); 1.34(t, J=7.1, 3H); 1.15(t, J=6.9, 3H)。
Example D.a 10: 4- (2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example a4) and 2- (2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane (example b.c2), the title compound was obtained as a white solid.
MS(ESI): m/z=422(MNa+, 100%); 400(MH+); 368; 316。
1H-NMR(300 MHz, DMSO-d6): 11.84(br.s, 1H,-NH); 8.95(s, 1H); 7.37(d, J=9.8, 1H); 7.17(d, J=13.5, 1H); 4.31(qu, J=7.1, 2H); 3.84(s, 3H); 3.83(d, J=6.9, 2H); 2.74(s, 3H); 1.34(t, J=7.1, 3H); 0.92(m, 1H); 0.36(m, 2H); 0.19(m, 2H)。
Example D.a 11: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example a4) and 2- (2-cyclopropylmethoxy-4-fluoro-5-methyl-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane (example b.c11), the title compound was obtained as a light yellow solid.
MS(ESI): m/z=384(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.83(s, 1H,-NH); 8.92(s, 1H); 7.52(d, J=9.7, 1H); 7.03(d, J=12.2, 1H); 4.31(qu, J=7.1, 2H); 3.87(d, J=6.9, 2H); 2.73(s, 3H); 2.24(d, J=1.3, 3H); 1.34(t, J=7.1, 3H); 0.94(m, 1H); 0.37(m, 2H); 0.22(m, 2H)。
Example D.a 12: 4- (2-Cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example a4) and 2- (2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane (example b.c12), the title compound was obtained as a light yellow solid.
MS(ESI): m/z=422(MNa+); 400(MH+, 100%); 386; 331。
1H-NMR(300 MHz, DMSO-d6): 11.81(br.s, 1H,-NH); 8.91(s, 1H); 7.45(d, J=11.8, 1H); 6.92(d, J=7.3, 1H); 4.31(qu, J=7.1, 2H); 3.96(s, 3H); 3.93(d, J=7.0, 2H); 2.74(s, 3H); 1.33(t, J=7.1, 3H); 0.94(m, 1H); 0.38(m, 2H); 0.23(m, 2H)。
Example D.a 13: 4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example a4) and 2- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (example b.c13), the title compound is obtained as an off-white solid.
MS(ESI): m/z=438(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.87(s, 1H,-NH); 8.95(s, 1H); 7.63(d, J=2.4, 1H); 7.54(dd, J=8.6, 2.4, 1H); 7.14(d, J=8.6, 1H); 4.31(qu, J=7.1, 2H); 3.99(m, 2H); 3.90(d, J=6.9. .2H); 3.71(m, 2H); 2.73(s, 3H); 1.58(s, 3H); 1.34(t, J=7.1, 3H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example D.a 14: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example a4) and 2- (2-cyclopropylmethoxy-5-ethyl-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan (example b.c14), the title compound was obtained as a light yellow solid.
MS(ESI): m/z=380(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.83(s, 1H,-NH); 8.94(s, 1H); 7.43(d, J=2.4, 1H); 7.35(dd, J=8.4, 2.4, 1H); 7.07(d, J=8.4, 1H); 4.31(qu, J=7.1, 2H); 3.86(d, J=6.9, 2H); 2.73(s, 3H); 2.63(qu, J=7.5, 2H); 1.34(t, J=7.1, 3H); 1.18(t, J=7.5, 3H); 0.93(m, 1H); 0.35(m, 2H); 0.21(m, 2H)。
Example D.a 15: 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example a4) and 2- [2- (cyclopropylmethoxy) -5- (propan-2-yl) phenyl ] -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (example b.c15), the title compound was obtained as an off-white solid.
MS(ESI): m/z=394(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.84(s, 1H,-NH); 8.94(s, 1H); 7.45(d, J=2.4, 1H); 7.39(dd, J=8.6, 2.4, 1H); 7.08(d; J=8.6, 1H); 4.31(qu, J=7.1, 2H); 3.86(d, J=6.9, 2H); 2.94(sept, J=6.9, 1H); 2.73(s, 3H); 1.34(t, J=7.1, 3H); 1.22(d, J=6.9, 6H); 0.93(m, 1H); 0.35(m, 2H); 0.21(m, 2H)。
Example D.a 16: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid methyl ester
Starting from methyl 4-chloro-2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example a.11) and 2- (2-cyclopropylmethoxy-5-methyl-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan (example b.c.8), the title compound was obtained as an off-white solid.
MS(ESI): m/z=496(MH+ , 100%)
1H-NMR(300 MHz, DMSO-d6): 7.31(dd, J=8.4, 2.0, 1H); 7.23(d, J=2-0, 1H); 7.03(d, J=8.4,1H); 5.38(d, J=11.0, 1H); 4.98(d, J=11.0, 1H); 3.85(s, 3H); 3.79(dd, J=10.4, 6.6, 1H); 3.75(dd, J=10.4, 6.9, 1H); 2.87(m, 2H); 2.78(s, 3H); 2.67(s, 3H); 2.31(s, 3H); 0.87(m, 1H); 0.52(m, 2H); 0.30(m, 2H); 0.03(m, 2H);-0.17(s, 9H)。
Example D.a 17: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid methyl ester
Starting from methyl 4-chloro-2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example a.11) and 2- (2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane (example b.c.15), the title compound was obtained as an off-white solid.
MS(ESI): 530(MH+, 100%)
1H-NMR(300 MHz, DMSO-d6): 7.29(d, J=11.5, 1H); 6.92(d, J=7.3, 1H), 5.43(d, J=11.0, 1H); 5.03(d, J=11.0, 1H); 3.95(s, 3H); 3.85(s, 3H); 3.83(m, 2H); 2.95(m, 2H); 2.80(s, 3H); 2.67(s, 3H); 0.88(m, 1H); 0.55(m, 2H); 0.31(m, 2H); 0.04(m, 2H);-0.17(s, 9H)。
Example D.a 18: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid methyl ester
Starting from methyl 4-chloro-2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example a.11) and 2- (2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl) -4,4,5, 5-tetramethyl- [1,3,2] dioxaborolane (example b.c.2), the title compound was obtained as an off-white solid.
MS(ESI): m/z=530(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 7.23(d, J=9.9, 1H); 7.16(d, J=13.1, 1H); 5.36(d, J=10.9, 1H); 4.97(d, J=10.9, 1H); 3.85(s, 3H); 3.81(s, 3H); 3.79(dd, J=10.2, 6.4, 1H); 3.72(dd, J=10.2, 6.9, 1H); 3.04-2.87(m, 2H); 2.79(s, 3H); 2.68(s, 3H); 0.86(m, 1H); 0.57(m, 2H); 0.30(m, 2H); 0.01(m, 2H);-0.15(s, 9H)。
Example D.a 19: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4-chloro-6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example a4) and 2- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (example b. c16), the title compound was obtained as a white solid.
1H-NMR(300 MHz, DMSO-d6): 11.93(s, 1H,-NH); 8.97(s, 1H); 7.81(d, J=2.1, 1H); 7.74(dd, J=8.8, 2.1, 1H); 7.30(d, J=8.8, 1H); 7.08(t, J=55.9, 1H); 4.32(qu, J=7.1, 2H); 3.96(d, J=6.9, 2H); 2.74(s, 3H); 1.34(t, J=7.1, 3H); 0.97(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example D. b 1: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Sodium hydride (1.77 g; -60% dispersion in oil) was washed with hexane (2X25) and suspended in anhydrous DMF (150 mL) and anhydrous DMSO (50 mL). A1 of example d.a.4- (5-cyclopropylmethoxy-benzo [1,3 ] in several minor portions ]Dioxol-4-yl) -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxylic acid ethyl ester (14.55 g; 36.8 mmol) was added to the well-stirred suspension. After the addition was complete, the reaction mixture was stirred at 60 ℃ for one hour and cooled to 10 ℃ before slowly adding (2-chloromethoxy-ethyl) -trimethyl-silane (7.98 g; 47.8 mmol). After stirring overnight at room temperature, the mixture was poured onto ice-cold water and extracted repeatedly with dichloromethane. With MgSO4The combined organic layers were dried and the solvent was evaporated. The crude product was purified by silica gel column chromatography (ethyl acetate/cyclohexane-1: 1) to give the title compound as a pale yellow viscous oil.
MS(ESI): m/z=526(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 8.99(s, 1H); 7.00(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.02(d, J=0.6, 1H); 5.92(d, J=0.6, 1H); 5.39(d, J=10.9, 1H); 5.13(d, J=10.9, 1H); 4.35(qu, J=7.1, 2H); 3.76(dd, J=10.2, 6.6, 1H); 3.67(dd, J=10.2, 6.8, 1H); 3.01(m, 2H); 2.82(s, 3H); 1.35(t, J=7.1, 3H); 0.86(m, 1H); 0.62(m, 2H); 0.29(m, 2H); 0.00(m, 2H);-0.13(s, 9H)。
The following compounds were prepared using a procedure analogous to that described in example d.b. 1 above.
Example D. b 2: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
The title compound was prepared starting from ethyl 4- (2-cyclopropylmethoxy-4-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.a2) and commercially available (2-chloromethoxy-ethyl) -trimethyl-silane as a pale yellow viscous oil.
MS(ESI): m/z=500(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 8.97(s, 1H); 7.49(dd, J=8.4, 6.9, 1H); 7.09(dd, J=11.3, 2.4, 1H); 6.97(ddd, J=8.4, 8.4, 2.4, 1H); 6.41(d, J=10.9, 1H); 4.99(d, J=10.9, 1H); 4.35(qu, J=7.1, 2H); 3.89(dd, J=10.3, 6.5, 1H); 3.80(dd, J=10.3, 7.0, 1H); 2.93(m, 2H); 2.82(s, 3H); 1.35(t, J=7.1, 3H); 0.91(m, 1H); 0.56(dd, J=9.5, 6.9, 2H); 0.33(m, 2H): 0.06(m, 2H);-0.16(s, 9H)。
Example D. b 3: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
The title compound was prepared starting from ethyl 4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.a3) and commercially available (2-chloromethoxy-ethyl) -trimethyl-silane as a pale yellow viscous oil.
MS(ESI): m/z=500(MH+)。
1H-NMR(300 MHz, DMSO-d6): 8.99(s, 1H); 7.38(ddd, J=9.1, 8.4, 3.2, 1H); 7.30(dd, J=8.6, 3.2, 1H); 7.19(dd, J=9.1, 4.4, 1H); 5.42(d, J=10.9, 1H); 5.00(d, J=10.9, 1H); 4.35(qu, J=7.1, 2H); 3.83(dd, J=10.4, 6.6, 1H); 3.76(dd, J=10.4, 6.9, 1H); 2.94(m, 2H); 2.82(s, 3H); 1.35(t, J=7.1, 3H); 0.88(m, 1H); 0.56(m, 2H); 0.31(m, 2H); 0.03(m, 2H);-0.15(s, 9H)。
Example D. b 4: 4- (2-ethoxy-5-fluorophenyl) -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from ethyl 4- (2-ethoxy-5-fluorophenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.a4) and commercially available (2-chloromethoxy-ethyl) -trimethyl-silane, the title compound was obtained as a yellow viscous oil.
MS(ESI): m/z=474(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 8.98(s, 1H); 7.39(ddd, J=9.1, 8.8, 3.3, 1H); 7.29(dd, J=8.6, 3.3, 1H); 7.20(dd, J=9.1, 4.4, 1H); 5.40(d, J=11.0, 1H); 4.98(d, J=11.0, 1H); 4.35(qu, J=7.1, 2H); 3.99(qu, J=6.9, 2H); 2.99-2.88(m, 2H); 2.82(s, 3H); 1.35(t, J=7.1, 3H); 1.01(t, J=6.9, 3H); 0.57(m, 2H);-0.15(s, 9H)。
Example D.b. b 5: 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4- (2-cyclopropylmethoxy-4-methoxy-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example d.a5) and commercially available (2-chloromethoxy-ethyl) -trimethyl-silane, the title compound was obtained as a yellow viscous oil.
MS(ESI): m/z=512(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 8.94(s, 1H); 7.40(d, J=8.4, 1H); 6.72(dd, J=8.4, 2.2, 2H); 6.69(d, J=2.2, 1H); 5.46(d, J=10.9, 1H); 5.06(d, J=10.9, 1H); 4.35(qu, J=7.0, 2H); 3.88(dd, J=10.2, 5.5, 1H); 3.85(s, 3H); 3.77(dd, J=10.2, 6.9, 1H); 2.91(t, J=8.0, 2H); 2.82(s, 3H); 1.35(t, J=7.0, 3H); 0.88(m, 1H); 0.52(m, 2H); 0.32(m, 2H); 0.06(m, 2H);-0.18(s, 9H)。
Example D. b 6: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4- (2-cyclopropylmethoxy-5-methoxy-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example d.a6) and commercially available (2-chloromethoxy-ethyl) -trimethyl-silane, the title compound was obtained as a yellow viscous oil.
MS(ESI): m/z=512(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 8.98(s, 1H), 7.10(d, J =1.5, 2H), 7.01(t, J =1.5, 1H), 5.42(d, J =11.0, 1H), 5.04(d, J =11.0, 1H), 4.35(qu, J =7.1, 2H), 3.76(s, 3H and dd, J =10.2, 6.5, 1H), 3.70(dd, J =10.2, 6.9, 1H), 2.92(m, 2H), 2.82(s, 3H), 1.35(t, J =7.1, 3H), 0.85(m, 1H), 0.54(m, 2H), 0.29(m, 2H), 0.00(m, 2H); 0.18(s, 9H).
Example D.b. 7: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example d.a7) and commercially available (2-chloromethoxy-ethyl) -trimethyl-silane, the title compound was obtained as a yellow viscous oil.
MS(ESI): m/z=496(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 8.97(s, 1H); 7.33(dd, J=8.5, 2.0, 1H); 7.26(d, J=2.0, 1H); 7.05(d, J=8.5, 1H); 5.43(d, J=11.0, 1H); 5.03(d, J=11.0, 1H); 4.35(qu, J=7.1, 2H); 3.81(dd, J=10.2, 6.5, 1H); 3.74(dd, J=10.2, 6.9, 1H); 2.89(m, 2H); 2.81(s, 3H); 2.32(s, 3H); 1.35(t, J=7.1, 3H); 0.88(m, 1H); 0.55(m, 2H); 0.31(m, 2H); 0.03(m, 2H);-0.17(s, 9H)。
Example D. b 8: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from ethyl 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.a8) and commercially available (2-chloromethoxy-ethyl) -trimethyl-silane, the title compound was obtained as a yellow viscous oil.
MS(ESI): m/z=550(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 9.01(s, 1H); 7.90(dd, J=8.8, 2.1, 1H); 7.77(d, J=2.1, 1H); 7.38(d, J=8.8, 1H); 5.40(d, J=10.9, 1H); 4.96(d, J=10.9, 1H); 4.36(qu, J=7.1, 2H); 3.98(dd, J=10.4, 6.6, 1H); 3.91(dd, J=10.4, 7.1, 1H); 2.92(t, J=8.2, 2H); 2.83(s, 3H); 1.36(t, J=7.1, 3H); 0.94(m, 1H); 0.51(m, 2H); 0.35(m, 2H); 0.10(m, 2H);-0.18(s, 9H)。
Example D.b. 9: 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example d.a9) and commercially available (2-chloromethoxy-ethyl) -trimethyl-silane, the title compound was obtained as a yellow viscous oil.
MS(ESI): m/z=524(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.00(s, 1H); 7.91(dd, J=8.8, 2.2, 1H); 7.76(d, J=2.2, 1H); 7.40(d, J=8.8, 1H); 5.38(d, J=10.9, 1H); 4.94(d, J=10.9, 1H); 4.30(qu, J=7.1, 2H); 4.17-4.08(m, 2H); 2.93(t, J=8.3, 2H); 2.83(s, 3H); 1.35(t, J=7.1, 3H); 1.07(t, J=7.0, 3H); 0.59-0.45(m, 2H);-0.18(s, 9H)。
Example D.b. 10: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from ethyl 4- (2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.a10) and commercially available (2-chloromethoxy-ethyl) -trimethyl-silane, the title compound was obtained as a yellow viscous oil.
MS(ESI): m/z=552(MNa+); 530(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 8.98(s, 1H); 7.27(d, J=9.7, 1H); 7.18(d, J=13.3, 1H); 5.41(d, J=10.9, 1H); 5.03(d, J=10.9, 1H); 4.35(qu, J=7.1, 2H); 3.82(s, 3H); 3.80(dd, J=10.4, 6.7, 1H); 3.74(dd, J=10.4, 7.0, 1H); 2.97(m, 2H); 2.82(s, 3H); 1.35(t, J=7.1, 3H); 0.87(m, 1H); 0.56(m, 2H); 0.31(m, 2H); 0.02(m, 2H);-0.15(s, 9H)。
Example D. b 11: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example d.a11) and commercially available (2-chloromethoxy-ethyl) -trimethyl-silane, the title compound was obtained as a yellow solid.
MS(ESI): m/z=514(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 8.96(s, 1H); 7.37(d, J=8.9, 1H); 7.05(d, J=12.1, 1H); 5.43(d, J=11.0, 1H); 5.02(d, J=11.0, 1H); 4.35(qu, J=7.1, 2H); 3.85(dd, J=10.4, 6.6, 1H); 3.77(dd, J=10.4, 7.1, 1H); 2.94(m, 2H); 2.82(s, 3H); 2.23(d, J=1.3, 3H); 1.35(t, J=7.1, 3H); 0.89(m, 1H); 0.54(m, 2H); 0.33(m, 2H); 0.06(m, 2H);-0.16(s, 9H)。
Example D. b 12: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from ethyl 4- (2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.a12) and commercially available (2-chloromethoxy-ethyl) -trimethyl-silane, the title compound was obtained as a yellow viscous oil.
MS(ESI): m/z=552(MNa+, 100 %); 530(MH+); 458(MH+-C3H8Si)。
1H-NMR(300 MHz, DMSO-d6): 8.95(s, 1H); 7.30(d, J=11.5, 1H); 6.92(d, J=7.3, 1H); 5.46(d, J=11.1, 1H); 5.06(d, J=11.1, 1H); 4.34(qu, J=7.1, 2H); 3.94(s, 3H); 3.87(dd, J=10.2, 6.6, 1H); 3.80(dd, J=10.2, 7.0, 1H); 2.95(m, 2H); 2.81(s, 3H); 1.34(t, J=7.1, 3H); 0.87(m, 1H); 0.54(m, 2H); 0.31(m, 2H); 0.03(m, 2H);-0.18(s, 9H)。
Example D. b 13: 4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example d.a13) and commercially available (2-chloromethoxy-ethyl) -trimethyl-silane, the title compound was obtained as a yellow viscous oil.
MS(ESI): m/z=568(MH+, 100%)。
Example D. b 14: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester (example d.a14) and commercially available (2-chloromethoxy-ethyl) -trimethyl-silane, the title compound was obtained as a yellow viscous oil.
MS(ESI): m/z=510(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 8.97(s, 1H); 7.41(dd, J=8.6, 2.2, 1H); 7.29(d, J=2.2, 1H); 7.08(d, J=8.6, 1H); 5.42(d, J=10.9, 1H); 5.03(d, J=10.9, 1H); 4.35(qu, J=7.1, 2H); 3.84(dd, J=10.2, 6.4, 1H); 3.74(dd, J=10.2, 6.8, 1H); 2.89(m, 2H); 2.81(s, 3H); 2.62(qu, J=7.5, 2H); 1.34(t, J=7.1, 3H); 1.20(t, J=7.5, 3H); 0.93(m, 1H); 0.52(m, 2H); 0.32(m, 2H); 0.04(m, 2H);-0.18(s, 9H)。
Example D. b 15: 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid ethyl ester
Starting from ethyl 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.a15) and commercially available (2-chloromethoxy-ethyl) -trimethyl-silane, the title compound was obtained as a yellow viscous oil.
MS(ESI): m/z=524(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 8.97(s, 1H); 7.39(dd, J=8.6, 2.4, 1H); 7.32(d, J=2.4, 1H); 7.08(d; J=8.6, 1H); 5.41(d, J=10.9, 1H); 5.04(d, J=10.9, 1H); 4.35(qu, J=7.1, 2H); 3.82(dd, J=10.2, 6.6, 1H); 3.74(dd, J=10.2, 6.8, 1H); 2.98-2.84(m, 3H); 2.82(s, 3H); 1.36(t, J=7.1, 3H); 1.23(dd, J=6.9, 2.2, 6H); 0.89(m, 1H); 0.51(m, 2H); 0.31(m, 2H); 0.04(m, 2H);-0.19(s, 9H)。
Example D.c. 1: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Ethyl 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate from example D.b. 1 (15.28 g; 29.0 mmol) was dissolved in 1, 4-dioxane (150 mL) and aqueous LiOH (prepared from 1.04 g (43.5 mmol) and 75 mL of water). The stirred reaction mixture was heated to 80 ℃ until the starting material was consumed (according to LC-MS). The mixture was concentrated under reduced pressure and diluted with water. 2M citric acid was added, the pH was adjusted to 5, the product was precipitated, isolated by suction filtration, washed with a few portions of water and dried at 40 ℃ under high vacuum to give 13.55 g of the title compound as a pale yellow solid.
MS(ESI): m/z=498(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 8.93(s, 1H); 7.00(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.02(d, J=0.6, 1H); 5.91(d, J=0.6, 1H); 5.37(d, J=11.0, 1H); 5.11(d, J=11.0, 1H); 3.76(dd, J=10.2, 6.6, 2H); 3.68(dd, J=10.2, 6.8, 1H); 3.01(m, 2H); 2.84(s, 3H); 0.87(m, 1H); 0.61(m, 2H); 0.29(m, 2H); 0.00(m, 2H);-0.13(s, 9H)。
The following compounds were prepared using a procedure similar to that described in example d.c. 1 above.
Example D.c. 2: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from ethyl 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example D.b.2), the title compound was obtained as a light yellow solid.
MS(ESI): m/z=472(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 8.70(s, 1H); 7.46(dd, J=8.4, 6.9, 1H); 7.08(dd, J=11.5, 2.4, 1H); 6.95(ddd, J=8.4, 8.4, 2.4, 1H); 5.32(d, J=10.9, 1H); 4.93(d, J=10.9, 1H); 3.89(dd, J=10.3, 6.6, 1H); 3.79(dd, J=10.3, 6.9, 1H); 2.90(m, 2H); 2.89(s, 3H); 0.91(m, 1H); 0.54(dd, J=8.2, 7.8, 2H); 0.32(m, 2H): 0.06(m, 2H);-0.16(s, 9H)。
Example D.c. 3: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from ethyl 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example D.b. 3), the title compound was obtained as a yellow foam.
MS(ESI): m/z=472(MH+)。
1H-NMR(300 MHz, DMSO-d6): 8.77(s, 1H); 7.36(ddd, J=9.1, 8.9, 3.3, 1H); 7.27(dd, J=8.6, 3.3, 1H); 7.18(dd, J=9.1, 4.4, 1H); 5.35(d, J=10.9, 1H); 4.94(d, J=10.9, 1H); 3.83(dd, J=10.2, 6.6, 1H); 3.76(dd, J=10.2, 6.9, 1H); 2.92(m, 2H); 2.88(s, 3H); 0.88(m, 1H); 0.56(m, 2H); 0.30(m, 2H); 0.03(m, 2H);-0.16(s, 9H)。
Example D.c. 4: 4- (2-ethoxy-5-fluorophenyl) -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from ethyl 4- (2-ethoxy-5-fluorophenyl) -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example D.b. 4), the title compound was obtained as a pale yellow solid.
MS(ESI): m/z=446(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6, MeOH-d4): 8.78(s, 1H); 7.37(ddd, J=9.1, 8.9, 3.3, 1H); 7.27(dd, J=8.8, 3.3, 1H); 7.19(dd, J=9.1, 4.4, 1H); 5.33(d, J=11.0, 1H); 4.94(d, J=11.0, 1H); 3.99(qu, J=6.9, 2H); 3.01-2.86(m, 2H); 2.87(s, 3H); 1.02(t, J=6.9, 3H); 0.57(m, 2H);-0.15(s, 9H)。
Example D.c. 5: 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from ethyl 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.b. 5), the title compound was obtained as a yellow foam.
MS(ESI): m/z=484(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.35(br.s, 1H, CO2H); 8.92(s, 1H); 7.40(d, J=8.4, 1H); 6.72(dd, J=8.4, 2.2, 2H); 6.69(d, J=2.2, 1H); 5.46(d, J=10.9, 1H); 5.06(d, J=10.9, 1H); 3.87(dd, J=10.2, 6.4, 1H); 3.85(s, 3H); 3.78(dd, J=10.2, 6.9, 1H); 2.91(t, J=8.0, 2H); 2.82(s, 3H); 0.89(m, 1H); 0.52(m, 2H); 0.32(m, 2H); 0.06(m, 2H);-0.18(s, 9H)。
Example D.c. 6: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from ethyl 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.b. 6), the title compound was obtained as a yellow foam.
MS(ESI): m/z=484(MH+, 100%)。
Example D.c. 7: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from ethyl 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example D.b. 7), the title compound was obtained as a yellow solid.
1H-NMR(400 MHz, DMSO-d6): 12.35(br.s, 1H, CO2H); 8.96(s, 1H); 7.33(dd, J=8.6, 2.0, 1H); 7.27(d, J=2.0, 1H); 7.06(d, J=8.6, 1H); 5.43(d, J=11.0, 1H); 5.03(d, J=11.0, 1H); 3.82(dd, J=10.3, 6.5, 1H); 3.75(dd, J=10.2, 6.9, 1H); 2.89(m, 2H); 2.83(s, 3H); 2.32(s, 3H); 0.89(m, 1H); 0.52(m, 2H); 0.31(m, 2H); 0.04(m, 2H);-0.17(s, 9H)。
Example D.c. 8: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from ethyl 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.b. 8), the title compound was obtained as a light yellow solid.
MS(ESI): m/z=522(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 8.91(s, 1H); 7.90(dd, J=8.8, 2.1, 1H); 7.76(d, J=2.1, 1H); 7.38(d, J=8.8, 1H); 5.37(d, J=11.0, 1H); 4.94(d, J=11.0, 1H); 3.98(dd, J=10.5, 6.6, 1H); 3.91(dd, J=10.5, 7.0, 1H); 2.91(t, J=8.2, 2H); 2.86(s, 3H); 0.95(m, 1H); 0.51(m, 2H); 0.35(m, 2H); 0.10(m, 2H);-0.18(s, 9H)。
Example D.c. 9: 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from ethyl 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example D.b. 9), the title compound was obtained as a light yellow solid.
MS(ESI): m/z=496(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6, MeOH-d4): 8.75(s, 1H); 7.90(dd, J=8.8, 2.2, 1H); 7.74(d, J=2.2, 1H); 7.39(d, J=8.8, 1H); 5.30(d, J=11.0, 1H); 4.89(d, J=11.0, 1H); 4.18-4.06(m, 2H); 2.90(t, J=8.6, 2H); 2.89(s, 3H); 1.08(t, J=7.0, 3H); 0.52(m, 2H);-0.18(s, 9H)。
Example D.c. 10: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from ethyl 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.b. 10), the title compound was obtained as a yellow foam.
MS(ESI): m/z=524(MNa+); 502(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 12.38(br.s, 1H,-CO2H); 8.98(s, 1H); 7.28(d, J=9.7, 1H); 7.19(d, J=13.1, 1H); 5.42(d, J=10.9, 1H); 5.03(d, J=10.9, 1H); 3.82(s, 3H); 3.81(dd, J=10.3, 6.6, 1H); 3.73(dd, J=10.3, 7.0, 1H); 3.05-2.89(m, 2H); 2.83(s, 3H); 0.87(m, 1H); 0.56(m, 2H); 0.31(m, 2H); 0.02(m, 2H);-0.15(s, 9H)。
Example D.c. 11: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from ethyl 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.b. 11), the title compound was obtained as a light yellow solid.
MS(ESI): m/z=514(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 8.96(s, 1H); 7.37(d, J=8.9, 1H); 7.05(d, J=12.1, 1H); 5.43(d, J=11.0, 1H); 5.02(d, J=11.0, 1H); 4.35(qu, J=7.1, 2H); 3.85(dd, J=10.4, 6.6, 1H); 3.77(dd, J=10.4, 7.1, 1H); 2.94(m, 2H); 2.82(s, 3H); 2.23(d, J=1.3, 3H); 1.35(t, J=7.1, 3H); 0.89(m, 1H); 0.54(m, 2H); 0.33(m, 2H); 0.06(m, 2H);-0.16(s, 9H)。
Example D.c. 12: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from ethyl 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.b12), the title compound was obtained as a yellow foam.
MS(ESI): m/z=552(MNa+, 100 %); 530(MH+); 458(MH+-C3H8Si)。
1H-NMR(300 MHz, DMSO-d6): 8.95(s, 1H); 7.30(d, J=11.5, 1H); 6.92(d, J=7.3, 1H); 5.46(d, J=11.1, 1H); 5.06(d, J=11.1, 1H); 4.34(qu, J=7.1, 2H); 3.94(s, 3H); 3.87(dd, J=10.2, 6.6, 1H); 3.80(dd, J=10.2, 7.0, 1H); 2.95(m, 2H); 2.81(s, 3H); 1.34(t, J=7.1, 3H); 0.87(m, 1H); 0.54(m, 2H); 0.31(m, 2H); 0.03(m, 2H);-0.18(s, 9H)。
Example D.c. 13: 4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from ethyl 4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example D.b13), the title compound was obtained as a yellow foam.
MS(ESI): m/z=540(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 8.93(s, 1H); 7.56(dd, J=8.8, 2.4, 1H); 7.49(d, J=2.4, 1H); 7.14(d, J=8.8, 1H); 5.38(d, J=11.1, 1H); 5.03(d, J=11.1, 1H); 4.00(m, 2H); 3.86(dd, J=10.2, 6.4, 1H); 3.78(dd, J=10.2, 6.9, 1H); 3.73(m, 2H); 2.89(m, 2H); 2.84(s, 3H); 1.59(s, 3H); 0.91(m, 1H); 0.50(m, 2H); 0.32(m, 2H); 0.06(m, 2H);-0.20(s, 9H)。
Example D.c. 14: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from ethyl 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example D.b. 14), the title compound was obtained as a light yellow solid.
MS(ESI): m/z=510(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 8.97(s, 1H); 7.41(dd, J=8.6, 2.2, 1H); 7.29(d, J=2.2, 1H); 7.08(d, J=8.6, 1H); 5.42(d, J=10.9, 1H); 5.03(d, J=10.9, 1H); 4.35(qu, J=7.1, 2H); 3.84(dd, J=10.2, 6.4, 1H); 3.74(dd, J=10.2, 6.8, 1H); 2.89(m, 2H); 2.81(s, 3H); 2.62(qu, J=7.5, 2H); 1.34(t, J=7.1, 3H); 1.20(t, J=7.5, 3H); 0.93(m, 1H); 0.52(m, 2H); 0.32(m, 2H); 0.04(m, 2H);-0.18(s, 9H)。
Example D.c. 15: 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from ethyl 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.b. 15), the title compound was obtained as a yellow foam.
MS(ESI): m/z=496(MH+, 100%)。
Example D.c. 16: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from methyl 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example D.a16), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=482(MH+ , 100%)
1H-NMR(300 MHz, DMSO-d6): 12.32(br.s, 1H,-CO2H); 7.33(dd, J=8.4, 1.8, 1H); 7.24(d, J=1.8, 1H); 7.05(d, J=8.4, 1H); 5.42(d, J=11.0, 1H); 5.01(d, J=11.0, 1H); 3.80(dd, J=10.2, 6.6, 1H); 3.76(dd, J=10.2, 6.9, 1H); 2.89(m, 2H); 2.81(s, 3H); 2.70(s, 3H); 2.32(s, 3H); 0.89(m, 1H); 0.52(m, 2H); 0.31(m, 2H); 0.05(m, 2H);-0.17(s, 9H). .
Example D.c. 17: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from methyl 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.a17), the title compound was obtained as a pale yellow foam.
MS(ESI): 516(MH+, 100%)
1H-NMR(300 MHz, DMSO-d6): 12.32(br.s, 1H,-CO2H); 7.30(d, J=11.3, 1H); 6.93(d, J=7.3, 1H), 5.46(d, J=11.1, 1H); 5.05(d, J=11.1, 1H); 3.95(s, 3H); 3.85(m, 2H); 2.96(m, 2H); 2.82(s, 3H); 2.70(s, 3H); 0.89(m, 1H); 0.55(m, 2H); 0.33(m, 2H); 0.06(m, 2H);-0.17(s, 9H)。
Example D.c. 18: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from methyl 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.a18), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=516(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 7.25(d, J=9.7, 1H); 7.17(d, J=13.1, 1H); 5.38(d, J=10.8, 1H); 5.01(d, J=10.8, 1H); 3.82(s, 3H); 3.80(dd, J=10.4, 6.6, 1H); 3.73(dd, J=10.4, 7.0, 1H); 3.06-2.90(m, 2H); 2.82(s, 3H); 2.72(s, 3H); 0.88(m, 1H); 0.57(m, 2H); 0.33(m, 2H); 0.04(m, 2H);-0.15(s, 9H)。
Example D.d 1: 4- { [ (4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid from example D.c1 (3.98 g; 8.0 mmol), triethylamine (2.43 g; 24.0 mmol) and HOBt (1.08 g; 8.0 mmol) were stirred in dry dichloromethane (40 mL) for 30 minutes, after which EDC (1.84 g; 9.6 mmol) was added. The reaction mixture was stirred at room temperature for one hour. After addition of 4-amino-piperidine-1-carboxylic acid tert-butyl ester hydrochloride (2.27 g; 9.6 mmol), the reaction mixture was stirred at room temperature until the starting material was consumed (according to LC-MS) and subjected to silica gel chromatography (ethyl acetate/cyclohexane-1: 1) to give the title compound as a colorless foam.
MS(ESI): m/z=680(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.02(d, J=7.2, 1H,-NH); 9.01(s, 1H); 7.01(d, J=8.4, 1H); 6.57(d, J=8.4, 1H); 6.07(s, 1H); 5.92(s, 1H); 5.39(d, J=11.0, 1H); 5.12(d, J=11.0, 1H); 4.06(m, 1H); 3.85(m, 2H); 3.76(dd, J=10.2, 6.5, 1H); 3.68(dd, J=10.2, 6.9, 1H); 3.13-2.94(m, 4H); 2.91(s, 3H); 1.93(m, 2H); 1.46(m, 2H); 1.42(s, 9H); 0.86(m, 1H); 0.61(m, 2H); 0.29(m, 2H); 0.01(m, 2H);-0.13(s, 9H)。
The following compounds were prepared using a procedure similar to that described in example d.d1 above.
Example D tert-butyl (trans-4- { [ (4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c. 1) and commercially available tert-butyl trans- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a pale yellow viscous oil. The compound can be further processed without characterization.
Example D tert-butyl (cis-4- { [ (4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c. 1) and commercially available tert-butyl cis- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a pale yellow viscous oil. The compound can be further processed without characterization.
Example D tert-butyl (3R) -3- { [ (4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } pyrrolidine-1-carboxylate
Starting from 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c. 1) and commercially available tert-butyl (R) -3-amino-pyrrolidine-1-carboxylate, the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=666(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.13(d, J=6.8, 1H,-NH); 8.99(s, 1H); 7.01(d, J=8.6, 1H); 6.57(d, J=8.6, 1H); 6.02(d, J=0.6, 1H); 5.92(d, J=0.6, 1H); 5.40(d, J=10.9, 1H); 5.12(d, J=10.9, 1H); 4.50(m, 1H); 3.76(dd, J=10.2, 6.6, 1H); 3.67(dd, J=10.2, 6.9, 1H); 3.61(m, 1H); 3.43(m, 2H); 3.25(m, 1H); 3.00(m, 2H); 2.91(s, 3H); 2.22(m, 1H); 1.96(m, 1H); 1.41(s, 9H); 0.86(m, 1H); 0.61(m, 2H); 0.29(m, 2H); 0.01(m, 2H);-0.14(s, 9H)。
Example D.d 5: (3R)*,4R*) -3- { [ (4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl)]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Amino } -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
From 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxylic acid (example d. c1) and commercially available (3R)*,4R*) Starting from tert-butyl-3-amino-4-hydroxy-pyrrolidine-1-carboxylate, the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=682(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.06(br.s, 1H,-NH); 8.97(s, 1H); 7.02(d, J=8.6, 1H); 6.57(d, J=8.6, 1H); 6.02(s, 1H); 5.92(s, 1H); 5.48(d, J=3.8, 1H,-OH); 5.40(d, J=11.0, 1H); 5.12(d, J=11.0, 1H); 4.24(m, 2H); 3.76(dd, J=10.2, 6.6, 1H); 3.67(dd, J=10.2,6.9, 1H and m, 1H), 3.56(m, 1H), 3.23(m, 2H), 3.09-2.92(m, 2H), 2.91(s, 3H), 1.43(s, 9H), 0.86(m, 1H), 0.61(m, 2H), 0.29(m, 2H), 0.01(m, 2H), 0.13(s, 9H).
Example D.d 6: 4- { [ (4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c.2) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=654(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 9.07(d, J=7.7, 1H,-NH); 8.99(s, 1H); 7.49(dd, J=8.4, 6.8, 1H); 7.10(dd, J=11.3, 2.4, 1H); 6.97(ddd, J=8.4, 8.4, 2.4, 1H); 5.41(d, J=11.1, 1H); 4.98(d, J=11.1, 1H); 4.08(m, 1H); 3.90(dd, J=10.2, 6.6, 1H); 3.81(dd, J=10.2, 7.1, 1H); 3.92-3.78(m, 2H); 3.06(m, 2H); 2.92(m, 2H); 2.91(s, 3H); 1.93(m, 2H); 1.45(m, 2H); 1.42(s, 9H); 0.91(m, 1H); 0.54(dd, J=9.1, 7.3, 2H); 0.34(m, 2H): 0.08(m, 2H);-0.16(s, 9H)。
Example D tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c.2) and commercial tert-butyl trans- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=668(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 8.99(s, 1H); 8.90(d, J=7.7, 1H,-NH); 7.49(dd, 8.4, 6.9, 1H); 7.10(dd, 11.3, 2.2, 1H); 6.97(ddd, 8.4, 8.4, 2.2, 1H); 6.72(d, J=7.9, 1H,-NH); 5.40(d, J=11.1, 1H); 4.98(d, J=11.1, 1H); 3.90(dd, J=10.2, 6.6, 1H); 3.80(dd, J=10.2, 7.1, 1H); 3.79(m, 1H); 3.29(m, 1H); 2.92(m, 2H); 2.90(s, 3H); 2.00(m, 2H); 1.85(m, 2H); 1.39(s, 9H); 1.36(m, 4H); 0.91(m, 1H); 0.54(m, 2H); 0.33(m, 2H); 0.07(m, 2H);-0.16(s 9H)。
Example D tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c.2) and commercially available tert-butyl cis- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=668(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 9.29(d, J =7.7, 1H, -NH), 9.04(s, 1H), 7.50(dd, 8.4, 6.7, 1H), 7.12(dd, 11.5, 2.4, 1H), 6.97(ddd, 8.4, 8.4, 2.4, 1H and br.s, 1H, -NH), 5.42(d, J =10.9, 1H), 4.98(d, J =10.9, 1H), 4.07(m, 1H), 3.85(dd, J =10.4, 6.6, 1H), 3.80(dd, J =10.4, 7.1, 1H), 3.42(m, 1H), 2.91(m, 2H and s, 3H), 1.88-1.48(m, 8H), 1.40(s = 9.7, 0.4, 1H), 1.54 (dd, 1H), 2H) 0.09(m, 2H); 0.16(s 9H).
Example D tert-butyl (3R) -3- { [ (4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } pyrrolidine-1-carboxylate
Starting from 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c.2) and commercial tert-butyl (R) -3-amino-pyrrolidine-1-carboxylate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=640(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 9.17(d, J=6.7, 1H,-NH); 8.98(s, 1H); 7.50(dd, J=8.4, 6.9, 1H); 7.10(dd, J=11.3, 2.4, 1H); 6.97(ddd, J=8.4, 8.4, 2.4, 1H); 5.42(d, J=11.0, 1H); 4.99(d, J=11.0, 1H); 4.50(m, 1H); 3.90(dd, J=10.2, 6.4, 1H); 3.80(dd, J=10.2, 7.1, 1H); 3.62(m, 1H); 3.43(m, 2H); 3.27(m, 1H); 2.92(m, 2H); 2.91(s. .3H); 2.22(m, 1H); 1.96(m, 1H); 1.41(s, 9H); 0.91(m, 1H); 0.54(dd, J=9.1, 7.3, 2H); 0.33(m, 2H); 0.07(m, 2H);-0.16(s, 9H)。
Example D tert-butyl (3R,4R) -3- { [ (4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } -4-hydroxypyrrolidine-1-carboxylate (d 10:)
From 4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxylic acid (example d. c2) and commercially available (3R)*,4R*) Starting from tert-butyl-3-amino-4-hydroxy-pyrrolidine-1-carboxylate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=656(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 9.11(br.s, 1H,-NH); 8.95(s, 1H); 7.50(dd, J=8.4, 6.9, 1H); 7.10(dd, J=11.5, 2.4, 1H); 6.97(ddd, J=8.4, 8.4, 2.4, 1H); 5.48(d, J=5.5, 1H,-OH); 5.42(d, J=11.1, 1H); 4.99(d, J=11.1, 1H); 4.26(m, 1H); 4.20(m, 1H); 3.90(dd, J=10.2, 6.6, 1H); 3.80(dd, J=10.2, 6.9, 1H); 3.68(m, 1H); 3.56(m, 1H); 3.25(m, 2H); 2.94(m, 2H); 2.91(s, 3H); 1.43(s, 9H); 0.90(m, 1H); 0.54(m, 2H); 0.34(m, 2H); 0.08(m, 2H),-0.16(s, 9H)。
Example D.d 11: (3S)*,4S*) -4- { [ (4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Amino } -3-hydroxypiperidine-1-carboxylic acid tert-butyl ester
From 4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxylic acid (example d. c2) and (3R)*,4R*) Starting from tert-butyl-4-amino-3-hydroxy-piperidine-1-carboxylate (example C2), the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=670(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 9.11(d, J =7.5, 1H, -NH), 8.99(s, 1H), 7.50(dd, J =8.4, 7.1, 1H), 7.11(dd, J =11.3, 2.4, 1H), 6.98(ddd, J =8.4, 8.4, 2.4, 1H), 5.42(d, J =11.0, 1H), 5.26(t, J =5.1, 1H, -OH), 4.99(d, J =11.0, 1H), 3.99-3.75(m, 5H), 3.45(m, 1H), 3.27(m, 1H), 3.06-2.88(m, 3H), 2.92(s, 3H), 2.79(m, 1H), 2.07(m, 1H), 1.43(s, 9H, 0, 0.55H), 2.55 (m, 1H), 2H) 0.10(m, 2H); 0.15(s, 9H).
Example D tert-butyl (4- { [ (4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate: (4- { [ (4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-))
Starting from 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c.3) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=654(MH+)。
1H-NMR(300 MHz, DMSO-d6): 9.05(d, J=7.7, 1H,-NH); 9.01(s, 1H); 7.39(ddd, J=9.1, 8.8, 3.1, 1H); 7.30(dd, J=8.6, 3.1, 1H); 7.20(dd, J=9.1, 4.4, 1H); 5.42(d, J=11.0, 1H); 4.99(d, J=11.0, 1H); 4.08(m, 1H); 3.84(dd, J=10.4, 6.6, 1H); 3.83(m, 2H); 3.77(dd, J=10.4, 7.1, 1H); 3.06(m, 2H); 2.94(m, 2H); 2.92(s, 3H); 1.93(m, 2H); 1.45(m, 2H); 1.42(s, 9H); 0.88(m, 1H); 0.55(m, 2H); 0.32(m, 2H); 0.04(m, 2H);-0.15(s, 9H)。
Example D tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (d 13
Starting from 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c.3) and commercial tert-butyl trans- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=668(MH+)。
1H-NMR(300 MHz, DMSO-d6) 9.01(s, 1H), 8.89(d, J =7.9, 1H, -NH), 7.38(ddd, J =9.1, 8.4, 3.3, 1H), 7.30(dd, J =8.6, 3.3, 1H), 7.20(dd, J =9.1, 4.4, 1H), 6.73(d, J =7.1, 1H, -NH), 5.42(d, J =11.0, 1H), 4.99(d, J =11.0, 1H), 3.84(dd, J =10.2, 6.6, 1H), 3.76(dd, J =10.2, 6.9, 1H and m, 1H), 3.28(m, 1H), 2.93(m, 2H), 2.91(s, 3H), 2.01(m, 2H), 2.9, 1H (m, 1H), 1H (m, 34H), 1H) (ii) a 0.55(m, 2H); 0.31(m, 2H); 0.04(m, 2H);-0.16(s, 9H)。
Example D tert-butyl (4- { [ (4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (14
Starting from 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c.3) and commercially available tert-butyl cis- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=668(MH+)。
1H-NMR(300 MHz, DMSO-d6): 9.26(d, J=7.9, 1H,-NH); 9.05(s, 1H); 7.39(ddd, J=9.1, 8.7, 3.1, 1H); 7.30(dd, J=8.7, 3.1, 1H); 7.20(dd, J=9.1, 4.4, 1H); 6.92(m, 1H,-NH); 5.42(d, J=11.1, 1H); 4.99(d, J=11.1, 1H); 4.07(m, 1H); 3.85(dd, J=10.4, 6.6, 1H); 3.77(dd, J=10.4, 7.0, 1H); 3.43(m, 1H); 2.94(m, 2H); 2.92(s, 3H); 1.85-1.52(m, 8H); 1.40(s, 9H); 0.87(m, 1H); 0.56(m, 2H); 0.32(m, 2H); 0.05(m, 2H);-0.15(s, 9H)。
Example D.d15: (3R,4R) -4- { [ (4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } -3-hydroxypiperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c.3) and commercial tert-butyl (R) -3-amino-pyrrolidine-1-carboxylate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=640(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.16(d, J=6.8, 1H,-NH); 8.99(s, 1H); 7.39(ddd, J=9.1, 8.4, 3.3, 1H); 7.30(ddd, J=8.6, 3.3, 1.1, 1H); 7.20(dd, J=9.1, 4.4, 1H); 5.43(d, J=10.9, 1H); 4.99(d, J=10.9, 1H); 4.50(m, 1H); 3.84(dd, J=10.2, 6.6, 1H); 3.76(d, J=10.2, 7.0, 1H); 3.62(m, 1H); 3.43(m, 2H); 3.27(m, 1H); 2.94(m, 2H); 2.92(s, 3H); 2.21(m, 1H); 1.96(m, 1H); 1.42(s, 9H); 0.88(m, 1H); 0.56(dd, J=9.1, 7.2, 2H); 0.31(m, 2H); 0.04(m, 2H);-0.16(s, 9H)。
Example D.d16: (3R)*,4R*) -4- { [ (4- [2- (cyclopropylmethoxy) -5-fluorophenyl)]-6-methyl-5- { [2- (trimethylsilyl) ethoxy ]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Amino } -3-hydroxypiperidine-1-carboxylic acid tert-butyl ester
From 4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxylic acid (example D. c3) and (3R)*,4R*) Starting from tert-butyl-4-amino-3-hydroxy-piperidine-1-carboxylate (example C2), the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=670(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 9.10(d, J =7.5, 1H, -NH), 9.01(s, 1H), 7.39(ddd, J =8.9, 8.9, 3.3, 1H), 7.30(ddd, J =8.4, 3.1, 0.7, 1H), 7.20(dd, J =8.9, 4.4, 1H), 5.43(d, J =11.1, 1H), 5.24(dd, J =5.1, 5.1, 1H, -OH), 4.99(d, J =11.1, 1H), 4.02-3.71(m, 5H), 3.45(m, 1H), 3.00-2.88(m, 3H), 2.92(s, 3H), 2.78(m, 1H), 2.07(m, 1H), 1.42(s, 9H, 1H), 0.89(m, 0.06, 0.89H), 2.06 (m, 1H), 2H) -0.15(s, 9H).
Example D.d 17: 4- ({ [4- (2-ethoxy-5-fluorophenyl) -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl ] carbonyl } amino) piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- (2-ethoxy-5-fluorophenyl) -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c. 4) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=628(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6, MeOH-d4) 9.05(d, J =7.5, 1H, -NH), 9.00(s, 1H), 7.40(ddd, J =9.1, 8.9, 3.3, 1H), 7.30(dd, J =8.6, 3.3, 1H), 7.21(dd, J =9.1, 4.4, 1H), 5.41(d, J =11.0, 1H), 4.98(d, J =11.0, 1H), 4.08(m, 1H), 3.99(qu, J =7.1, 2H), 3.85(m, 2H), 3.06(m, 2H), 2.94(m, 2H), 2.91(s, 3H), 1.93(m, 2H), 1.42(s, 9H and m, 2H), 1.02(t, J =7.5, 1H), -0.56 (m, 2H), 15.15 (m, 15H).
Example D.d 18: 4- { [ (4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 5) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=666(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 9.09(d, J =7.5, 1H, -NH), 8.96(s, 1H), 7.41(d, J =8.4, 1H), 6.73(dd, J =8.4, 2.2, 2H), 6.70(d, J =2.2, 1H), 5.46(d, J =10.9, 1H), 5.05(d, J =10.9, 1H), 4.06(m, 1H), 3.87(dd, J =10.2, 6.6, 1H), 3.85(s, 3H), 3.83(m, 2H), 3.78(dd, J =10.2, 7.1, 1H), 3.08(m, 2H), 2.91(s, 3H and m, 2H); 1.93(m, 2H); 1.45(m, 2H); 1.42(s, 9H); 0.89(m, 1H); 0.51(m, 2H); 0.33(m, 2H); 0.07(m, 2H);-0.18(s, 9H)。
Example D tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (19
Starting from 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 5) and commercial tert-butyl trans- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a colorless foam.
MS(ESI): m/z=680(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 8.96(s, 1H), 8.93(d, J =7.9, 1H, -NH), 7.41(d, J =8.4, 1H), 6.73(dd, J =8.4, 2.2, 2H), 6.70(d, J =2.2, 1H and br.s, 1H, -NH), 5.46(d, J =11.1, 1H), 5.05(d, J =11.1, 1H), 3.87(dd, J =10.2, 6.4, 1H), 3.85(s, 3H), 3.77(dd, J =10.2, 7.0, 1H and m, 1H), 3.28(m, 1H), 2.90(s, 3H and m, 2H), 2.00(m, 2H), 1.85(m, 2H), 1.9.9 (s, 1H), 1.9 (m, 1H), 89(m, 0, 89H), 2H) 0.33(m, 2H), 0.07(m, 2H), 0.18(s, 9H).
Example D tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (d 20:)
Starting from 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 5) and commercial cis- (4-amino-cyclohexyl) -carbamic acid tert-butyl ester, the title compound was obtained as a colorless foam.
MS(ESI): m/z=680(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 9.29(d, J =7.7, 1H, -NH), 9.01(s, 1H), 7.41(d, J =8.4, 1H), 6.92(br.s, 1H, -NH), 6.73(dd, J =8.4, 2.2, 2H), 6.70(d, J =2.2, 1H), 5.46(d, J =10.9, 1H), 5.06(d, J =10.9, 1H), 4.07(m, 1H), 3.88(dd, J =10.2, 6, 1H), 3.85(s, 3H), 3.78(dd, J =10.2, 7.1, 1H), 3.43(m, 1H), 2.91(s, 3H and m, 2H), 1.86-1.53(m, 8H), 1.40(s, 1H), 0.51(m, 1H), 0.34(m, 1H), 2H) 0.08(m, 2H); 0.18(s, 9H).
Example D tert-butyl (3R) -3- { [ (4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } pyrrolidine-1-carboxylate
Starting from 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 5) and commercial tert-butyl (R) -3-amino-pyrrolidine-1-carboxylate, the title compound was obtained as a colorless foam.
MS(ESI): m/z=652(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 9.20(d, J =6.8, 1H, -NH), 8.95(s, 1H), 7.41(d, J =8.4, 1H), 6.73(dd, J =8.4, 2.2, 2H), 6.69(d, J =2.2, 1H), 5.47(d, J =11.1, 1H), 5.06(d, J =11.1, 1H), 4.50(m, 1H), 3.87(dd, J =10.2, 6.6, 1H), 3.85(s, 3H), 3.78(dd, J =10.2, 7.1, 1H), 3.62(m, 1H), 3.43(m, 2H), 3.25(m, 1H), 2.91(s, 3H and m, 2H), 2.22(m, 1H), 1.96(m, 1H), 1.51 (m, 1H), 0.51(m, 1H), 2H) 0.33(m, 2H), 0.07(m, 2H), 0.17(s, 9H).
Example D tert-butyl (3R,4R) -3- { [ (4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } -4-hydroxypyrrolidine-1-carboxylate
From 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxylic acid (example d. c5) and commercially available (3R)*,4R*) Starting from tert-butyl-3-amino-4-hydroxy-pyrrolidine-1-carboxylate, the title compound was obtained as a colorless foam.
MS(ESI): m/z=668(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 9.13(br.s, 1H, -NH), 8.92(s, 1H), 7.41(d, J =8.4, 1H), 6.73(dd, J =8.4, 2.2, 2H), 6.70(d, J =2.2, 1H), 5.48(d, J =6.2, 1H), 5.47(d, J =11.0, 1H), 5.06(d, J =11.0, 1H), 4.26(m, 1H), 4.20(m, 1H), 3.87(dd, J =10.4, 6.6, 1H), 3.85(s, 3H), 3.77(dd, J =10.4, 7.3, 1H), 3.68(m, 1H), 3.55(m, 1H), 3.24(m, 2H), 2.91(s, 2H), 3.51 (m, 1H), 89(m, 1H), 2H) 0.33(m, 2H), 0.07(m, 2H), 0.18(s, 9H).
Example D.d 23: 4- { [ (4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 6) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a colorless foam.
MS(ESI): m/z=666(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.07(d, J=7.7, 1H,-NH); 9.00(s, 1H); 7.11(d, J=1.6, 2H); 7.02(t, J=1.6, 1H); 5.42(d, J=10.9, 1H); 5.04(d, J =10.9, 1H), 4.08(m, 1H), 3.85(m, 2H), 3.77(dd, J =10.2, 6.6, 1H), 3.76(s, 3H), 3.70(dd, J =10.2, 6.9, 1H), 3.06(m, 2H), 2.91(s, 3H and m, 2H), 1.93(m, 2H), 1.46(m, 2H), 1.42(s, 9H), 0.86(m, 1H), 0.53(m, 2H), 0.30(m, 2H), 0.01(m, 2H); 0.17(s, 9H).
Example D tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 6) and commercial tert-butyl trans- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=680(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 9.00(s, 1H), 8.91(d, J =7.7, 1H, -NH), 7.11(d, J =1.6, 2H), 7.02(t, J =1.6, 1H), 6.72(d, J =7.5, 1H, -NH), 5.41(d, J =11.0, 1H), 5.03(d, J =11.0, 1H), 3.77(dd, J =10.2, 6.6, 1H), 3.76(s, 3H and m, 1H), 3.70(dd, J =10.2, 6.9, 1H), 3.29(m, 1H), 2.90(s, 3H and m, 2H), 2.01(m, 2H), 1.86(m, 2H), 1.39(s, 9H), 1.34(m, 4H), 0.85(m, 0.53H), 2.53 (m, 0H, 2H) 0.01(m, 2H); 0.17(s, 9H).
Example D tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate d25
Starting from 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 6) and commercial cis- (4-amino-cyclohexyl) -carbamic acid tert-butyl ester, the title compound was obtained as a colorless foam.
MS(ESI): m/z=680(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 9.27(d, J =7.7, 1H, -NH), 9.04(s, 1H), 7.11(d, J =1.6, 2H), 7.02(t, J =1.6, 1H), 6.92(~ br.d, 1H, -NH), 5.41(d, J =11.0, 1H), 5.03(d, J =11.0, 1H), 4.07(m, 2H), 3.78(dd, J =10.2, 6.6, 1H), 3.76(s, 3H), 3.71(dd, J =10.2, 6.9, 1H), 3.43(m, 1H), 2.91(s, 3H and m, 2H), 1.85-1.52(m, 8H), 1.40(s, 9H), 0.86(m, 1H), 0.54(m, 2H), 0.02(m, 17H), 9H) In that respect
Example D tert-butyl (3R) -3- { [ (4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } pyrrolidine-1-carboxylate
Starting from 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 6) and commercial tert-butyl (R) -3-amino-pyrrolidine-1-carboxylate, the title compound was obtained as a colorless foam.
MS(ESI): m/z=652(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 9.18(d, J =6.8, 1H, -NH), 8.98(s, 1H), 7.11(d, J =1.8, 2H), 7.02(t, J =1.8, 1H), 5.43(d, J =10.9, 1H), 5.03(d, J =10.9, 1H), 4.50(m, 1H), 3.76(dd, J =10.4, 6.6, 1H and s, 3H), 3.70(dd, J =10.4, 6.9, 1H), 3.62(m, 1H), 3.43(m, 2H), 3.26(m, 1H), 2.91(s, 3H and m, 2H), 2.21(m, 1H), 1.96(m, 1H), 1.41(s, 9H), 0.85(m, 1H), 0.53(m, 0.01H), 2H) -0.17(s, 9H).
Example D.d27: (3R,4R) -4- { [ (4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } -3-hydroxypiperidine-1-carboxylic acid tert-butyl ester
From 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxylic acid (example D.c.6) and (3R)*,4R*) Starting from tert-butyl-4-amino-3-hydroxy-piperidine-1-carboxylate (example C2), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=682(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 9.11(d, J =7.3, 1H, -NH), 8.99(s, 1H), 7.11(d, J =1.6, 2H), 7.02(t, J =1.6, 1H), 5.43(d, J =10.9, 1H), 5.24(t, J =4.9, 1H, -OH), 5.04(d, J =10.9, 1H), 3.99-3.66(m, 5H), 3.76(s, 3H), 3.45(m, 1H), 2.91(s, 3H and m, 1H), 2.79(m, 1H), 2.07(m, 1H), 1.42(s, 9H and m, 1H), 0.86(m, 1H), 0.53(m, 2H), 0.30(m, 2H), 0.02(m, 2H), 0.17(s, 17H).
Example D.d 28: 4- { [ (4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c. 7) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=650(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.08(d, J=7.7, 1H,-NH); 8.98(s, 1H); 7.34(dd, J=8.4, 2.0, 1H); 7.26(d, J=2.0, 1H); 7.07(d, J=8.4, 1H); 5.43(d, J=11.0, 1H); 5.02(d, J=11.0, 1H); 4.08(m, 1H); 3.87(m, 2H); 3.82(dd, J=10.4, 6.6, 1H); 3.75(dd, J=10.4, 7.0, 1H); 3.06(m, 2H); 2.93-2.86(m, 2H); 2.90(s, 3H); 2.32(s, 3H); 1.93(m, 2H); 1.46(m, 2H); 1.43(s, 9H); 0.88(m, 1H); 0.52(m, 2H); 0.31(m, 2H); 0.05(m, 2H);-0.17(s, 9H)。
Example D tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c. 7) and commercial tert-butyl trans- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=664(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 1H-NMR(400 MHz, DMSO-d6): 8.98(s, 1H); 8.92(d, J=7.7, 1H,-NH); 7.34(dd, J=8.4, 2.0, 1H); 7.27(d, J=2.0, 1H); 7.07(d, J=8.4, 1H); 6.72(d, J=6.6, 1H,-NH); 5.42(d, J=11.0, 1H); 5.02(d, J=11.0, 1H); 3.81(dd, J=10.3, 6.5, 1H); 3.78(m, 1H); 3.74(dd, J=10.2, 7.0, 1H); 3.28(m, 1H); 2.90(s, 3H); 2.88(m, 2H); 2.32(s, 3H); 2.00(m, 2H); 1.86(m, 2H); 1.39(s, 9H); 1.36(m, 4H); 0.88(m, 1H); 0.51(m, 2H); 0.31(m, 2H); 0.04(m, 2H);-0.18(s, 9H)。
Example D tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (d 30
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c. 7) and commercial tert-butyl cis- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a colorless foam.
MS(ESI): m/z=664(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.31(d, J=7.7, 1H,-NH); 9.03(s, 1H); 7.34(dd, J=8.4, 2.0, 1H); 7.27(d, J=2.0, 1H); 7.07(d, J=8.4, 1H); 6.89(br.s, 1H,-NH); 5.42(d, J=11.0, 1H); 5.04(d, J=11.0, 1H); 4.09(m, 1H); 3.83(dd, J=10.2, 6.6, 1H); 3.75(dd, J=10.2, 6.9, 1H); 3.44(m, 1H); 2.91(s, 3H); 2.90(m, 2H); 2.33(s, 3H); 1.86-1.55(m, 8H); 1.41(s, 9H); 0.90(m, 1H); 0.53(m, 2H); 0.33(m, 2H); 0.06(m, 2H);-0.17(s, 9H)。
Example D.d 31: 4- { [ (4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 8) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a colorless foam.
MS(ESI): m/z=704(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6) 9.05(d, J =7.6, 1H, -NH), 9.03(s, 1H), 7.91(dd, J =8.8, 2.1, 1H), 7.77(d, J =2.1, 1H), 7.39(d, J =8.8, 1H), 5.40(d, J =11.0, 1H), 4.95(d, J =11.0, 1H), 4.08(m, 1H), 3.98(dd, J =10.4, 6.6, 1H), 3.91(dd, J =10.4, 7.1, 1H), 3.85(m, 2H), 3.06(m, 2H), 2.92(s, 3H and t, J =8.2, 2H), 1.94(m, 2H), 1.47(m, 2H), 1.42(s, 0.5H), 0.35(m, 0.5H), 2H) -0.19(s, 9H).
Example D tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-2-d-e
Starting from 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c8) and commercial tert-butyl trans- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a colorless foam.
MS(ESI): m/z=718(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6) 9.03(s, 1H), 8.89(d, J =7.7, 1H, -NH), 7.90(dd, J =8.8, 2.1, 1H), 7.77(d, J =2.1, 1H), 7.39(d, J =8.8, 1H), 6.72(d, J =7.9, 1H, -NH), 5.40(d, J =11.0, 1H), 4.94(d, J =11.0, 1H), 3.98(dd, J =10.5, 6.6, 1H), 3.91(dd, J =10.5, 7.1, 1H), 3.78(m, 1H), 3.29(m, 1H), 2.91(s, 3H and t, J =8.0, 2H), 2.01(m, 2H), 1.85(m, 1H), 3.0 (m, 1H), 50.50 (m, 1H), 2H) 0.35(m, 2H), 0.11(m, 2H), 0.19(s, 9H).
Example D tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate 33: (cis-4- { [ (4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5- { [ 3- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c8) and commercial tert-butyl cis- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a colorless foam.
MS(ESI): m/z=718(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6) 9.26(d, J =7.7, 1H, -NH), 9.07(s, 1H), 7.91(dd, J =8.8, 2.1, 1H), 7.78(d, J =2.1, 1H), 7.40(d, J =8.8, 1H), 6.93(br.s, 1H, -NH), 5.40(d, J =10.9, 1H), 4.94(d, J =10.9, 1H), 4.08(m, 1H), 3.99(dd, J =10.2, 6.7, 1H), 3.92(dd, J =10.2, 7.1, 1H), 3.43(m, 1H), 2.92(s, 3H and t, J =8.1, 2H), 1.86-1.51(m, 8H), 1.40(s, 9H), 0.1H (0.95, 0.0.36H), 0.36(m, 0.12H), 2H) -0.19(s, 9H).
Example D.d 34: 4- { [ (4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c. 9) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=678(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 9.08(d, J =7.7, 1H, -NH), 9.05(s, 1H), 7.96(dd, J =8.8, 2.2, 1H), 7.80(d, J =2.2, 1H), 7.74(d, J =8.8, 1H), 5.41(d, J =11.0, 1H), 4.97(d, J =11.0, 1H), 4.22-4.04(m, 2H and m, 1H), 3.88(m, 2H), 3.09(m, 2H), 2.95(s, 3H and m, 2H), 1.97(m, 2H), 1.50(m, 2H), 1.46(s, 9H), 1.11(t, J =7.0, 3H), 0.55(m, 2H) — 0.15(s, 9H).
Example D.d 35: 4- { [ (4- [ 2-cyclopropylmethoxy-4-fluoro-5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 10) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a colorless foam.
MS(ESI): m/z=684(MH+, 100 %); 628(MH+-C4H8)。
1H-NMR(300 MHz, DMSO-d6): 9.06(d, J=7.5, 1H,-NH); 9.00(s, 1H); 7.27(d, J=9.7, 1H); 7.19(d, J=13.1, 1H); 5.42(d, J=10.9, 1H); 5.03(d, J=10.9, 1H); 4.08(m, 1H); 3.87(m, 2H); 3.82(s, 3H); 3.80(dd, J=10.3, 6.7, 1H); 3.75(dd, J=10.3, 7.1, 1H); 3.06(m, 2H); 3.03-2.88(m, 2H); 2.91(s, 3H); 1.93(m, 2H); 1.46(m, 2H); 1.42(s, 9H); 0.87(m, 1H); 0.55(m, 2H); 0.31(m, 2H); 0.04(m, 2H);-0.16(s, 9H)。
Example D tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate 36: (trans-4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 10) and commercial tert-butyl trans- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a colorless foam.
MS(ESI): m/z=698(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 9.00(s, 1H), 8.90(d, J =7.7, 1H), 7.27(d, J =9.7, 1H), 7.19(d, J =13.3, 1H), 6.72(d, J =7.5, 1H, -NH), 5.41(d, J =10.9, 1H), 5.03(d, J =10.9, 1H), 3.82(s, 3H and m, 1H), 3.80(dd, J =10.4, 6.7, 1H), 3.72(dd, J =10.4, 7.0, 1H), 3.29(m, 1H), 3.03-2.88(m, 2H), 2.91(s, 3H), 2.00(m, 2H), 1.85(m, 2H), 1.39(s, 9H), 1.36(m, 4H), 0.86H (m, 1H); 0.55(m, 2H); 0.31(m, 2H); 0.03(m, 2H);-0.16(s, 9H)。
Example D tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (d 37
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 10) and commercial tert-butyl cis- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a colorless foam.
MS(ESI): m/z=698(MH+, 100 %); 642(MH+-C4H8)。
1H-NMR(300 MHz, DMSO-d6): 9.26(d, J=7.8, 1H,-NH); 9.04(s, 1H); 7.27(d, J=9.5, 1H); 7.19(d, J=13.3, 1H); 6.91(br.s, 1H,-NH); 5.42(d, J=10.9, 1H); 5.02(d, J=10.9, 1H); 4.07(m, 1H); 3.82(s, 3H); 3.81(dd, J=10.2, 6.7, 1H); 3.73(dd, J=10.2, 7.0, 1H); 3.43(m, 1H); 3.04-2.89(m, 2H); 2.92(s, 3H); 1.87-1.51(m, 8H); 1.40(s, 9H); 0.88(m, 1H); 0.55(m, 2H); 0.32(m, 2H); 0.04(m, 2H);-0.16(s, 9H)。
Example D.d38: (3R)*,4R*) -4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl)]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Amino } -3-hydroxypiperidine-1-carboxylic acid tert-butyl ester
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxylic acid (example d. c10) and (3R)*,4R*) Starting from tert-butyl (4-amino-3-hydroxy-piperidine-1-carboxylate (example C2), the preparation is obtainedThe title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=700(MH+, 100 %); 644(MH+-C4H8)。
1H-NMR(300 MHz, DMSO-d6) 9.12(d, J =7.3, 1H, -NH), 9.01(s, 1H), 7.28(dd, J =9.7, 1.4, 1H), 7.20(d, J =12.6, 1H), 5.44(d, J =10.9, 1H), 5.27(dd, J =4.9, 4.2, 1H, -OH), 5.02(d, J =10.9, 1H), 3.99-3.68(m, 5H), 3.82(s, 3H), 3.44(m, 1H), 3.03-2.86(m, 3H), 2.92(s, 3H), 2.79(m, 1H), 2.07(m, 1H), 1.42(s, 9H and m, 1H), 0.87(m, 1H), 0.55(m, 2H), 0.32(m, 2H), 2.05 (m, 16H), 9H) In that respect
Example D.d39: (3S)*,4S*) -3- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl)]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Amino } -4-hydroxypiperidine-1-carboxylic acid tert-butyl ester
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxylic acid (example d. c10) and (3S)*,4S*) Starting from tert-butyl-3-amino-4-hydroxy-piperidine-1-carboxylate (example C3), the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=700(MH+, 100 %); 644(MH+-C4H8)。
Example D.d 40: 4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c11) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=668(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 9.07(d, J =7.7, 1H, -NH), 8.98(s, 1H), 7.38(d, J =9.3, 1H), 7.06(d, J =12.1, 1H), 5.43(d, J =11.0, 1H), 5.01(d, J =11.0, 1H), 4.08(m, 1H), 3.86(m, 2H and dd, J =10.8, 6.6, 1H), 3.77(dd, J =10.8, 7.1, 1H), 3.06(m, 2H), 2.94(m, 2H), 2.91(s, 3H), 2.24(d, J =1.3, 3H), 1.93(m, 2H), 1.45(m, 2H), 1.42(s, 9H), 0.90(m, 1H), 0.53(m, 2H), 0.33H (m, 17H), 9H) In that respect
Example D tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c11) and commercial tert-butyl trans- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=682(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 8.98(s, 1H), 8.91(d, J =7.9, 1H, -NH), 7.38(d, J =8.8, 1H), 7.05(d, J =11.9, 1H), 6.72(br.d, J =7.9, 1H, -NH), 5.42(d, J =10.9, 1H), 5.00(d, J =10.9, 1H), 3.86(dd, J =10.2, 6.6, 1H), 3.76(m, 1H and dd, J =10.2, 7.1, 1H), 3.29(m, 1H), 2.94(m, 2H), 2.92(m, 2H), 2.90(s, 3H), 2.23(d, J =1.1, 3H), 2.00(m, 2H), 1.85(m, 2H), 1.7 (m, 1H), 0.89(m, 3H), 2H) 0.32(m, 2H); 0.06(m, 2H); 0.17(s, 9H).
Example D tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c11) and commercial tert-butyl cis- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=682(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.28(d, J=7.7, 1H,-NH); 9.03(s, 1H); 7.39(d, J=8.9, 1H); 7.06(d, J=11.9, 1H); 6.91(br.s, 1H,-NH); 5.43(d, J=11.1, 1H); 5.01(d, J=11.1, 1H); 4.07(m, 1H); 3.87(dd, J=10.4, 6.6, 1H); 3.77(dd, J=10.4, 7.1, 1H); 3.43(m, 1H); 2.94(m, 2H); 2.91(s, 3H); 2.24(d, J=1.3, 3H); 1.86-1.51(m, 8H); 1.40(s, 9H); 0.90(m, 1H); 0.53(m, 2H); 0.34(m, 2H); 0.07(m, 2H);-0.16(s, 9H)。
Example D.d 43: (3R,4R) -4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } -3-hydroxypiperidine-1-carboxylic acid tert-butyl ester
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxylic acid (example D.c. 11) and (3R)*,4R*) Starting from tert-butyl-4-amino-3-hydroxy-piperidine-1-carboxylate (example C2), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=684(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.11(d, J=7.3, 1H,-NH); 8.98(s, 1H); 7.39(d, J=8.9, 1H); 7.06(d, J=11.9, 1H); 5.44(d, J=11.0, 1H); 5.24(dd, J=4.9, 3.7, 1H,-OH); 5.02(d, J=11.0 1H); 4.00-3.37(m, 3H); 3.86(ddd, J=10.4, 7.9, 1.1, 1H); 3.77(ddd, J=10.4, 7.1, 2.7, 1H); 3.45(m, 1H); 2.98(m, 1H); 2.93(m, 2H); 2.92(s, 3H); 2.79(m, 1H); 2.24(s, 3H); 2.07(m, 1H); 1.42(s, 9H); 1.38(m, 1H); 0.90(m, 1H); 0.54(m, 2H); 0.34(m, 2H); 0.07(m, 2H);-0.16(s, 9H)。
Example D.d 44- { [ (4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 12) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=684(MH+, 100%); 628(MH+-C4H8)。
1H-NMR(300 MHz, DMSO-d6): 9.07(d, J=7.7, 1H,-NH); 8.98(s, 1H); 7.32(d, J=11.3, 1H); 6.94(d, J=7.3, 1H); 5.47(d, J=11.1, 1H); 5.07(d, J=11.1, 1H); 4.07(m, 1H); 3.96(s, 3H); 3.92-3.79(m, 4H); 3.06(m, 2H); 2.95(m, 2H); 2.92(s, 3H); 1.93(m, 2H); 1.45(m, 2H); 1.41(s, 9H); 0.88(m, 1H); 0.54(m, 2H); 0.33(m, 2H); 0.06(m, 2H);-0.17(s, 9H)。
Example D tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (d 45
Starting from 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 12) and commercial tert-butyl trans- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=698(MH+, 100%); 642(MH+-C4H8)。
1H-NMR(300 MHz, DMSO-d6): 8.98(s, 1H); 8.91(d, J=7.7, 1H,-NH); 7.32(d, J=11.3, 1H); 6.94(d, J=7.3, 1H); 6.72(d, J=7.5, 1H,-NH); 5.47(d, J=10.9 1H); 5.06(d, J=10.9, 1H); 3.96(s, 3H); 3.89(dd, J=10.2, 6.6, 1H); 3.81(dd, J=10.2, 7.1, 1H); 3.77(m, 2H); 2.94(m, 2H); 2.91(s, 3H); 2.00(m, 2H); 1.85(m, 2H); 1.39(s, 9H); 1.36(m, 4H); 0.88(m, 1H); 0.54(m, 2H); 0.32(m, 2H); 0.05(m, 2H);-0.18(s, 9H)。
Example D tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 12) and commercial tert-butyl cis- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a colorless foam.
MS(ESI): m/z=698(MH+, 100%); 642(MH+-C4H8)。
1H-NMR(300 MHz, DMSO-d6): 9.27(s, 1H,-NH); 9.02(s, 1H); 7.32(d, J=11.3, 1H); 6.91(d, J=7.3, 1H); 6.91(br.s, 1H,-NH); 5.47(d, J=11.1 1H); 5.07(d, J=11.1, 1H); 4.07(m, 1H); 3.96(s, 3H); 3.90(dd, J=10.3, 6.6, 1H); 3.82(dd, J=10.3, 6.9, 1H); 3.43(m, 1H); 3.05(m, 2H); 2.92(s, 3H); 1.77(m, 2H); 1.64(m, 6H); 1.40(s, 9H); 0.89(m, 1H); 0.54(m, 2H); 0.33(m, 2H); 0.07(m, 2H);-0.17(s, 9H)。
Example D.d47: (3R)*,4R*) -4- { [ (4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl) ]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Amino } -3-hydroxypiperidine-1-carboxylic acid tert-butyl ester
From 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxylic acid (example d. c12) and (3R)*,4R*) Starting from tert-butyl-4-amino-3-hydroxy-piperidine-1-carboxylate (example C2), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=700(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.12(d, J=7.7, 1H,-NH);[8.98(s), 8.96(s), 1H)]; 7.34(d, J=11.5, 1H); 6.94(d, J=7.3, 1H);[5.50(d, J=11.0), 5.49(d, J=11.0), 1H)]5.27(t, J =4.9, 1H, -OH), 5.07(d, J =11.0, 1H), 3.96(s, 3H), 3.95-3.75(m, 5H), 3.44(m, 1H), 2.93(s, 3H and m, 3H), 2.79(m, 1H), 2.07(m, 1H), 1.42(s, 9H and m, 1H), 0.88(m, 1H), 0.54(m, 2H), 0.33(m, 2H), 0.06(m, 2H); 0.17(s, 9H).
Example D.d 48: 4- { [ (4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c. 14) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=664(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.08(d, J=7.5, 1H,-NH); 8.99(s, 1H); 7.37(dd, J=8.6, 2.2, 1H); 7.29(d, J=2.2, 1H); 7.08(d, J=8.6, 1H); 5.42(d, J=11.1, 1H); 5.03(d, J=11.1, 1H); 4.08(m, 1H); 3.87(m, 2H); 3.82(dd, J=10.2, 6.6, 1H); 3.75(dd, J=10.2, 6.9. .1H); 3.06(m, 2H); 2.94-2.82(m, 2H); 2.91(s, 3H); 2.63(qu, J=7.6, 2H); 1.94(m, 2H); 1.46(m, 2H); 1.40(s, 9H); 1.20(t, J=7.6, 3H); 0.89(m, 1H); 0.51(m, 2H); 0.32(m, 2H); 0.05(m, 2H);-0.19(s, 9H)。
Example D tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c. 14) and commercial tert-butyl trans- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=678(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 8.99(s, 1H), 8.92(d, J =7.3, 1H, -NH), 7.37(dd, J =8.6, 2.2, 1H), 7.29(d, J =2.2, 1H), 7.08(d, J =8.6, 1H), 6.72(d, J =8.1, 1H, -NH), 5.42(d, J =10.9, 1H), 5.02(d, J =10.9, 1H), 3.82(dd, J =10.2, 6.6, 1H), 3.74(dd, J =10.2, 6.9.. 1H and m, 1H), 3.27(m, 1H), 2.90(s, 3H), 2.88(t, J =8.2, 2H), 2.63(qu, 7.5, 2H), 2.27 (m, 1H), 2.90(s, 3H), 2.88(t, J =8.2, 2H), 2.63(qu, 7.5, 2H), 2 (m, 1H), 4H) 1.20(t, J =7.6, 3H), 0.88(m, 1H), 0.50(m, 2H), 0.31(m, 2H), 0.04(m, 2H), 0.19(s, 9H).
Example D tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c. 14) and commercial cis- (4-amino-cyclohexyl) -carbamic acid tert-butyl ester, the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=678(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 1H9.28(d, J =7.9, 1H, -NH), 9.03(s, 1H), 7.35(dd, J =8.6, 2.2, 1H), 7.30(d, J =2.2, 1H), 7.09(d, J =8.6, 1H), 6.92(br.d, J-7.2, 1H, -NH), 5.42(d, J =11.1, 1H), 5.03(d, J =11.1, 1H), 4.07(m, 1H), 3.83(dd, J =10.2, 6.4, 1H), 3.75(dd, J =10.2, 6.9.. 1H and m, 1H), 3.43(m, 1H), 2.91(s, 3H), 2.89(m, 2H), 2.64 (J = 10.9, 1H), and m, 1H), 3.43(m, 1H), 2.91(s, 3H), 2.89(m, 2H), 2.64 (J =7.9, 1H), 5.86 (t-1H, 1H), j =7.5, 3H), 0.90(m, 1H), 0.51(m, 2H), 0.33(m, 2H), 0.06(m, 2H), 0.18(s, 9H).
Example D.d 51: (3R)*,4R*) -3- { [ (4- [2- (cyclopropylmethoxy) -5-ethylphenyl)]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Amino } -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
From 4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d) ]Pyrimidine-7-carboxylic acid (example d. c14) and commercially available (3R)*,4R*) Starting from tert-butyl-3-amino-4-hydroxy-pyrrolidine-1-carboxylate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=666(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.13(br.s, 1H,-NH); 8.95(s, 1H); 7.37(dd, J=8.6, 2.4, 1H); 7.29(d, J=2.4, 1H); 7.09(d, J=8.6, 1H); 5.48(d, J=3.8, 1H,-OH); 5.43(d, J=10.9, 1H); 5.03(d, J=10.9, 1H); 4.27(m, 1H); 4.21(m, 1H); 3.83(d, J=10.2, 6.6, 1H); 3.74(ddd, J=10.2, 7.1, 0.9, 1H); 3.69(m, 1H); 3.56(m, 1H); 3.24(m, 2H); 2.91(s, 3H); 2.88(m, 2H); 2.63(qu, J=7.5, 2H); 1.40(s, 9H); 1.20(t, J=7.5, 3H); 0.87(m, 1H); 0.50(m, 2H); 0.32(m, 2H); 0.05(m, 2H);-0.18(s, 9H)。
Example D.d 52: 4- { [ (4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c15) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=678(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.08(d, J=7.7, 1H,-NH); 8.99(s, 1H); 7.40(dd, J=8.6, 2.2, 1H); 7.32(d, J=2.2, 1H); 7.09(d; J=8.6, 1H); 5.42(d, J=10.9, 1H); 5.04(d, J=10.9, 1H); 4.08(m, 1H); 3.90-3.79(m, 3H); 3.75(dd, J=10.2, 6.9, 1H); 3.06(m, 2H); 2.98-2.82(m, 3H); 2.91(s, 3H); 1.93(m, 2H); 1.47(m, 2H); 1.40(s, 9H); 1.22(dd, J=6.9, 2.2, 6H); 0.89(m, 1H); 0.50(m, 2H); 0.32(m, 2H); 0.05(m, 2H);-0.19(s, 9H)。
Example D tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5- (propan-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [2- (cyclopropylmethoxy) -5- (propan-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c15) and commercial tert-butyl trans- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=692(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 8.99(s, 1H), 8.92(d, J =7.7, 1H, -NH), 7.40(dd, J =8.6, 2.4, 1H), 7.32(d, J =2.4, 1H), 7.09(d; J =8.6, 1H), 6.72(br.d, J =8.6, 1H, -NH), 5.41(d, J =11.0, 1H), 5.03(d, J =11.0, 1H), 3.82(dd, J =10.2, 6.6, 1H), 3.74(dd, J =10.2, 6.9, 1H and m, 2H), 3.27(m, 1H), 2.99-2.80(sept, J =6.9, 1H and m, 2H), 2.90(s, 3H), 2.01(m, 2H), 2.80 (ddh, 1H), 2.9, 4 (ddh, 1H), 4H (ddh, 1H), j =6.9, 2.4, 6H), 0.89(m, 1H), 0.49(m, 2H), 0.32(m, 2H), 0.05(m, 2H), 0.19(s, 9H).
Example D tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -5- (propan-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [2- (cyclopropylmethoxy) -5- (propan-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c15) and commercial tert-butyl cis- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=692(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.28(d, J=7.9, 1H,-NH); 9.03(s, 1H); 7.41(dd, J =8.6, 2.4, 1H), 7.33(d, J =2.4, 1H), 7.09(d; J =8.6, 1H), 6.92(br.d, J-6.9, 1H, -NH), 5.41(d, J =11.0, 1H), 5.04(d, J =11.0, 1H), 4.07(m, 1H), 3.83(dd, J =10.4, 6.6, 1H), 3.75(dd, J =10.4, 6.9, 1H), 3.43(m, 1H), 2.91(s, 3H and m, 2H and sept, J =6.9, 1H), 1.85-1.53(m, 8H), 1.40(s, 9H), 1.24(dd, J = 6.4, 6.0H), 0.06(m, 0.06, 0H), 2H) -0.19(s, 9H).
Example D.d 55: 4- { [ (4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c13) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound is obtained as a pale yellow viscous oil.
MS(ESI): m/z=722(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6) 9.08(d, J =7.6, 1H, -NH), 9.00(s, 1H), 7.57(dd, J =8.7, 2.3, 1H), 7.50(d, J =2.3, 1H), 7.15(d, J =8.7, 1H), 5.40(d, J =11.0, 1H), 5.04(d, J =11.0, 1H), 4.09(m, 1H), 4.00(m, 2H), 3.90-3.70(m, 6H), 3.06(m, 2H), 2.97-2.83(s, 3H and m, 2H), 1.99(s, 3H), 1.94(m, 2H), 1.46(m, 2H), 1.43(s, 9H), 0.90(m, 1H), 0.49(m, 2H), 0.33(m, 2H), 0.07(m, 2H), 9H) In that respect
Example D tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate
Starting from 4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c13) and commercial tert-butyl trans- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=736(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6) 9.00(s, 1H), 8.93(d, J =7.6, 1H, -NH), 7.56(dd, J =8.7, 2.3, 1H), 7.50(d, J =2.3, 1H), 7.15(d, J =8.7, 1H), 6.72(br.d, J-7.5, 1H, -NH), 5.40(d, J =11.1, 1H), 5.03(d, J =11.1, 1H), 4.00(m, 2H), 3.86(dd, J =10.2, 6.6, 1H), 3.78 (dd.. J =10.2, 6.9, 1H), 3.73(m, 2H and m, 1H), 3.27(m, 1H), 2.97-2.82(m, 2H), 2.91(s, 3.1H), 2.91(s, 3.3.3H, 1H), 3.27(m, 1H), 9H) 1.34(m, 4H), 0.90(m, 1H), 0.49(m, 2H), 0.33(m, 2H), 0.06(m, 2H), 0.20(s, 9H).
Example D.d 57- { [ (4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example D.c. 16) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=664(MH+, 100%)
1H-NMR(300 MHz, DMSO-d6): 9.31(d, J=7.5, 1H,-NH); 7.32(dd, J=8.4, 2.0, 1H); 7.22(d, J=2.0, 1H); 7.04(d, J=8.4, 1H); 5.39(d, J=11.0, 1H); 4.98(d, J=11.0, 1H); 4.15-4.01(m, 1H); 3.87-3.69(m, 4H); 3.12(m, 2H); 2.87(m, 5H); 2.71(s, 3H); 2.32(s, 3H); 1.99-1.87(m, 2H); 1.46(m, 2H); 1.43(s, 9H); 0.89(m, 1H); 0.51(m, 2H); 0.32(m, 2H); 0.05(m, 2H);-0.17(s, 9H). 。
Example D.d 58: 4- { [ (4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 17) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a colorless foam.
MS(ESI): 698(MH+, 100%)
1H-NMR(300 MHz, DMSO-d6): 9.30(d, J=7.5, 1H,-NH); 7.28(d, J=11.3, 1H); 6.93(d, J=7.3, 1H), 5.43(d, J=11.0, 1H); 5.02(d, J=11.0, 1H); 4.13-4.00(m, 1H); 3.95(s, 3H); 3.93-3.74(m, 4H); 3.12(m, 2H); 2.94(m, 2H); 2.89(s, 3H); 2.71(s, 3H); 1.98-1.86(m, 2H); 1.47(m, 2H); 1.42(s, 9H); 0.88(m, 1H); 0.54(m, 2H); 0.33(m, 2H); 0.07(m, 2H);-0.17(s, 9H)。
Example D.d 59: 4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 18) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a colorless foam.
MS(ESI): m/z=698(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 9.29(d, J =7.5, 1H, -NH), 7.22(d, J =9.9, 1H), 7.17(d, J =13.3, 1H), 5.36(d, J =10.9, 1H), 4.97(d, J =10.9, 1H), 4.07(m, 1H), 3.81(s, 3H and dd, J =10.4, 6.6, 1H and m, 2H), 3.72(dd, J =10.4, 7.1, 1H), 3.12(m, 2H), 3.04-2.90(m, 2H), 2.88(s, 3H), 2.72(s, 3H), 1.93(m, 2H), 1.47(m, 2H), 1.40(s, 9H), 0.87(m, 1H), 0.56(m, 2H), 0.04(m, 2H), 0.32(m, 2H), 9H) In that respect
Example D60: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1S,2S) -2-hydroxycyclopentyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 18) and the commercially available (1S,2S) -2-amino-cyclopentanol, the title compound was obtained as a colorless foam.
MS(ESI): m/z=551(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.04(d, J=7.1, 1H,-NH); 8.98(s, 1H); 7.34(dd, J=8.6, 2.0, 1H); 7.27(d, J=2.0, 1H); 7.06(d, J=8.6, 1H); 5.43(d, J=11.0, 1H); 5.02(d, J=11.0, 1H); 4.91(dd, J=4.2, 1.3, 1H;-OH); 4.09(m, 1H); 4.00(m, 1H); 3.82(dd, J=10.2, 6.6, 1H); 3.74(dd, J=10.2, 6.9, 1H); 2.91(s, 3H); 2.88(t, J=7.8, 2H); 2.32(s, 3H); 2.12(m, 1H); 1.91(m, 1H); 1.74(m, 2H); 1.54(m, 2H); 0.88(m, 1H); 0.52(m, 2H); 0.32(m, 2H); 0.04(m, 2H);-0.17(s, 9H)。
Example D.d 61: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1S,2R) -2-hydroxycyclopentyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 18) and the commercially available (1R,2S) -2-amino-cyclopentanol, the title compound was obtained as a colorless foam.
MS(ESI): m/z=551(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.26(d, J=7.9, 1H,-NH); 8.96(s, 1H); 7.34(dd, J=8.4, 1.8, 1H); 7.28(d, J=1.8, 1H); 7.06(d, J=8.4, 1H); 5.43(d, J=11.1, 1H); 5.02(d, J=11.1, 1H); 4.92(dd, J=4.0, 3.8, 1H;-OH); 4.17(m, 1H); 4.04(m, 1H); 3.82(ddd, J=10.4, 6.6, 1.5, 1H); 3.74(ddd, J=10.4, 6.9, 2.2, 1H); 2.92(s, 3H); 2.88(t, J=7.9, 2H); 2.32(s, 3H); 2.03-1.73(m, 3H); 1.71-1.47(m, 3H); 0.88(m, 1H); 0.52(m, 2H); 0.31(m, 2H); 0.05(m, 2H);-0.17(s, 9H)。
Example D.d 62: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1R,2R) -2-hydroxycyclopentyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.c. 18) and the commercially available (1R,2R) -2-amino-cyclopentanol, the title compound was obtained as a colorless foam.
MS(ESI): m/z=551(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.04(d, J=7.1, 1H,-NH); 8.98(s, 1H); 7.34(dd, J=8.6, 2.0, 1H); 7.27(d, J=2.0, 1H); 7.06(d, J=8.6, 1H); 5.43(d, J=11.0, 1H); 5.02(d, J=11.0, 1H); 4.91(dd, J=4.2, 1.3, 1H;-OH); 4.09(m, 1H); 4.00(m, 1H); 3.82(dd, J=10.2, 6.6, 1H); 3.74(dd, J=10.2, 6.9, 1H); 2.91(s, 3H); 2.88(t, J=7.8, 2H); 2.32(s, 3H); 2.12(m, 1H); 1.91(m, 1H); 1.74(m, 2H); 1.54(m, 2H); 0.88(m, 1H); 0.52(m, 2H); 0.32(m, 2H); 0.04(m, 2H);-0.17(s, 9H)。
Example D.e1: 4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
A solution of tert-butyl 4- { [ (4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (3.74 g; 5.5 mmol), tetrabutylammonium fluoride trihydrate (5.21 g; 16.5 mmol) and ethane-1, 2-diamine (0.50 g; 8.25 mmol) from example D.d1 in tetrahydrofuran (40 mL) was heated to gentle reflux until the starting material was completely consumed (according to LC-MS). The crude product was purified by silica gel column chromatography (ethyl acetate/cyclohexane-1: 1 to 2:1) to give the title compound as a colorless solid.
MS(ESI): m/z=550(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.99(s, 1H,-NH); 8.93(s, 1H); 8.74(d, J=7.7, 1H,-NH); 7.00(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H); 4.04(m, 1H); 3.85(m, 2H); 3.76(d, J=6.8, 2H); 3.05(m, 2H); 2.76(s, 3H); 1.92(m, 2H); 1.44(m, 2H); 1.42(s, 9H); 0.87(m, 1H); 0.30(m, 2H); 0.12(m, 2H)。
The following compounds were prepared using a procedure similar to that described in example d.e. 1 above.
Example D tert-butyl { trans-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (trans-4- { [ (4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d2), the title compound was obtained as a colorless solid.
MS(ESI): m/z=564(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.96(s, 1H, -NH), 8.93(s, 1H), 8.58(d, J =7.7, 1H, -NH), 7.00(d, J =8.6, 1H), 6.71(br.d, J ~ 7.7, 1H, -NH), 6.55(d, J =8.6, 1H), 6.00(s, 2H), 3.76(d, J =6.8, 2H and m, 1H), 3.27(m, 1H), 2.76(s, 3H), 1.99(m, 2H), 1.84(m, 2H), 1.39(s, 9H), 1.34(m, 4H), 0.88(m, 1H), 0.30(m, 2H), 0.12(m, 2H).
Example D tert-butyl { cis-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (cis-4- { [ (4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d3), the title compound was obtained as a colorless solid.
MS(ESI): m/z=694(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 9.23(d, J=7.8, 1H,-NH); 9.05(s, 1H); 7.02(d, J=8.6, 1H); 6.91(br.d, J ~ 6.4, 1H,-NH); 6.57(d, J=8.6, 1H); 6.03(d, J=0.6, 1H); 5.92(d, J=0.6, 1H); 5.39(d, J=10.8, 1H); 5.12(d, J=10.8, 1H); 4.07(m, 1H); 3.76(dd, J=10.2, 6.6, 2H); 3.68(dd, J=10.2, 6.9, 1H); 3.34(m, 1H); 3.01(m, 2H); 2.92(s, 3H); 1.86-1.51(m, 8H); 1.40(s, 9H); 0.87(m, 1H); 0.61(m, 2H); 0.30(m, 2H); 0.02(m, 2H);-0.13(s, 9H)。
Example D tert-butyl (3R) -3- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylate (e4) }
Starting from tert-butyl (3R) -3- { [ (4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } pyrrolidine-1-carboxylate (example D.d4), the title compound was obtained as a colorless solid.
MS(ESI): m/z=536(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.03(s, 1H,-NH); 8.92(s, 1H); 8.85(d, J=6.8, 1H,-NH); 7.00(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H); 4.49(m, 1H); 3.76(d, 6.8, 2H); 3.61(m, 1H); 3.42(m, 2H); 3.22(m, 1H); 2.77(s, 3H); 2.20(m, 1H); 1.95(m, 1H); 1.42(s, 9H); 0.88(m, 1H); 0.30(m, 2H); 0.12(m, 2H)。
Example D.e5: (3R)*,4R*) -3- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
From (3R)*,4R*) -3- { [ (4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl)]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Starting from tert-butyl amino } -4-hydroxypyrrolidine-1-carboxylate (example d.d5), the title compound is obtained as a pale yellow viscous oil.
MS(ESI): m/z=552(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.05(br.s, 1H,-NH); 8.89(s, 1H); 8.79(br.s, 1H,-NH); 7.01(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H); 5.47(d, J=3.8, 1H,-OH); 4.21(m, 2H); 3.76(d, J=6.8, 2H); 3.68(m, 1H); 3.55(m, 1H); 3.26(m, 2H); 2.77(s, 3H); 1.43(s, 9H); 0.86(m, 1H); 0.31(m, 2H); 0.12(m, 2H)。
Example D.e6: 4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- { [ (4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (example D.d6), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=524(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.79(s, 1H, -NH), 8.94 (s.1H), 8.80(d, J =7.7, 1H, -NH), 7.66(dd, J =8.4, 6.9, 1H), 7.08(dd, J =11.5, 2.4, 1H), 6.96(ddd, J =8.4, 8.4, 2.4, 1H), 4.05(m, 1H), 3.91(d, J =6.9, 2H), 3.85(m, 2H), 3.05(m, 2H), 2.78(s, 3H), 1.92(m, 2H), 1.42(m, 2H and s, 9H), 0.96(m, 1H), 0.38(m, 2H): 0.25(m, 2H).
Example D tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d7), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=538(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.80(s, 1H,-NH); 8.95(s, 1H); 8.64(d, J=7.7, 1H,-NH); 7.66(dd, 8.4, 6.9, 1H); 7.09(dd, 11.3, 2.4, 1H); 6.96(ddd, 8.4, 8.4, 2.4, 1H); 6.77(d, J=7.7, 1H,-NH); 3.90(d, J=6.9, 2H); 3.76(m, 1H); 3.31(m, 1H); 2.77(s, 3H); 1.98(m, 2H); 1.85(m, 2H); 1.39(s, 9H); 1.33(m, 4H); 0.95(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example D tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate: (E8) }
Starting from tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d8), the title compound was obtained as a colorless viscous oil.
MS(ESI): m/z=538(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.76(s, 1H,-NH); 8.98(s, 1H); 8.97(d, J=6.6, 1H,-NH); 7.66(dd, 8.5, 7.1, 1H); 7.09(dd, 11.6, 2.3, 1H); 6.96(ddd, 8.5, 8.5, 2.3, 1H); 6.92(br.s, 1H,-NH); 4.04(m, 1H); 3.91(d, J=7.0, 2H); 3.43(m, 1H); 2.78(s, 3H); 1.85-1.54(m, 8H); 1.40(s, 9H); 0.96(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example D.e9: (3R) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester
Starting from (3R) -tert-butyl 3- { [ (4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } pyrrolidine-1-carboxylate (example d.d9), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=510(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.83(s, 1H,-NH); 8.93(s, 1H); 8.91(d, J=6.7, 1H,-NH); 7.66(dd, J=8.4, 6.9, 1H); 7.08(dd, J=11.5, 2.4, 1H); 6.96(ddd, J=8.4, 8.4, 2.4, 1H); 4.49(m, 1H); 3.91(d, J=6.9, 2H); 3.62(m, 1H); 3.43(m, 2H); 3.23(m, 1H); 2.79(s. .3H); 2.21(m, 1H); 1.94(m, 1H); 1.42(s, 9H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example D.e10: (3R)*,4R*) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
From (3R)*,4S*) -3- { [ (4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Starting from tert-butyl amino } -4-hydroxypyrrolidine-1-carboxylate (example d.d10), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=526(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.85(s, 1H,-NH); 8.91(s, 1H); 8.84(br.s, 1H,-NH); 7.66(dd, J=8.4, 6.9, 1H); 7.08(dd, J=11.7, 2.4, 1H); 6.96(ddd, J=8.4, 8.4, 2.4, 1H); 5.47(d, J=3.8, 1H,-OH); 4.26(m, 1H); 4.19(m, 1H); 3.91(d, 7.1, 2H); 3.68(m, 1H); 3.55(m, 1H); 3.25(m, 2H); 2.79(s. .3H); 1.43(s, 9H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example D.e11: (3S)*,4S*) -4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester
From (3S)*,4S*) -4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoroPhenyl radical]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Starting from tert-butyl amino } -3-hydroxypiperidine-1-carboxylate (example d.d11), the title compound is obtained as a colorless solid.
MS(ESI): m/z=540(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.798 s, 1H, -NH), 8.94(s, 1H), 8.84(d, J =7.3, 1H, -NH), 7.65(dd, J =8.6, 6.9, 1H), 7.08(dd, J =11.7, 2.4, 1H), 6.96(ddd, J =8.6, 8.6, 2.4, 1H), 5.24(d, J =4.9, 1H, -OH), 3.98-3.74(m, 3H), 3.91(d, J =6.9, 2H, -NH, 3.43(m, 1H), 2.98(m, 1H), 2.78 (s.. 3H), 2.06(m, 1H), 1.42(s, 9H and m, 1H), 0.96(m, 1H), 0.38(m, 2H), 0.25(m, 1H).
Example D.e12: 4- ({1- [4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl ] -formyloxy } -amino) -piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl (4- { [ (4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d12), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=524(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.83(s, 1H, -NH), 8.97(s, 1H), 8.79(d, J =7.6, 1H, -NH), 7.43(dd, J =9.0, 3.2, 1H), 7.37(ddd, J =9.1, 8.3, 3.2, 1H), 7.19(dd, J =9.1, 4.4, 1H), 4.07(m, 1H), 3.87(d, J =6.9, 2H), 3.84(m, 2H), 3.05(m, 2H), 2.79(s, 3H), 1.92(m, 2H), 1.42(s, 9H and m, 2H), 0.94(m, 1H), 0.36(m, 2H), 0.23(m, 2H).
Example D tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate: (E13)
Starting from tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d13), the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=538(MH+)。
1H-NMR(300 MHz, DMSO-d6): 11.81(br.s, 1H,-NH); 8.97(s, 1H); 8.62(d, J=7.8, 1H,-NH); 7.42(dd, J=8.9, 3.1, 1H); 7.36(ddd, J=9.0, 8.6, 3.1, 1H); 7.18(dd, J=9.0, 4.4, 1H); 6.72(d, J=7.5, 1H,-NH); 3.87(d, J=6.9, 2H); 3.82-3.70(m, 2H); 2.78(s, 3H); 1.98(m, 2H); 1.85(m, 2H); 1.39(s, 9H); 1.35(m, 4H); 0.93(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example D.e14 tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (4- { [ (4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d14), the title compound was obtained as a colorless solid.
MS(ESI): m/z=538(MH+)。
1H-NMR(300 MHz, DMSO-d6): 11.81(br.s, 1H,-NH); 9.00(s, 1H); 8.96(d, J=7.7, 1H,-NH); 7.43(dd, J=8.9, 3.3, 1H); 7.38(ddd, J=8.9, 8.2, 3.3, 1H); 7.19(dd, J=8.9, 4.4, 1H); 6.92(br.s, 1H,-NH); 4.04(m, 1H); 3.88(d, J=6.9, 2H); 3.42(m, 1H); 2.79(s, 3H); 1.85-1.53(m, 8H); 1.40(s, 9H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example D.e15: (3R) -3- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester
Starting from (3R) -tert-butyl 3- { [ (4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } pyrrolidine-1-carboxylate (example d.d15), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=510(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.87(s, 1H,-NH); 8.95(s, 1H); 8.89(d, J=6.8, 1H,-NH); 7.42(dd, J=8.9, 3.3, 1H); 7.38(ddd, J=9.1, 8.4, 3.3, 1H); 7.19(dd, J=9.1, 4.4, 1H); 4.49(m, 1H); 3.87(d, J=6.9, 2H); 3.62(m, 1H); 3.42(m, 2H); 3.22(m, 1H); 2.79(s, 3H); 2.20(m, 1H); 1.94(m, 1H); 1.42(s, 9H); 0.93(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example D.e16: (3R)*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester
From (3R)*,4R*) -4- { [ (4- [2- (cyclopropylmethoxy) -5-fluorophenyl)]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Starting from tert-butyl amino } -3-hydroxypiperidine-1-carboxylate (example d.d16), the title compound is obtained as a colorless solid.
MS(ESI): m/z=540(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.83(s, 1H,-NH); 8.97(s, 1H); 8.83(d, J=7.5, 1H,-NH); 7.42(ddd, J=9.1, 8.9, 3.3, 1H); 7.36(dd, J=8.2, 3.2, 1H); 7.19(dd, J=9.1, 4.4, 1H);5.24(d, J =4.9, 1H, -OH), 3.99-3.74(m, 3H), 3.87(d, J =6.8, 2H), 3.43(m, 1H), 2.98(m, 1H), 2.79(s, 3H and m, 1H), 2.06(m, 1H), 1.42(s, 9H and m, 1H), 0.94(m, 1H), 0.36(m, 2H), 0.22(m, 2H).
Example D.e17: 4- ({ [4- (2-ethoxy-5-fluorophenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl ] carbonyl } amino) piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- ({ [4- (2-ethoxy-5-fluorophenyl) -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl ] carbonyl } amino) piperidine-1-carboxylate (example D.d17), the title compound was obtained as a colorless solid.
MS(ESI): m/z=498(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6, MeOH-d4) 11.87(br.s, 1H, -NH), 8.96(s, 1H), 8.78(d, J =7.7, 1H, -NH), 7.43(ddd, J =9.1, 8.9, 3.3, 1H), 7.38(dd, J =8.2, 3.3, 1H), 7.22(dd, J =9.1, 4.4, 1H), 4.08(qu, J =6.9, 2H and m, 1H), 3.85(m, 2H), 3.05(m, 2H), 2.78(s, 3H), 1.92(m, 2H), 1.42(s, 9H and m, 2H), 1.11(t, J =6.9, 3H).
Example D.e18: 4- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- { [ (4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (example D.d18), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=
1H-NMR(300 MHz, DMSO-d6):
Example D tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d19) the title compound was obtained as a colorless solid.
MS(ESI): m/z=550(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.64(s, 1H, -NH), 8.91(s, 1H), 8.66(d, J =7.7, 1H, -NH), 7.58(d, J =8.4, 1H), 6.72(dd, J =8.4, 2.2, 1H), 6.68(d, J =2.2, 1H and br.s, 1H, -NH), 3.90(d, J =6.9, 2H), 3.85(s, 3H), 3.76(m, 1H), 3.28(m, 1H), 2.77(s, 3H), 1.99(m, 2H), 1.85(m, 2H), 1.39(s, 9H), 1.37-1.21(m, 4H), 0.95(m, 1H), 0.37(m, 2H), 0.26(m, 2H).
Example D tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate: (E20) }
Starting from tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d20), the title compound was obtained as a colorless solid.
MS(ESI): m/z=550(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.64(s, 1H,-NH); 8.99(d, J=7.9, 1H,-NH); 8.94(s, 1H); 7.59(d, J=8.4, 1H); 6.92(br.s, 1H,-NH); 6.72(dd, J=8.4, 2.2, 1H); 6.69(d, J=2.2, 1H); 4.03(m, 1H); 3.91(d , J=6.9, 2H); 3.86(s, 3H); 3.43(m, 1H); 2.77(s, 3H); 1.84-1.54(m, 8H); 1.40(s, 9H); 0.96(m, 1H); 0.38(m, 2H); 0.27(m, 2H)。
Example D.e21: (3R) -3- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester
Starting from (3R) -tert-butyl 3- { [ (4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } pyrrolidine-1-carboxylate (example d.d21), the title compound was obtained as a light yellow solid.
MS(ESI): m/z=522(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.71(s, 1H,-NH); 8.93(d, J=6.8, 1H,-NH); 8.89(s, 1H); 7.59(d, J=8.4, 1H); 6.72(dd, J=8.4, 2.2, 1H); 6.69(d, J=2.2, 1H); 4.48(m, 1H); 3.91(d, J=6.9, 2H); 3.86(s, 3H); 3.61(m, 1H); 3.43(m, 2H); 3.22(m, 1H); 2.78(s, 3H); 2.21(m, 1H); 1.93(m, 1H); 1.42(s, 9H); 0.96(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example D.e22: (3R)*,4R*) -3- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
From (3R)*,4R*) -3- { [ (4- [2- (cyclopropylmethoxy) -4-methoxyphenyl)]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Starting from tert-butyl amino } -4-hydroxypyrrolidine-1-carboxylate (example d.d22), the title compound was obtained as a colorless solid.
MS(ESI): m/z=538(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.73(br.s, 1H, -NH), 8.87(s, 1H and br.s, 1H, -NH), 7.59(d, J =8.4, 1H), 6.72(dd, J =8.4, 2.2, 1H), 6.69(d, J =2.2, 1H), 5.46(d, J =3.8, 1H, -OH), 4.25(m, 1H), 3.90(d, J =6.9, 2H), 3.86(s, 3H), 3.68(m, 1H), 3.54(m, 1H), 3.23(m, 2H), 2.78(s, 3H), 1.43(s, 9H), 0.96(m, 1H), 0.38(m, 2H), 0.26(m, 2H).
Example D.e23: 4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- { [ (4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (example D.d23), the title compound was obtained as a colorless viscous oil.
MS(ESI): m/z=536(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.76(s, 1H, -NH), 8.96(s, 1H), 8.80(d, J =7.7, 1H, -NH), 7.17(t, J =1.8, 1H), 7.11(d, J =1.8, 2H), 4.07(m, 1H), 3.87(m, 2H), 3.82(d, J =6.8, 2H), 3.77(s, 3H), 3.05(m, 2H), 2.78(s, 3H), 1.92(m, 2H), 1.42(s, 9H and m, 2H), 0.92(m, 1H), 0.34(m, 2H), 0.19(m, 2H).
Example D tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate: (E24) }
Starting from tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d24), the title compound was obtained as a colorless foam.
MS(ESI): m/z=450(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.07(s, 1H,-NH); 9.01(s, 1H); 8.59(d, J=7.9, 1H,-NH); 8.03(br.d, J ~ 4.8, 3H,-NH3 +) 7.20(t, J =1.8, 1H), 7.14(d, J =1.8, 2H), 3.84(d, J =6.9, 2H and m, 1H), 3.78(s, 3H), 3.09(m, 1H), 2.80(s, 3H), 2.04(m, 4H), 1.47(m, 4H), 0.92(m, 1H), 0.34(m, 2H), 0.19(m, 2H).
Example D.e25 tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d25), the title compound was obtained as a colorless foam.
MS(ESI): m/z=549(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 8.99(s, 1H); 8.97(d, J=7.9, 1H,-NH); 7.18(t, J=1.8, 1H); 7.11(d, J=1.8, 2H); 6.92(br.d, J ~ 7.1, 1H,-NH); 4.03(m, 1H); 3.83(d, J=6.9, 2H); 3.77(s, 3H); 3.43(m, 1H); 2.78(s, 3H); 1.85-1.52(m, 8H); 1.40(s, 9H); 0.92(m, 1H); 0.35(m, 2H); 0.20(m, 2H)。
Example D.e26: (3R) -3- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester
Starting from (3R) -3- { [ (4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } pyrrolidine-1-carboxylic acid tert-butyl ester (example D.d26), the title compound was obtained as a colorless viscous oil.
MS(ESI): m/z=522(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.80(s, 1H,-NH); 8.94(s, 1H); 8.91(d, J=6.8, 1H,-NH); 7.18(t, J=1.6, 2H); 7.11(d, J=1.6, 1H); 4.49(m, 1H); 3.82(d, J=6.9, 2H); 3.77(s, 2H); 3.62(m, 1H); 3.42(m, 2H); 3.22(m, 1H); 2.78(s, 3H); 2.21(m, 1H); 1.94(m, 1H); 1.42(s, 9H); 0.92(m, 1H); 0.34(m, 2H); 0.19(m, 2H)。
Example D.e27: (3R)*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester
From (3R)*,4R*) -4- { [ (4- [2- (cyclopropylmethoxy) -5-methoxyphenyl) ]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Starting from tert-butyl amino } -3-hydroxypiperidine-1-carboxylate (example d.d27), the title compound is obtained as a colorless viscous oil.
MS(ESI): m/z=552(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.76(s, 1H), 8.95(s, 1H), 8.85(d, J =7.3, 1H, -NH), 7.18(t, J =1.6, 1H), 7.11(d, J =1.6, 2H), 5.24(d, J =4.9, 1H, -OH), 3.98-3.79(m, 3H), 3.82(d, J =6.8, 2H), 3.77(s, 3H), 3.43(m, 1H), 2.98(m, 1H), 2.78(s, 3H and m, 1H), 2.06(m, 1H), 1.42(s, 9H), 1.38(m, 1H), 0.92(m, 1H), 0.35(m, 2H), 0.20(m, 2H).
Example D.e28: 4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- { [ (4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (example D.d28), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=520(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6) 11.73(s, 1H, -NH), 8.94(s, 1H), 8.82(d, J =7.7, 1H, -NH), 7.43(d, J =2.2, 1H), 7.33(dd, J =8.6, 2.0, 1H), 7.06(d, J =8.6, 1H), 4.06(m, 1H), 3.86(d, J =6.9, 2H and m, 2H), 3.05(m, 2H), 2.78(s, 3H), 2.33(s, 3H), 1.92(m, 2H), 1.43(s, 9H and m, 2H), 0.94(m, 1H), 0.35(m, 2H), 0.22(m, 2H).
Example D tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d29), the title compound was obtained as a colorless solid.
MS(ESI): m/z=534(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.71(s, 1H,-NH); 8.94(s, 1H); 8.65(d, J=7.7, 1H,-NH); 7.43(d, J=2.2, 1H); 7.32(dd, J=8.6, 2.0, 1H); 7.05(d, J=8.6, 1H); 6.72(d, J=7.1, 1H,-NH); 3.85(d, J=6.9, 2H); 3.76(m, 1H); 3.30(m, 1H); 2.77(s, 3H); 2.33(s, 3H); 1.99(m, 2H); 1.85(m, 2H); 1.39(s, 9H); 1.33(m, 4H); 0.94(m, 1H); 0.35(m, 2H); 0.22(m, 2H)。
Example D tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate: (E30) }
Starting from tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d30), the title compound was obtained as a colorless solid.
MS(ESI): m/z=534(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 9.00(d, J=9.3, 1H,-NH); 8.98(s, 1H); 7.43(d, J=2.1, 1H); 7.33(dd, J=8.4, 2.1, 1H); 7.06(d, J=8.4, 1H); 6.97(d, J=7.7, 1H,-NH); 4.03(m, 1H); 3.86(d, J=6.9, 2H); 3.42(m, 1H); 2.78(s, 3H); 2.32(s, 3H); 1.81-1.51(m, 8H); 1.40(s, 9H); 0.94(m, 1H);0.37(m, 2H); 0.23(m, 2H)。
Example D.e31: 4- [ ({4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- { [ (4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (example D.d31), the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=574(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.90(s, 1H,-NH); 8.99(s, 1H); 8.79(d, J=7.7, 1H,-NH); 7.91(d, J=2.0, 1H); 7.89(dd, J=8.8, 2.0, 1H); 7.38(d, J=8.8, 1H); 4.05(m, 1H); 4.00(d, J=6.9, 2H); 3.85(m, 2H); 3.05(m, 2H); 2.79(s, 3H); 1.93(m, 2H); 1.45(m, 2H); 1.43(s, 9H); 0.98(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example D tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d32), the title compound was obtained as a pale yellow solid.
Alternatively, the title compound was prepared from 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.g. 2) and commercial trans- (4-amino-cyclohexyl) -carbamic acid tert-butyl ester according to the method described in example d.d 1.
MS(ESI): m/z=588(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.87(s, 1H,-NH); 8.99(s, 1H); 8.62(d, J=7.7, 1H,-NH); 7.91(d, J=2.0, 1H); 7.89(dd, J=8.6, 2.0, 1H); 7.38(d, J=8.6, 1H); 6.72(d, J=7.2, 1H,-NH); 4.00(d, J=7.0, 2H); 3.76(m, 1H); 3.29(m, 1H); 2.78(s, 3H); 2.00(m, 2H); 1.85(m, 2H); 1.39(s, 9H); 1.36(m, 4H); 0.98(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example D tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate 33
Starting from tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d33) the title compound was obtained as a colorless solid.
MS(ESI): m/z=588(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.87(s, 1H,-NH); 9.03(s, 1H); 8.96(d, J=7.7, 1H,-NH); 7.91(d, J=2.1, 1H); 7.89(dd, J=8.5, 2.1, 1H); 7.38(d, J=8.5, 1H); 6.92(br.s, 1H,-NH); 4.06(m, 1H); 4.00(d, J=6.9, 2H); 3.43(m, 1H); 2.79(s, 3H); 1.84-1.54(m, 8H); 1.40(s, 9H); 0.99(m, 1H); 0.40(m, 2H); 0.28(m, 2H)。
Example D.e34: 4- [ ({4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- { [ (4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (example D.d34), the title compound was obtained as a colorless solid.
MS(ESI): m/z=548(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.92(s, 1H, -NH), 8.98(s, 1H), 8.78(d, J =7.7, 1H, -NH), 7.92(d, J =2.2, 1H), 7.90(dd, J =9.5, 2.2, 1H), 7.42(d, J =9.5, 1H), 4.21(qu, J =7.0, 2H), 4.06(m, 1H), 3.85(m, 2H), 3.05(m, 2H), 2.79(s, 3H), 1.97(m, 2H), 1.92(m, 2H), 1.42(s, 9H and m, 2H), 1.15(t, J =7.0, 3H).
Example D.e35: 4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- { [ (4- [ 2-cyclopropylmethoxy-4-fluoro-5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (example D.d35), the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=554(MH+, 100 %); 498(MH+-C4H8); 454(MH+-C5H8O2)。
1H-NMR(300 MHz, DMSO-d6) 11.78(s, 1H, -NH), 8.96(s, 1H), 8.79(d, J =7.8, 1H, -NH), 7.39(d, J =9.8, 1H), 7.18(d, J =13.5, 1H), 4.04(m, 1H), 3.87(m, 2H), 3.84(s, 3H and d, J =6.9, 2H), 3.05(m, 2H), 2.78(s, 3H), 1.93(m, 2H), 1.42(s, 9H and m, 1H), 1.29(m, 1H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example D tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example d.d36), the title compound was obtained as a colorless solid.
MS(ESI): m/z=568(MH+, 100 %); 512(MH+-C4H8)。
1H-NMR(300 MHz, DMSO-d6) 11.73(s, 1H, -NH), 8.96(s, 1H), 8.64(d, J =7.9, 1H, -NH), 7.39(d, J =9.9, 1H), 7.18(d, J =13.3, 1H), 6.72(d, J =7.7, 1H, -NH), 3.84(s, 3H and d, J =6.8, 2H), 3.76(m, 1H), 3.27(m, 1H), 2.78(s, 3H), 1.99(m, 2H), 1.85(m, 2H), 1.39(s, 9H), 1.35(m, 4H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example D tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example d.d37), the title compound was obtained as a colorless solid.
MS(ESI): m/z=568(MH+, 100 %); 512(MH+-C4H8); 468(MH+-C5H8O2)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 8.99(s, 1H); 8.96(d, J=7.7, 1H,-NH); 7.39(d, J=9.9, 1H); 7.19(d, J=13.3, 1H); 6.91(br.s, 1H,-NH); 4.03(m, 1H); 3.85(s, 3H); 3.84(d, J=6.8, 2H); 3.43(m, 1H); 2.78(s, 3H); 1.77(m, 2H); 1.64(m, 6H); 1.40(s, 9H); 0.93(m, 1H); 0.36(m, 2H); 0.21(m, 2H)。
Example D.e38: (3R)*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester
From (3R)*,4R*) -4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl)]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Starting from tert-butyl amino } -3-hydroxypiperidine-1-carboxylate (example d.d38), the title compound is obtained as a pale yellow viscous oil.
MS(ESI): m/z=570(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.75(s, 1H,-NH); 8.96(s, 1H); 8.84(d, J=7.3, 1H,-NH); 7.40(d, J=9.9, 1H); 7.18(d, J=13.3, 1H); 5.24(d, J=4.9, 1H,-OH); 3.99-3.73(m, 3H), 3.84(s, 3H and d, J =6.8, 2H), 3.43(m, 1H), 2.98(m, 1H), 2.79(s, 3H and m, 1H), 2.06(m, 1H), 1.42(s, 9H), 1.37(m, 1H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example D.e39: (3S)*,4S*) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester
From (3S)*,4S*) -3- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl)]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Starting from tert-butyl amino } -4-hydroxypiperidine-1-carboxylate (example d.d39), the title compound is obtained as a colorless solid.
MS(ESI): m/z=570(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.76(s, 1H, -NH), 8.92(s, 1H), 8.86(d, J =7.5, 1H, -NH), 7.40(d, J =9.9, 1H), 7.18(d, J =13.3, 1H), 5.09(d, J =4.6, 1H, -OH), 3.84(s, 3H and d, J =6.8, 2H and m, 3H), 3.69(m, 1H), 3.53(m, 1H), 3.31(m, 1H), 2.79(s, 3H), 1.90(m, 1H), 1.47(m, 1H), 1.31(br.s, 9H), 0.92(m, 1H), 0.36(m, 2H), 0.20(m, 2H).
Example D.e40: 4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (example D.d40), the title compound was obtained as a colorless solid.
MS(ESI): m/z=538(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.74(s, 1H, -NH), 8.93(s, 1H), 8.80(d, J =7.7, 1H, -NH), 7.54(d, J =9.1, 1H), 7.03(d, J =12.2, 1H), 4.06(m, 1H), 3.87(d, J =6.9, 2H), 3.84(m, 2H), 3.05(m, 2H), 2.78(s, 3H), 2.25(d, J =1.1, 3H), 1.92(m, 2H), 1.42(s, 9H and m, 2H), 0.95(m, 1H), 0.37(m, 2H), 0.24(m, 2H).
Example D tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d41), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=552(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(s, 1H,-NH); 8.93(s, 1H); 8.63(d, J=7.7, 1H,-NH); 7.54(dd, J=9.1, 0.6, 1H); 7.03(d, J=11.9, 1H); 6.72(d, J=6.9, 1H,-NH); 3.87(d, J=6.9, 2H); 3.76(m, 1H); 3.29(m, 1H); 2.77(s, 3H); 2.25(d, J=1.1, 3H); 1.99(m, 2H); 1.86(m, 2H); 1.39(s, 9H); 1.35(m, 4H); 0.95(m, 1H); 0.37(m, 2H); 0.23(m, 2H)。
Example D.e42 { cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester
Starting from tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d42), the title compound was obtained as a colorless viscous oil.
MS(ESI): m/z=552(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.72(s, 1H, -NH), 8.97(s, 1H and d, J =7.7, 1H, -NH), 7.54(d, J =9.7, 1H), 7.03(d, J =12.2, 1H), 6.92(br.s, 1H, -NH), 4.04(m, 1H), 3.88(d, J =6.9, 2H), 3.43(m, 1H), 2.78(s, 3H), 2.25(d, J =1.1, 3H), 1.81-1.52(m, 8H), 1.40(s, 9H), 0.95(m, 1H), 0.37(m, 2H), 0.24(m, 2H).
Example D.e43: (3R)*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester
From (3R)*,4R*) -4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl)]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d)]Pyrimidin-7-yl) carbonyl]Starting from tert-butyl amino } -3-hydroxypiperidine-1-carboxylate (example d.d43), the title compound is obtained as a colorless foam.
MS(ESI): m/z=554(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.74(s, 1H,-NH); 8.93(s, 1H); 8.84(d, J=7.3, 1H,-NH); 7.54(d, J=9.1, 1H); 7.03(d, J=12.0, 1H); 5.23(d, J=5.1, 1H,-OH); 3.99-3.74(m, 3H); 3.87(d, J=6.9, 2H); 3.43(m, 1H); 2.98(m, 1H); 2.81(m, 1H); 2.78(s, 3H); 2.25(d, J=1.1, 3H); 2.06(m, 1H); 1.42(s, 9H); 1.37(m, 1H); 0.94(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example D.e44: 4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- { [ (4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (example d.d44), the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=554(MH+, 100%); 498(MH+-C4H8); 454(MH+-C5H8O)。
1H-NMR(300 MHz, DMSO-d6) 11.72(s, 1H, -NH), 8.92(s, 1H), 8.81(d, J =7.7, 1H, -NH), 7.47(d, J =11.9, 1H), 6.92(d, J =7.3, 1H), 4.05(m, 1H), 3.97(s, 3H), 3.94(d, J =6.9, 2H), 3.84(m, 2H), 3.05(m, 2H), 2.98(s, 3H), 1.92(m, 2H), 1.42(s, 9H and m, 2H), 0.96(m, 1H), 0.38(m, 2H), 0.25(m, 2H).
Example D tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate: (E45)
Starting from (example d.d45), the title compound was obtained as a colorless foam. The compound can be further processed without characterization.
Example D tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example d.d46), the title compound was obtained as a colorless foam.
MS(ESI): m/z=568(MH+, 100%); 512(MH+-C4H8); 468(MH+-C5H8O2)。
1H-NMR(300 MHz, DMSO-d6): 11.69(s, 1H,-NH); 8.98(d, J=7.8, 1H,-NH); 8.96(s, 1H); 7.47(d, J=11.9, 1H); 6.93(d, J=7.1, 1H); 6.92(br.s, 1H,-NH); 4.04(m, 1H); 3.97(s, 3H); 3.94(d, J=6.9, 2H); 3.43(m, 1H); 2.79(s, 3H); 1.76(m, 2H); 1.64(m, 6H); 1.40(s, 9H); 0.96(m, 1H); 0.39(m, 2H); 0.25(m, 2H)。
Example D.e47: (3R)*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester
From (3R)*,4R*) -4- { [ (4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl)]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d) ]Pyrimidin-7-yl) carbonyl]Starting from tert-butyl amino } -3-hydroxypiperidine-1-carboxylate (example d.d47), the title compound is obtained as a pale yellow foam.
MS(ESI): m/z=570(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.72(s, 1H, -NH), 8.92(s, 1H), 8.85(d, J =7.3, 1H, -NH), 7.42(d, J =11.9, 1H), 6.92(d, J =7.3, 1H), 5.23(d, J =4.9, 1H, -OH), 3.97(s, 3H), 3.94(d, J =6.9, 2H and m, 2H), 3.82(m, 1H), 3.43(m, 1H), 2.99(m, 1H), 2.79(s, 3H and m, 1H), 2.06(m, 1H), 1.42(s, 9H and m, 1H), 0.96(m, 1H), 0.38(m, 2H), 0.25(m, 2H).
Example D.e48: 4- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- { [ (4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (example D.d48), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=534(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.75(s, 1H,-NH); 8.95(s, 1H); 8.82(d, J=7.7, 1H,-NH); 7.45(d, J=2.4, 1H); 7.36(dd, J=8.4, 2.4, 1H); 7.08(d, J=8.4, 1H); 4.06(m, 1H); 3.86(d, J=6.8, 2H); 3.84(m, 2H); 3.05(m, 2H); 2.78(s, 3H); 2.64(qu, J=7.6, 2H); 1.93(m, 2H); 1.45(m, 2H); 1.43(s, 9H); 1.18(t, J=7.6, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example D.e49 tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d49), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=548(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(s, 1H,-NH); 8.95(s, 1H); 8.65(d, J=7.7, 1H,-NH); 7.45(d, J=2.4, 1H); 7.35(dd, J=8.4, 2.4, 1H); 7.07(d, J=8.4, 1H); 6.72(d, J=7.3, 1H,-NH); 3.86(d, J=6.8, 2H); 3.75(m, 1H); 3.27(m, 1H); 2.77(s, 3H); 2.63(qu, J=7.5, 2H); 2.00(m, 2H); 1.85(m, 2H); 1.39(s, 9H); 1.34(m, 4H); 1.17(t, J=7.6, 3H); 0.94(m, 1H); 0.35(m, 2H); 0.22(m, 2H)。
Example D tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate 50
Starting from tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d50), the title compound was obtained as a colorless solid.
MS(ESI): m/z=548(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.72(s, 1H, -NH), 8.98(s, 1H and d, J =7.1, 1H, -NH), 7.45(d, J =2.4, 1H), 7.36(dd, J =8.4, 2.4, 1H), 7.08(d, J =8.6, 1H), 6.93(br.s, 1H, -NH), 4.04(m, 1H), 3.87(d, J =6.8, 2H), 3.43(m, 1H), 2.78(s, 3H), 2.64(qu, J =7.5, 2H), 1.85-1.54(m, 8H), 1.40(s, 9H), 1.19(t, J =7.5, 3H), 0.94(m, 1H), 0.36(m, 2H), 0.23(m, 2H).
Example D.e51: (3R)*,4R*) -3- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
From (3R)*,4R*) -3- { [ (4- [2- (cyclopropylmethoxy) -5-ethylphenyl)]-6-methyl-5- { [2- (trimethylsilyl) ethoxy]Methyl } -5H-pyrrolo [3, 2-d) ]Pyrimidin-7-yl) carbonyl]Starting from tert-butyl amino } -4-hydroxypyrrolidine-1-carboxylate (example d.d51), the title compound is obtained as a pale yellow viscous oil.
MS(ESI): m/z=536(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.80(s, 1H,-NH); 8.91(s, 1H); 8.85(br.s, 1H,-NH); 7.45(d, J=2.4, 1H); 7.36(dd, J=8.4, 2.4, 1H); 7.08(d, J=8.4, 1H); 5.47(d, J=3.8, 1H,-OH); 4.25(m, 1H); 4.19(m, 1H); 3.86(d, J=6.8, 2H); 3.68(m, 1H); 3.55(m, 1H); 3.22(m, 2H); 2.78(s, 3H); 2.63(qu, J=7.6, 2H); 1.43(s, 9H); 1.18(t, J=7.6, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example D.e52: 4- [ ({4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- { [ (4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (example D.d52), the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=548(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.75(s, 1H, -NH), 8.95(s, 1H), 8.81(d, J =7.7, 1H, -NH), 7.47(d, J =2.4, 1H), 7.39(dd, J =8.6, 2.4, 1H), 7.08(d; J =8.6, 1H), 4.06(m, 1H), 3.87(d, J =6.8, 2H and m, 2H), 3.05(m, 2H), 2.94(sept, J =6.9, 1H), 2.77(s, 3H), 1.92(m, 2H), 1.45(m, 2H), 1.43(s, 9H), 1.22(d, J =6.9, 6H), 0.94(m, 1H), 0.36(m, 2H), 0.23(m, 2H).
Example D tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (propan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d53), the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=692(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 8.99(s, 1H), 8.92(d, J =7.7, 1H, -NH), 7.40(dd, J =8.6, 2.4, 1H), 7.32(d, J =2.4, 1H), 7.09(d; J =8.6, 1H), 6.72(br.d, J =8.6, 1H, -NH), 5.41(d, J =11.0, 1H), 5.03(d, J =11.0, 1H), 3.82(dd, J =10.2, 6.6, 1H), 3.74(dd, J =10.2, 6.9, 1H and m, 2H), 3.27(m, 1H), 2.99-2.80(sept, J =6.9, 1H and m, 2H), 2.90(s, 3H), 2.01(m, 2H), 2.80 (ddh, 1H), 2.9, 4 (ddh, 1H), 4H (ddh, 1H), j =6.9, 2.4, 6H), 0.89(m, 1H), 0.49(m, 2H), 0.32(m, 2H), 0.05(m, 2H), 0.19(s, 9H).
Example D tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5- (propan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (cis-4- { [ (4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d54), the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=562(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(s, 1H,-NH); 8.99(s, 1H); 8.98(d, J=7.1, 1H,-NH); 7.47(d, J=2.4, 1H); 7.40(dd, J=8.6, 2.4, 1H); 7.09(d; J=8.6, 1H); 6.82(br.d, J ~6.0, 1H,-NH); 4.04(m, 1H); 3.87(d, J=6.8, 2H); 3.43(m, 1H); 2.95(sept, J=6.9, 1H); 2.77(s, 3H); 1.85-1.52(m, 8H); 1.40(s, 9H); 1.22(d, J=6.9, 6H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example D.e55: 4- [ ({4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- { [ (4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (example D.d55), the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=722(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6) 9.08(d, J =7.6, 1H, -NH), 9.00(s, 1H), 7.57(dd, J =8.7, 2.3, 1H), 7.50(d, J =2.3, 1H), 7.15(d, J =8.7, 1H), 5.40(d, J =11.0, 1H), 5.04(d, J =11.0, 1H), 4.09(m, 1H), 4.00(m, 2H), 3.90-3.70(m, 6H), 3.06(m, 2H), 2.97-2.83(s, 3H and m, 2H), 1.99(s, 3H), 1.94(m, 2H), 1.46(m, 2H), 1.43(s, 9H), 0.90(m, 1H), 0.49(m, 2H), 0.33(m, 2H), 0.07(m, 2H), 9H) In that respect
Example D tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from tert-butyl (trans-4- { [ (4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } cyclohexyl) carbamate (example D.d56), the title compound was obtained as a pale yellow viscous oil.
MS(ESI): m/z=606(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.75(s, 1H,-NH); 8.97(s, 1H); 8.65(d, J=7.7, 1H,-NH); 7.66(d, J=2.4, 1H); 7.55(dd, J=8.7, 2.4, 1H); 7.14(d, J=8.7, 1H); 6.72(br.d, J ~ 7.3, 1H,-NH); 3.99(m, 2H); 3.90(d, J=6.9, 2H); 3.76(m, 1H); 3.71(m, 2H); 3.27(m, 1H); 2.77(s, 3H); 2.01(m, 2H); 1.99(s, 3H); 1.86(m, 2H); 1.39(s, 9H); 1.34(m, 4H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example D.e57: 4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- { [ (4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (example D.d57), the title compound was obtained as a colorless solid.
MS(ESI): m/z=534(MH+ , 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.58(s, 1H,-NH); 9.04(d, J=7.7, 1H,-NH); 7.38(d, J=2.2, 1H); 7.31(dd, J=8.4, 2.2, 1H); 7.04(d, J=8.4, 1H); 4.13-3.99(m, 1H); 3.89-3.74(m, 4H); 3.12(m, 2H); 2.74(s, 3H); 2.72(s, 3H); 2.32(s, 3H); 1.97-1.86(m, 2H); 1.48(m, 2H); 1.43(s, 9H); 0.93(m, 1H); 0.35(m, 2H); 0.22(m, 2H)。
Example D.e58: 4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- { [ (4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (example d.d58), the title compound was obtained as a colorless foam.
MS(ESI): 568(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.56(s, 1H,-NH); 9.04(d, J=7.7, 1H,-NH); 7.43(d, J=11.7, 1H); 6.91(d, J=7.3, 1H); 4.06(m, 1H); 3.96(s, 3H); 3.93(d, J=6.9, 2H); 3.87-3.73(m, 2H); 3.12(m, 2H); 2.75(s, 3H); 2.71(s, 3); 1.98-1.85(m, 2H); 1.46(m, 2H); 1.42(s, 9H); 0.95(m, 1H); 0.38(m, 2H); 0.24(m, 2H)。
Example D.e59: 4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from tert-butyl 4- { [ (4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidin-7-yl) carbonyl ] amino } piperidine-1-carboxylate (example d.d59), the title compound was obtained as a colorless foam.
MS(ESI): m/z=568(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.60(s, 1H,-NH); 9.02(d, J=7.7, 1H,-NH); 7.33(d, J=9.9, 1H); 7.16(d, J=13.3, 1H); 4.05(m, 1H); 3.84(s, 3H); 3.82(d, J=6.8, 2H); 3.78(m, 2H); 3.12(m, 2H); 2.74(s, 3H); 2.73(s, 3H); 1.99-1.86(m, 2H); 1.47(m, 2H); 1.42(s, 9H); 0.92(m, 1H); 0.35(m, 2H); 0.20(m, 2H)。
The following compounds were prepared using a procedure similar to that described in example d.d1 above.
Example D.e60: 4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.g. 1) and commercial tert-butyl 4-amino-piperidine-1-carboxylate, the title compound was obtained as a light yellow foam.
MS(ESI): m/z=556(MH+, 100%).
1H-NMR(300 MHz, DMSO-d6): 11.85(s, 1H,-NH); 8.98(s, 1H); 8.80(d, J =7.7, 1H, -NH),. 7.83(d, J =2.0, 1H); 7.74(dd, J =8.8, 2.0, 1H); 7.31(d, J =8.8, 1H); 7.08(t, J =56.0, 1H); 4.07(m, 1H); 3.96(d, J =6.9, 2H); 3.91-3.79(m, 2H); 3.05(m, 2H); 2.79(s, 3H); 1.93(m, 2H); 1.43(s, 9H and m, 2H); 0.97(m, 1H); 0.38(m, 2H); 0.26(m, 2H).
Example D.e61 { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.g. 1) and commercial tert-butyl trans- (4-amino-cyclohexyl) -carbamate, the title compound was obtained as a light yellow foam.
MS(ESI): m/z=570(MH+, 100%).
1H-NMR(300 MHz, DMSO-d6): 11.82(s, 1H,-NH); 8.98(s, 1H); 8.64(d, J=7.9, 1H,-NH); 7.82(d, J=2.0, 1H); 7.74(dd, J=8.6, 2.0, 1H); 7.31(d, J=8.6, 1H); 7.08(t, J=56.0, 1H); 6.72(br.d, J=8.2, 1H,-NH); 3.96(d, J=6.9, 2H); 3.76(m, 1H); 3.29(m, 1H); 2.78(s, 3H); 1.98(m, 2H); 1.85(m, 2H); 1.39(s, 9H); 1.36(m, 4H); 0.97(m, 1H); 0.37(m, 2H); 0.26(m, 2H)。
Example D.e62: { (1S)*,2S*,4S*) -4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-2-Fluorocyclohexyl } carbamic acid tert-butyl ester
From 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxylic acid (example D.g.1) and [ (1S)*,2S*,4S*) -4-amino-2-fluorocyclohexyl]Starting from tert-butyl carbamate (example C22), the title compound is obtained in pale yellowA colored foam.
MS(ESI): m/z=588(MH+, 100%).
1H-NMR(300 MHz, DMSO-d6) 11.85(s, 1H, -NH), 8.99(s, 1H), 8.73(d, J =7.7, 1H, -NH), 7.83(d, J =2.0, 1H), 7.74(dd, J =8.6, 2.0, 1H), 7.31(d, J =8.6, 1H), 7.08(t, J =56.0, 1H), 6.93(br.s, 1H, -NH), 4.41(m, 1H), 3.96(d, J =6.9, 2H), 3.90(m, 1H), 3.51(m, 1H), 2.78(s, 3H), 2.41(m, 1H), 1.99-1.77(m, 2H), 1.65(m, 1H), 1.40(s, 9H and m, 2H), 0.97(m, 1H), 0.26(m, 0.26H), 2H) In that respect
Example D.e63: { (1S)*,3S*,4S*) -4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-methylcyclohexyl } carbamic acid tert-butyl ester
From 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxylic acid (example D.g. 1) and [ (1R) *,3R*,4R*) -4-amino-3-methylcyclohexyl group]Starting from tert-butyl carbamate (example C11), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=584(MH+, 100%).
1H-NMR(300 MHz, DMSO-d6): 11.87(s, 1H,-NH); 8.99(s, 1H); 8.58(d, J=8.6, 1H,-NH); 7.83(s, 1H); 7.75(d, J=8.8, 1H); 7.31(d, J=8.8, 1H); 7.09(t, J=56.2, 1H); 6.78(d, J=7.7, 1H,-NH); 3.96(d, J=6.8, 2H); 3.49(m, 1H); 3.35(m, 1H); 2.79(s, 3H); 2.03-1.75(m, 4H); 1.58(m, 1H); 1.391(s, 9H); 1.38-1.21(m, 1H); 1.06(m, 1H); 0.99(m, 1H); 0.94(d, J=6.4, 3H); 0.39(m, 2H); 0.28(m, 2H)。
Example D tert-butyl { (1S,3S) -3- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclopentyl } carbamate: { (1S,3S) -3- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclopentyl } carbamate
Starting from 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.g1) and tert-butyl [ (1S,3S) -3-aminocyclopentyl ] carbamate hydrochloride (example C6), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=556(MH+, 100%).
1H-NMR(300 MHz, DMSO-d6): 11.82(s, 1H,-NH); 8.98(s, 1H); 8.75(d, J=7.3, 1H,-NH); 7.83(t, J=1.1, 1H); 7.74(td, J=8.7, 1.1, 1H); 7.31(d, J=8.7, 1H); 7.08(t, J=56.0, 1H); 6.95(br.d, J ~ 5.5, 1H,-NH); 4.42(m, 1H); 3.98(m, 1H); 3.96(d, J=7.1, 2H); 2.78(s, 3H); 2.20-1.98(m, 2H); 1.84(m, 2H); 1.49(m, 2H); 1.40(s, 9H); 0.97(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example D.e65: N- [ (1S)*,3S*,4S*) -4-azido-3-methylcyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxylic acid (example D.g. 1) and (1R)*,3R*,4R*) Starting from-4-azido-3-methylcyclohexylamine hydrochloride (example C12), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=510(MH+, 100%).
1H-NMR(300 MHz, DMSO-d6): 11.87(s, 1H,-NH); 8.98(s, 1H); 8.65(d, J=8.4, 1H,-NH); 7.83(s, 1H); 7.75(d, J=8.6, 1H); 7.31(d, J=8.6, 1H); 7.09(t, J=55.8, 1H); 3.96(d, J=7.1, 2H); 3.88(m, 1H); 3.12(m, 1H); 2.78(s, 3H); 2.13-1.99(m, 3H); 1.62-1.37(m, 3H); 1.21(m, 1H); 1.02(d, J=6.5, 3H); 0.97(m, 1H); 0.38(m, 2H); 0.27(m, 2H)。
Example D.e66: (2S,4S) -4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (example d.g. 1) and commercial tert-butyl (2S,4S) -4-amino-2-methylpyrrolidine-1-carboxylate, the title compound was obtained as a light yellow foam.
MS(ESI): m/z=557(MH+, 100%).
1H-NMR(400 MHz, DMSO-d6) 11.88(s, 1H, -NH), 8.94(s, 1H), 8.87(d, J =6.2, 1H, -NH), 7.83(s, 1H), 7.74(d, J =8.7, 1H), 7.31(d, J =8.7, 1H), 7.08(t, J =56.0, 1H), 4.55(m, 1H), 3.96(d, J =7.0, 2H and m, 1H), 3.61(m, 1H), 3.29(m, 1H), 2.79(s, 3H), 2.14(m, 1H), 1.92(m, 1H), 1.41(s, 9H), 1.23(d, J =5.6, 3H), 0.97(m, 1H), 0.38(m, 2H), 0.26(m, 2H).
Example D.e67: N- [ (1R)*,2R*,4R*) -4-azido-2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxylic acid (example D.g. 1) and (1S)*,2S*,4S*) Starting from-4-azido-2-fluorocyclohexylamine hydrochloride (example C23), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=514(MH+, 100%).
1H-NMR(300 MHz, DMSO-d6): 11.89(s, 1H,-NH); 8.99(s, 1H); 8.80(d, J=8.2, 1H,-NH); 7.83(t, J=1.0, 1H); 7.75(td, J=8.6, 1.0, 1H); 7.31(d, J=8.6, 1H); 7.09(t, J=56.0, 1H); 4.69(tdd, J=49.9, 10.0, 4.5, 1H); 4.11(m, 1H); 3.96(d, J=6.9, 2H); 3.69(m, 1H); 2.79(s, 3H); 2.43(m, 1H); 2.06(m, 1H); 1.95(m, 1H); 1.68(m, 1H); 1.50(m, 2H); 0.98(m, 1H); 0.39(m, 2H); 0.26(m, 2H)。
Example D.e68: { (1S)*,2S*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl)]-6-methyl-5H-pyrrolo [3,2-d ]Pyrimidin-7-yl } carbonyl) amino]-2-methylcyclopentyl } carbamic acid tert-butyl ester
From 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxylic acid (example D.g.1) and [ (1S)*,2S*,4R*) -4-amino-2-methylcyclopentyl]Starting from tert-butyl carbamate (example C33), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=570(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.83(s, 1H,-NH); 8.99(s, 1H); 8.78(d, J=7.5, 1H,-NH); 7.83(d, J=1.1, 1H); 7.74(dd, J=8.7, 1.1, 1H); 7.31(d, J=8.7, 1H); 7.09(t, J=56.0, 1H); 6.87(d, J=8.2, 1H,-NH); 4.37(m, 1H); 3.97(d, J=6.9, 2H); 3.55(m, 1H); 2.78(s, 3H); 2.30(m, 1H); 1.95-1.72(m, 3H); 1.40(s, 9H); 1.20(m, 1H); 1.04(d, J=6.6, 3H); 0.98(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example D.e69: N- [ (1R)*,2R*,4S*) -4-azido-2-methylcyclopentyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxylic acid (example D.g. 1) and (1S)*,2S*,4R*) -4-azido-2-carbaldehydeStarting from cyclopentylamine hydrochloride (example C34), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=496(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.86(s, 1H,-NH); 8.98(s, 1H); 8.74(d, J=7.9, 1H,-NH); 7.83(dd, J=0.9, 0.9, 1H); 7.74(ddd, J=8.7, 0.9, 0.9, 1H); 7.31(d, J=8.7, 1H); 7.08(t, J=56.0, 1H); 4.20(m, 1H); 4.04(m, 1H); 3.96(d, J=7.1, 2H); 2.79(s, 3H); 2.39(m, 1H); 2.13(m, 1H); 2.03-1.83(m, 2H); 1.31(m, 1H); 1.09(d, J=7.1, 3H); 0.98(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example D.e70: { (1S)*,2S*,4S*) -4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-2-fluorocyclopentyl } carbamic acid tert-butyl ester
From 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxylic acid (example D.g. 1) and [ (1R)*,2R*,4R*) -4-amino-2-fluorocyclopentyl group]Starting from tert-butyl carbamate (example C44), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=574(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.84(s, 1H,-NH); 8.97(s, 1H); 8.90(d, J=7.5, 1H,-NH); 7.83(~s, 1H); 7.74(~d, J=8.6, 1H); 7.31(d, J=8.6, 1H); 7.14(br.d, J ~ 5.1, 1H,-NH); 7.08(t, J=55.9, 1H); 4.93(dm, J=52.2, 1H); 4.60(m, 1H); 4.09(m, 1H); 3.96(d, J=6.9, 2H); 2.79(s, 3H); 2.44(m, 1H); 2.03(m, 2H); 1.83(m, 1H); 1.41(s, 9H); 0.98(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example D.e71: N- [ (1R)*,2R*,4R*) -4-azido-2-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxylic acid (example D.g. 1) and (1R)*,2R*,4R*) Starting from-4-azido-2-fluorocyclopentamine hydrochloride (example C45), the title compound was obtained as a pale yellow foam.
MS(ESI): m/z=500(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.90(s, 1H,-NH); 8.99(s, 1H); 8.85(d, J=7.5, 1H,-NH); 7.83(~s, 1H); 7.74(~d, J=8.7, 1H); 7.31(d, J=8.7, 1H); 7.08(t, J=56.0, 1H); 5.16(dm, J=53.7, 1H); 4.59(m, 1H); 4.37(m, 1H); 3.96(d, J=7.1, 2H); 2.79(s, 3H); 2.67-2.47(m, 1H); 2.26-1.86(m, 3H); 0.97(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example D.e72: { (1S)*,2R*,4S*) -4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-2-Fluorocyclohexyl } carbamic acid tert-butyl ester
From 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxylic acid (example D.g. 1) and [ (1R)*,2S*,4R*) -4-amino-2-fluorocyclohexyl]Starting from tert-butyl carbamate (example C55), the title compound was obtained as a pale yellow foam.
HR-MS(ESI): m/z=588.2797([MH]+, C30H37F3N5O4 +Calculating the value: 588.2792).
1H-NMR(400 MHz, DMSO-d6): 11.88(s, 1H,-NH); 8.99(s, 1H); 8.63(d, J=7.9, 1H,-NH); 7.83(s, 1H); 7.75(d, J=8.7, 1H); 7.31(d, J=8.7, 1H); 7.09(t, J=55.8, 1H); 6.97(d, J=7.7, 1H); 4.86(~d, J=50.3, 1H); 4.12(m, 1H); 3.96(d, J=7.1, 2H); 3.55(m, 1H); 2.79(s, 3H); 2.30(m, 1H); 1.99(m, 1H); 1.85-1.60(m, 3H); 1.55(m, 1H); 1.41(s, 9H); 0.95(m,1H); 0.39(m, 2H); 0.27(m, 2H)。
Example D.e73: N- [ (1S)*,2R*,4S*) -4-azido-2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d ]Pyrimidine-7-carboxylic acid (example D.g. 1) and (1R)*,2S*,4R*) Starting from-4-azido-2-fluorocyclohexylamine hydrochloride (example C56), the title compound was obtained as a pale yellow foam.
HR-MS(ESI): m/z=514.2176([MH]+, C25H27F3N7O2 +Calculating the value: 514.2173).
1H-NMR(400 MHz, DMSO-d6): 11.92(s, 1H,-NH); 8.99(s, 1H); 8.98(d, J=6.9, 1H,-NH); 7.84(~s, 1H); 7.75(~d, J=8.7, 1H); 7.32(d, J=8.7, 1H); 7.09(t, J=56.0, 1H); 4.99(~d, J=50.1, 1H); 4.20(dm, J=31.9, 1H); 3.97(d, J=7.0, 2H); 3.77(m, 1H); 2.80(s, 3H); 2.33(m, 1H); 2.05(m, 1H); 1.96-1.67(m, 3H); 1.59(m, 1H); 0.98(m, 1H); 0.39(m, 2H); 0.28(m, 2H)。
Example D.f. 1: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Tert-butyl 4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (2.72 g; 4.95 mmol) from example D.e1 was dissolved in anhydrous 2-propanol (50 mL). After addition of 4M HCl/dioxane (5.0 mL), the stirred reaction mixture was heated to 80 ℃ for two hours. At room temperature, methyl tert-butyl ether (100 mL) was added. The precipitated product is isolated by suction filtration, washed with several portions of methyl tert-butyl ether and dried under high vacuum at 40 ℃ to give the title compound as a yellow solid.
MS(ESI): m/z=450(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.38(s, 1H,-NH); 9.03(s, 1H); 9.00(br.s, 2H,-NH2 +); 8.66(d, J=7.5, 1H,-NH); 7.04(d, J=8.6, 1H); 6.58(d, J=8.6, 1H); 6.03(s, 2H); 4.15(m, 1H); 3.78(d, J=6.8, 2H); 3.31(m, 2H); 3.08(m, 2H); 2.80(s, 3H); 2.13(m, 2H); 1.79(m, 2H); 0.90(m, 1H); 0.32(m, 2H); 0.15(m, 2H)。
The following compounds were prepared using a procedure similar to that described in example d.f. 1 above.
Example D.f. 2: N- (trans-4-aminocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { trans-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example D.e2), the title compound was obtained as a yellow solid.
MS(ESI): m/z=464(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.27(s, 1H,-NH); 8.98(s, 1H); 8.54(d, J=7.9, 1H,-NH); 8.04(br.d, J ~ 4.8, 3H,-NH3 +); 7.04(d, J=8.6, 1H); 6.57(d, J=8.6, 1H); 6.02(s, 2H); 3.80(m, 1H); 3.77(d, J=6.8, 2H); 3.09(m, 1H); 2.79(s, 3H); 2.04(m, 4H); 1.47(m, 4H); 0.89(m, 1H); 0.31(m, 2H); 0.14(m, 2H)。
Example D.f. 3: N- (cis-4-aminocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { cis-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example D.e3), the title compound was obtained as a yellow solid.
MS(ESI): m/z=464(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.40(s, 1H,-NH); 9.10(s, 1H); 8.91(d, J=7.5, 1H,-NH); 8.15(br.s, 3H,-NH3 +); 7.05(d, J=8.6, 1H); 6.58(d, J=8.6, 1H); 6.04(s, 2H); 4.12(m, 1H); 3.79(d, J=6.8, 2H); 3.17(m, 1H); 2.81(s, 3H); 1.96-1.64(m, 8H); 0.91(m, 1H); 0.33(m, 2H); 0.16(m, 2H)。
Example D.f. 4: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from (3R) -3- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (example d.e4), the title compound was obtained as a yellow solid.
MS(ESI): m/z=436(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.39(s, 1H,-NH); 9.32(br.s, 2H,-NH2 +); 9.02(s, 1H); 8.80(d, J=6.8, 1H,-NH); 7.04(d, J=8.6, 1H); 6.58(d, J=8.6, 1H); 6.03(s, 2H); 4.63(m, 1H); 3.78(d, 6.8, 2H); 3.52(m, 1H); 3.39(m, 1H); 3.26(m, 1H); 3.17(m, 1H); 2.79(s, 3H); 2.34(m, 1H); 2.01(m, 1H); 0.89(m, 1H); 0.31(m, 2H); 0.14(m, 2H)。
Example D.f. 5: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From (3R)*,4R*) -3- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]Starting from tert-butyl-4-hydroxypyrrolidine-1-carboxylate (example d.e5), the title compound is obtained as a yellow solid.
MS(ESI): m/z=452(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6, MeOH-d4): 9.04(s, 1H); 7.05(d, J=8.6, 1H); 6.60(d, J=8.6, 1H); 6.04(s, 2H); 4.43(m, 2H); 3.79(d, J=6.9, 2H); 3.67(m, 1H); 3.47(m, 1H); 3.33(m, 1H); 3.20(m, 1H); 2.81(s, 3H); 0.91(m, 1H); 0.33(m, 2H); 0.16(m, 2H)。
Example D.f6: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (example d.e6), the title compound was obtained as a yellow solid.
MS(ESI): m/z=424(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 12.15(s, 1H,-NH); 9.03(s. .1H); 8.99(br.s, 2H,-NH2 +); 8.71(d, J=7.7, 1H,-NH); 7.68(dd, J=8.4, 6.9, 1H); 7.12(dd, J=11.7, 2.4, 1H); 6.99(ddd, J=8.4, 8.4, 2.4, 1H); 4.15(m, 1H); 3.93(d, J=7.1, 2H); 3.31(m, 2H); 3.07(m, 2H); 2.80(s, 3H); 2.13(m, 2H); 1.79(m, 2H); 0.96(m, 1H); 0.38(m, 2H): 0.26(m, 2H)。
Example D.f7: N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e7), the title compound was obtained as a yellow solid.
MS(ESI): m/z=438(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 12.18(s, 1H,-NH); 9.00(s, 1H); 8.56(d, J=7.8, 1H,-NH); 8.10(br.s, 3H,-NH3 +); 7.68(dd, 8.4, 6.9, 1H); 7.12(dd, 11.7, 2.4, 1H); 7.00(ddd, 8.4, 8.4, 2.4, 1H); 3.93(d, J=6.9, 2H); 3.81(m, 1H); 3.08(m, 1H); 2.81(s, 3H); 2.04(m, 4H); 1.47(m, 4H); 0.96(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example D.f8: N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example D.e8), the title compound was obtained as a yellow solid.
MS(ESI): m/z=438(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 12.15(s, 1H,-NH); 9.09(s, 1H); 8.97(d, J=7.5, 1H,-NH); 8.14(br.s, 3H,-NH3 +); 7.69(dd, 8.6, 6.9, 1H); 7.12(dd, 11.7, 2.4, 1H); 7.00(ddd, 8.6, 8.6, 2.4, 1H); 4.13(m, 1H); 3.93(d, J=7.1, 2H); 3.18(m, 1H); 2.81(s, 3H); 1.87(m, 4H); 1.74(m, 4H); 0.97(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example D.f9: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from (3R) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (example d.e9), the title compound was obtained as a yellow solid.
MS(ESI): m/z=410(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 12.15(s, 1H,-NH); 9.31(br.s, 2H,-NH2 +); 9.01(s, 1H); 8.85(d, J=6.6, 1H,-NH); 7.68(dd, J=8.4, 6.9, 1H); 7.11(dd, J=11.7, 2.4, 1H); 6.99(ddd, J=8.4, 8.4, 2.4, 1H); 4.63(m, 1H); 3.93(d, J=7.1, 2H); 3.51(m, 1H); 3.39(m, 1H); 3.27(m, 1H); 3.16(m, 1H); 2.80(s. .3H); 2.35(m, 1H); 2.01(m, 1H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example D.f10: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From (3R)*,4R*) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]Starting from tert-butyl-4-hydroxypyrrolidine-1-carboxylate (example d.e10), the title compound is obtained as a yellow solid.
MS(ESI): m/z=426(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 12.07(s, 1H,-NH); 9.42(br.s, 2H,-NH2 +); 8.99(s, 1H); 8.85(d, J=6.0, 1H,-NH); 7.68(dd, J=8.4, 6.9, 1H); 7.11(dd, J=11.7, 2.4, 1H); 6.98(ddd, J=8.4, 8.4, 2.4, 1H); 4.53-4.34(m, 2H); 3.92(d, 7.1, 2H); 3.63(m, 1H); 3.43(m, 1H); 3.27(m, 1H); 3.16(m, 1H); 2.80(s. .3H); 0.95(m, 1H); 0.37(m, 2H); 0.26(m, 2H)。
Example D.f. 11: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4S*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From (3S) *,4S*) -4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]Starting from tert-butyl-3-hydroxypiperidine-1-carboxylate (example d.e. 11), the title compound is obtained as a yellow solid.
MS(ESI): m/z=440(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 12.20(s, 1H,-NH);[9.37(br.s), 9.04(br.s), 2H,-NH2 +); 9.04(s, 1H); 8.78(d, J=7.3, 1H,-NH); 7.69(dd, J=8.6, 6.9, 1H); 7.12(dd, J=11.7, 2.4, 1H); 7.00(ddd, J=8.6, 8.6, 2.4, 1H); 4.02(m, 1H); 3.93(d, 7.1, 2H); 3.63(m, 1H); 3.88(m, 1H); 3.26(m, 2H); 3.05(m, 1H); 2.86(m, 1H); 2.82(s. .3H); 2.24(m, 1H); 1.76(m, 1H); 0.97(m, 1H); 0.38(m, 2H); 0.27(m, 2H)。
Example D.f12: 4- (2-Cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride
Starting from 4- ({1- [4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl ] -formyloxy } -amino) -piperidine-1-carboxylic acid tert-butyl ester (example d.e12), the title compound was obtained as a yellow solid.
MS(ESI): m/z=424(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.03(br.s, 1H,-NH); 9.02(s, 1H); 8.78(br.s, 2H,-NH2 +); 8.75(d, J=6.5, 1H,-NH); 7.44(dd, J=9.0, 3.2, 1H); 7.40(ddd, J=9.1, 8.2, 3.2, 1H); 7.20(dd, J=9.1, 4.4, 1H); 4.15(m, 1H); 3.88(d, J=7.0, 2H); 3.32(m, 2H); 3.08(m, 2H); 2.80(s, 3H); 2.13(m, 2H); 1.78(m, 2H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example D.f13: N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e13), the title compound was obtained as a yellow solid.
MS(ESI): m/z=438(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.04(s, 1H,-NH); 8.99(s, 1H); 8.60(d, J=7.9, 1H,-NH); 8.07(br.s, 3H,-NH3 +); 7.44(dd, J=8.4, 3.2, 1H); 7.39(ddd, J=8.9, 8.3, 3.2, 1H); 7.20(dd, J=8.9, 4.3, 1H); 3.88(d, J=7.1, 2H); 3.81(m, 1H); 3.09(m, 1H); 2.80(s, 3H); 2.04(m, 4H); 1.47(m, 4H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example D.f. 14N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example D.e14), the title compound was obtained as a yellow solid.
MS(ESI): m/z=438(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.10(br.s, 1H,-NH); 9.08(s, 1H); 8.98(d, J=7.5, 1H,-NH); 8.15(br.s, 3H,-NH3 +); 7.46(dd, J=8.9, 3.3, 1H); 7.41(ddd, J=8.9, 8.6, 3.3, 1H); 7.21(dd, J=9.1, 4.4, 1H); 4.12(m, 1H); 3.89(d, J=6.9, 2H); 3.18(m, 1H); 2.81(s, 3H); 1.95-1.67(m, 8H); 0.95(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example D.f15: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from (3R) -3- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (example d.e15), the title compound was obtained as a yellow solid.
MS(ESI): m/z=410(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.15(s, 1H,-NH); 9.34(br.s, 2H,-NH2 +); 9.02(s, 1H); 8.86(d, J=6.6, 1H,-NH); 7.46(dd, J=8.9, 3.2, 1H); 7.41(ddd, J=9.1, 8.4, 3.2, 1H); 7.21(dd, J=9.1, 4.4, 1H); 4.64(m, 1H); 3.89(d, J=6.9, 2H); 3.50(m, 1H); 3.39(m, 1H); 3.27(m, 1H); 3.16(m, 1H); 2.81(s, 3H); 2.35(m, 1H); 2.01(m, 1H); 0.94(m, 1H); 0.35(m, 2H); 0.23(m, 2H)。
Example D.f16: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From (3R)*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]Starting from tert-butyl-3-hydroxypiperidine-1-carboxylate (example d.e16), the title compound is obtained as a yellow solid.
MS(ESI): m/z=440(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6, MeOH-d4) 9.05(s, 1H), 7.46(ddd, J =9.1, 8.8, 3.1, 1H), 7.40(dd, J =8.2, 3.1, 1H), 7.22(dd, J =9.1, 4.4, 1H), 4.03(m, 1H), 3.90(d, J =6.9, 2H and m, 1H), 3.30(m, 1H), 3.25(m, 1H), 3.09(m, 1H), 2.90(m, 1H), 2.82(s, 3H), 2.27(m, 1H), 1.76(m, 1H), 0.95(m, 1H), 0.37(m, 2H), 0.24(m, 2H).
Example D.f17: 4- (2-ethoxy-5-fluorophenyl) -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- ({ [4- (2-ethoxy-5-fluorophenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl ] carbonyl } amino) piperidine-1-carboxylate (example d.e17), the title compound was obtained as a yellow solid.
MS(ESI): m/z=398(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.11(br.s, 1H,-NH); 9.02(s, 1H); 8.96(br.s, 2H,-NH2 +); 8.72(d, J=7.5, 1H,-NH); 7.45(ddd, J=9.1, 8.9, 3.3, 1H); 7.41(dd, J=8.2, 3.3, 1H); 7.24(dd, J=9.1, 4.4, 1H); 4.14(m, 1H); 4.08(qu, J=6.9, 2H); 3.31(m, 2H); 3.08(m, 2H); 2.80(s, 3H); 2.12(m, 2H); 1.78(m, 2H); 1.11(t, J=6.9, 3H)。
Example D.f 18: 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (example d.e18), the title compound was obtained as a yellow solid.
MS(ESI): m/z=436(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.28(br.s, 1H,-NH); 9.04(s, 1H); 8.98(br.s, 2H,-NH2 +); 8.66(d, J=7.5, 1H,-NH); 7.62(d, J=8.4, 1H); 6.77(dd, J=8.4, 2.2, 2H); 6.73(d, J=2.2, 1H); 4.03(m, 1H); 3.93(d, J=6.9, 2H); 3.88(s, 3H); 3.31(m, 2H); 3.08(m, 2H); 2.82(s, 3H); 2.12(m, 2H); 1.79(m, 2H); 0.97(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example D.f19: N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e19), the title compound was obtained as a yellow solid.
MS(ESI): m/z=450(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.39(s, 1H,-NH); 9.03(s, 1H); 8.48(d, J=7.7, 1H,-NH); 8.11(br.d, J ~ 4.2, 3H,-NH3 +); 7.62(d, J=8.4, 1H); 6.78(dd, J=8.4, 2.2, 1H); 6.74(d, J=2.2, 1H); 3.94(d , J=6.9, 2H); 3.88(s, 3H); 3.81(m, 1H); 3.08(m, 1H); 2.83(s, 3H); 2.04(m, 4H); 1.47(m, 4H); 0.97(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example D.f. 20N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e20), the title compound was obtained as a yellow solid.
MS(ESI): m/z=450(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.35(br.s, 1H,-NH); 9.14(s, 1H); 8.94(d, J=7.7, 1H,-NH); 8.19(br.s, 3H,-NH3 +); 7.63(d, J=8.4, 1H); 6.78(dd, J=8.4, 2.2, 2H); 6.75(d, J=2.2, 1H); 4.14(m, 1H); 3.94(d , J=6.9, 2H); 3.88(s, 3H); 3.18(m, 1H); 2.83(s, 3H); 1.96-1.66(m, 8H); 0.98(m, 1H); 0.39(m, 2H); 0.28(m, 2H)。
Example D.f. 21: 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from (3R) -3- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (example d.e21), the title compound was obtained as a yellow solid.
MS(ESI): m/z=422(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.28(br.s, 1H,-NH); 9.31(br.s, 2H,-NH2 +); 9.02(s, 1H); 8.81(d, J=6.8, 1H,-NH); 7.63(d, J=8.4, 1H); 6.77(dd, J=8.4, 2.2, 2H); 6.73(d, J=2.2, 1H); 4.63(m, 1H); 3.93(d , J=7.1, 2H); 3.88(s, 3H); 3.51(m, 1H); 3.39(m, 1H); 3.27(m, 1H); 3.16(m, 1H); 2.82(s, 3H); 2.35(m, 1H); 2.01(m, 1H); 0.97(m, 1H); 0.38(m, 2H); 0.27(m, 2H)。
Example D.f22: 4- [2- (cyclopropylmethoxy)) -4-methoxyphenyl group]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From (3R)*,4R*) -3- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]Starting from tert-butyl-4-hydroxypyrrolidine-1-carboxylate (example d.e22), the title compound is obtained as a yellow solid.
MS(ESI): m/z=438(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.36(br.s, 1H,-NH);[9.64(br.s, 1H), 9.48(br.s, 1H),-NH2 +]; 9.01(s, 1H); 8.78(d, J=6.2, 1H,-NH); 7.63(d, J=8.4, 1H); 6.77(dd, J=8.4, 2.2, 2H); 6.74(d, J=2.2, 1H); 4.39(m, 2H); 3.94(d , J=6.9, 2H); 3.88(s, 3H); 3.63(m, 1H); 3.43(m, 1H); 3.26(m, 1H); 3.15(m, 1H); 2.82(s, 3H); 0.97(m, 1H); 0.38(m, 2H); 0.27(m, 2H)。
Example D.f23: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (example d.e23), the title compound was obtained as a yellow solid.
MS(ESI): m/z=436(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.12(s, 1H,-NH); 9.04(s, 1H); 8.94(br.s, 2H,-NH2 +); 8.72(d, J=7.5, 1H,-NH); 7.20(t, J=1.6, 1H); 7.15(d, J=1.6, 1H); 4.16(m, 1H); 3.84(d, J=6.8, 2H); 3.78(s, 3H); 3.31(m, 2H); 3.08(m, 2H); 2.81(s, 3H); 2.13(m, 2H); 1.79(m, 2H); 0.93(m, 1H); 0.35(m, 2H); 0.20(m, 2H)。
Example D.f24: N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e24), the title compound was obtained as a yellow solid.
MS(ESI): m/z=450(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.07(s, 1H,-NH); 9.01(s, 1H); 8.59(d, J=7.9, 1H,-NH); 8.03(br.d, J ~ 4.8, 3H,-NH3 +) 7.20(t, J =1.8, 1H), 7.14(d, J =1.8, 2H), 3.84(d, J =6.9, 2H and m, 1H), 3.78(s, 3H), 3.09(m, 1H), 2.80(s, 3H), 2.04(m, 4H), 1.47(m, 4H), 0.92(m, 1H), 0.34(m, 2H), 0.19(m, 2H).
Example D.f25: N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e25), the title compound was obtained as a yellow solid.
MS(ESI): m/z=450(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.15(br.s, 1H,-NH); 9.11(s, 1H); 8.96(d, J=7.5, 1H,-NH); 8.13(br.s, 3H,-NH3 +); 7.22(t, J=1.6, 1H); 7.15(d, J=1.6, 2H); 4.13(m, 1H); 3.85(d, J=6.9, 2H); 3.78(s, 3H); 3.18(m, 1H); 2.82(s, 3H); 1.95-1.67(m, 8H); 0.93(m, 1H); 0.35(m, 2H); 0.21(m, 2H)。
Example D.f 26: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from (3R) -3- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (example d.e26), the title compound was obtained as a yellow solid.
MS(ESI): m/z=422(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6, MeOH-d4): 9.07(s, 1H); 7.24(dd, J=2.2, 0.9, 2H); 7.17(d, J=2.2, 1H); 7.16(d, J=0.9, 1H); 4.64(m, 1H); 3.85(d, J=6.9, 2H); 3.78(s, 2H); 3.53(m, 1H); 3.44(m, 1H); 3.29(m, 1H); 3.22(m, 1H); 2.83(s, 3H); 2.37(m, 1H); 2.04(m, 1H); 0.93(m, 1H); 0.35(m, 2H); 0.21(m, 2H)。
Example D.f27: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From (3R)*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]Starting from tert-butyl-3-hydroxypiperidine-1-carboxylate (example d.e27), the title compound is obtained as a yellow solid.
MS(ESI): m/z=452(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6, MeOH-d4): 9.09(s, 1H); 7.24(s, 1H); 7.18(s, 2H); 4.04(m, 1H); 3.93(m, 1H); 3.86(d, J=6.8, 2H); 3.80(m, 3H); 3.32(m, 1H); 3.25(m, 1H); 3.09(m, 1H); 2.90(m, 1H); 2.84(s, 3H); 2.27(m, 1H); 1.77(m, 1H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example D.f28: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (example d.e28), the title compound was obtained as a yellow solid.
MS(ESI): m/z=420(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.25(br.s, 1H,-NH); 9.11(br.s, 2H,-NH2 +); 9.06(s, 1H); 7.47(d, J=2.1, 1H); 7.39(dd, J=8.4, 2.1, 1H); 7.10(d, J=8.6, 1H); 4.12(m, 1H); 3.88(d, J=6.9, 2H); 3.31(m, 2H); 3.08(m, 2H); 2.81(s, 3H); 2.34(s, 3H); 2.13(m, 2H); 1.79(m, 2H); 0.93(m, 1H); 0.36(m, 2H); 0.25(m, 2H)。
Example D.f29N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e29), the title compound was obtained as a yellow solid.
MS(ESI): m/z=434(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.25(br.s, 1H,-NH); 9.03(s, 1H); 8.55(d, J=7.9, 1H,-NH); 8.09(br.d, J=4.2, 3H,-NH3 +); 7.46(d, J=2.1, 1H); 7.39(dd, J=8.4, 2.1, 1H); 7.11(d, J=8.6, 1H); 3.88(d, J=6.9, 2H); 3.82(m, 1H); 3.09(m, 1H); 2.81(s, 3H); 2.34(s, 3H); 2.04(m, 4H); 1.47(m, 4H); 0.93(m, 1H); 0.36(m, 2H); 0.24(m, 2H)。
Example D.f30: N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e30), the title compound was obtained as a yellow solid.
MS(ESI): m/z=534(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 9.00(d, J=9.3, 1H,-NH); 8.98(s, 1H); 7.43(d, J=2.1, 1H); 7.33(dd, J=8.4, 2.1, 1H); 7.06(d, J=8.4, 1H); 6.97(d, J=7.7, 1H,-NH); 4.03(m, 1H); 3.86(d, J=6.9, 2H); 3.42(m, 1H); 2.78(s, 3H); 2.32(s, 3H); 1.81-1.51(m, 8H); 1.40(s, 9H); 0.94(m, 1H);0.37(m, 2H); 0.23(m, 2H)。
Example D.f31: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- [ ({4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (example d.e31), the title compound was obtained as a yellow solid.
MS(ESI): m/z=474(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.11(s, 1H,-NH); 9.04(s, 1H); 8.98(br.s, 2H,-NH2 +); 8.75(d, J=7.5, 1H,-NH); 7.93(d, J=2.0, 1H); 7.91(dd, J=8.8, 2.0, 1H); 7.39(d, J=8.8, 1H); 4.16(m, 1H); 4.01(d, J=6.9, 2H); 3.32(m, 2H); 3.08(m, 2H); 2.80(s, 3H); 2.13(m, 2H); 1.79(m, 2H); 0.98(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example D.f 32N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e32), the title compound was obtained as a yellow solid.
MS(ESI): m/z=488(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.08(s, 1H,-NH); 9.01(s, 1H); 8.61(d, J=8.6, 1H,-NH); 8.07(br.s, 3H,-NH3 +); 7.92(d, J=2.0, 1H); 7.91(dd, J=8.8, 2.0, 1H); 7.39(d, J=8.8, 1H); 4.01(d, J=7.0, 2H); 3.81(m, 2H); 3.09(m, 2H); 2.80(s, 3H); 2.04(m, 4H); 1.48(m, 4H); 0.98(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example D.f 33N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d. e33), the title compound was obtained as a yellow solid.
MS(ESI): m/z=488(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 12.04(s, 1H,-NH); 9.08(s, 1H); 8.98(d, J=7.3, 1H,-NH); 7.99(br.s, 3H,-NH3 +); 7.94(d, J=2.1, 1H); 7.92(dd, J=8.7, 2.1, 1H); 7.40(d, J=8.7, 1H); 4.13(m, 1H); 4.02(d, J=6.9, 2H); 3.20(m, 1H); 2.82(s, 3H); 1.89(m, 4H); 1.75(m, 4H); 0.99(m, 1H); 0.41(m, 2H); 0.29(m, 2H)。
Example D.f 34: 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- [ ({4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (example d.e34), the title compound was obtained as a yellow solid.
MS(ESI): m/z=448(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.15(br.s, 1H,-NH); 9.04(s, 1H); 8.99(br.s, 2H,-NH2 +); 8.73(d, J=7.1, 1H,-NH); 7.93(d, J=2.2, 1H); 7.92(dd, J=9.5, 2.2, 1H); 7.43(d, J=9.5, 1H); 4.22(qu, J=6.9, 2H); 4.17(m, 1H); 3.31(m, 2H); 3.08(m, 2H); 2.80(s, 3H); 2.13(m, 2H); 1.79(m, 2H); 1.16(t, J=6.9, 3H)。
Example D.f 35: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (example d.e35), the title compound was obtained as a yellow solid.
MS(ESI): m/z=454(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 12.11(s, 1H,-NH); 9.04(s, 1H); 8.96(br.s, 3H, NH2 +); 8.72(d, J=6.9, 1H,-NH); 7.43(d, J=9.9, 1H); 7.22(d, J=13.3, 1H); 4.15(m, 1H); 3.86(d, J=6.9, 2H); 3.85(s, 3H); 3.31(m, 2H); 3.08(m, 2H); 2.81(s, 3H); 2.13(m, 2H); 1.79(m, 2H); 0.93(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example D.f36: N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e36), the title compound was obtained as a yellow solid.
MS(ESI): m/z=468(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 12.15(s, 1H,-NH); 9.02(s, 1H); 8.56(d, J=7.7, 1H,-NH); 8.09(br.s, 3H, NH3 +); 7.43(d, J=9.7, 1H); 7.22(d, J=13.5, 1H); 3.86(d, J=6.9, 2H); 3.85(s, 3H); 3.79(m, 1H); 3.08(m, 1H); 2.81(s, 3H); 2.04(m, 4H); 1.47(m, 4H); 0.92(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example D.f37N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e37), the title compound was obtained as a yellow solid.
MS(ESI): m/z=468(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 12.19(s, 1H,-NH); 9.12(s, 1H); 8.95(d, J=7.5, 1H,-NH); 8.18(br.s, 3H, NH3 +); 7.45(d, J=9.7, 1H); 7.23(d, J=13.5, 1H); 4.14(m, 1H); 3.87(d, J=6.9, 2H); 3.86(s, 3H); 3.17(m, 1H); 2.82(s, 3H); 1.81(m, 8H); 0.94(m, 1H); 0.37(m, 2H); 0.23(m, 2H)。
Example D.f38: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl ]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From (3R)*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]Starting from tert-butyl-3-hydroxypiperidine-1-carboxylate (example d.e38), the title compound is obtained as a yellow solid.
MS(ESI): m/z=470(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6, MeOH-d4) 9.08(s, 1H), 7.47(d, J =9.9, 1H), 7.24(d, J =13.3, 1H), 4.05(m, 1H), 3.87(s, 3H and d, J =6.9, 2H and m, 1H), 3.29(m, 2H), 3.11(m, 1H), 2.92(m, 1H), 2.84(s, 3H), 2.28(m, 1H), 1.76(m, 1H), 0.95(m, 1H), 0.38(m, 2H), 0.25(m, 2H).
Example D.f 39: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From (3S)*,4S*) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]Starting from tert-butyl-4-hydroxypiperidine-1-carboxylate (example d.e39), the title compound is obtained as a yellow solid.
MS(ESI): m/z=470(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6, MeOH-d4) 9.05(s, 1H), 7.45(d, J =9.7, 1H), 7.23(d, J =13.3, 1H), 4.08(m, 1H), 3.86(s, 3H and d, J =6.8, 2H and m, 1H), 3.50(m, 1H), 3.30(m, 1H), 3.00(m, 1H), 2.83(s, 3H), 2.10(m, 1H), 1.73(m, 1H), 0.94(m, 1H), 0.37(m, 2H), 0.24(m, 2H).
Example D.f. 40: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (example d.e40), the title compound was obtained as a yellow solid.
MS(ESI): m/z=438/(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.32(s, 1H,-NH); 9.10(br.s, 2H,-NH2 +); 9.06(s, 1H); 8.66(d, J=7.5, 1H,-NH); 7.58(d, J=8.9, 1H); 7.09(d, J=12.1, 1H); 4.14(m, 1H); 3.90(d, J=7.1, 2H); 3.31(m, 2H); 3.07(m, 2H); 2.82(s, 3H); 2.26(d, J=0.9, 3H); 2.13(m, 1H); 1.80(m, 2H); 0.96(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example D.f 41N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e41), the title compound was obtained as a yellow solid.
MS(ESI): m/z=452(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.97(s, 1H,-NH); 8.96(s, 1H); 8.66(d, J=7.9, 1H,-NH); 7.98(br.d, J ~ 4.6, 3H,-NH3 +); 7.55(dd, J=9.1, 0.6, 1H); 7.06(d, J=12.0, 1H); 3.88(d, J=7.1, 2H); 3.82(m, 1H); 3.09(m, 1H); 2.79(s, 3H); 2.25(d, J=1.1, 3H); 2.04(m, 4H); 1.47(m, 4H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example D.f42N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example D.e42), the title compound was obtained as a yellow solid.
MS(ESI): m/z=452(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.20(br.s, 1H,-NH); 9.10(s, 1H); 8.96(d, J=7.5, 1H,-NH); 8.16(br.s, 3H,-NH3 +); 7.58(dd, J=8.9, 0.6, 1H); 7.08(d, J=12.1, 1H); 4.13(m, 1H); 3.90(d, J=6.9, 2H); 3.17(m, 1H); 2.82(s, 3H); 2.26(d, J=1.1, 3H); 1.93-1.56(m, 8H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example D.f43: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From (3R)*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]Starting from tert-butyl-3-hydroxypiperidine-1-carboxylate (example d.e43), the title compound is obtained as a yellow solid.
MS(ESI): m/z=454(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.51(s, 1H,-NH);[9.62(br.m, 1H), 9.18(br.m, 1H),-NH2 +]9.06(s, 1H), 8.70(d, J =7.1, 1H, -NH), 7.60(d, J =8.9, 1H), 7.10(d, J =12.0, 1H), 4.01(m, 1H), 3.91(d, J =7.1, 2H and m, 1H), 3.26(m, 2H), 3.04(m, 2H), 2.84(s, 3H and m, 1H), 2.26(s, 3H), 2.23(m, 1H), 1.78(m, 1H), 0.97(m, 1H), 0.38(m, 2H), 0.26(m, 2H).
Example D.f 44: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (example d.e44), the title compound was obtained as a yellow solid.
MS(ESI): m/z=454(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.27(br.s, 1H,-NH); 9.10(br.s, 2H,-NH2 +); 9.04(s, 1H); 8.67(d, J=7.5, 1H,-NH); 7.53(d, J=11.9, 1H); 6.96(d, J=7.3, 1H); 4.15(m, 1H); 3.99(s, 3H); 3.97(d, J=6.9, 2H); 3.31(m, 2H); 3.07(m, 2H); 2.82(s, 3H); 2.13(m, 2H); 1.80(m, 2H); 0.97(m, 1H); 0.39(m, 2H); 0.26(m, 2H)。
Example D.f45: N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e45), the title compound was obtained as a yellow solid.
MS(ESI): m/z=468(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.32(br.s, 1H,-NH); 9.01(s, 1H); 8.51(d, J=7.7, 1H,-NH); 8.18(br.d, J=4.6, 3H,-NH3 +); 7.54(d, J=11.7, 1H); 6.96(d, J=7.3, 1H); 3.99(s, 3H); 3.97(d, J=7.4, 2H); 3.81(m, 1H); 3.07(m, 1H); 2.83(s, 3H); 2.05(m, 4H); 1.48(m, 4H); 0.97(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example D.f 46N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e46), the title compound was obtained as a yellow solid.
MS(ESI): m/z=468(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.36(br.s, 1H,-NH); 9.14(s, 1H); 8.94(d, J=7.7, 1H,-NH); 8.25(br.s, 3H,-NH3 +); 7.55(d, J=11.7, 1H); 6.97(d, J=7.3, 1H); 4.14(m, 1H); 3.99(s, 3H); 3.97(d, J=7.1, 2H); 3.16(m, 1H); 2.84(s, 3H); 1.86(m, 4H); 1.74(m, 4H); 0.98(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example D.f 47: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From (3R)*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-ylCarbonyl) amino group]Starting from tert-butyl-3-hydroxypiperidine-1-carboxylate (example d.e47), the title compound is obtained as a yellow solid.
MS(ESI): m/z=470(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6, MeOH-d4): 9.04(s, 1H); 7.54(d, J=11.9, 1H); 6.96(d, J=7.3, 1H); 4.02(m, 1H); 3.99(s, 3H); 3.94(d, J=6.9, 2H); 3.88(m, 1H); 3.29(m, 2H); 3.10(m, 1H); 2.93(m, 1H); 2.84(s, 3H); 2.29(m, 1H); 1.78(m, 1H); 0.98(m, 1H); 0.40(m, 2H); 0.27(m, 2H)。
Example D.f48: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (example d.e48), the title compound was obtained as a yellow solid.
MS(ESI): m/z=434(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.22(s, 1H,-NH); 9.06(s, 1H); 9.00(br.s, 2H,-NH2 +); 8.69(d, J=7.5, 1H,-NH); 7.48(d, J=2.2, 1H); 7.42(dd, J=8.6, 2.2, 1H); 7.12(d, J=8.6, 1H); 4.16(m, 1H); 3.89(d, J=6.9, 2H); 3.31(m, 2H); 3.08(m, 2H); 2.81(s, 3H); 2.65(qu, J=7.5, 2H); 2.13(m, 2H); 1.79(m, 2H); 1.20(t, J=7.5, 3H); 0.95(m, 1H); 0.36(m, 2H); 0.24(m, 2H)。
Example D.f 49N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e49), the title compound was obtained as a yellow solid.
MS(ESI): m/z=448(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.21(s, 1H,-NH); 9.02(s, 1H); 8.55(d, J=7.7, 1H,-NH); 8.09(br.s, 3H,-NH3 +); 7.48(d, J=2.2, 1H); 7.42(dd, J=8.6, 2.2, 1H); 7.12(d, J=8.6, 1H); 3.89(d, J=6.9, 2H); 3.81(m, 1H); 3.08(m, 1H); 3.08(m, 2H); 2.81(s, 3H); 2.64(qu, J=7.5, 2H); 2.05(m, 4H); 1.48(m, 4H); 1.20(t, J=7.5, 3H); 0.95(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example D.f50: N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e50), the title compound was obtained as a yellow solid.
MS(ESI): m/z=448(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.18(br.s, 1H,-NH); 9.11(s, 1H); 8.96(d, J=7.7, 1H,-NH); 8.15(br.s, 3H,-NH3 +); 7.48(d, J=2.2, 1H); 7.42(dd, J=8.6, 2.2, 1H); 7.13(d, J=8.6, 1H); 4.13(m, 1H); 3.89(d, J=6.8, 2H); 3.18(m, 1H); 3.08(m, 1H); 2.82(s, 3H); 2.65(qu, J=7.5, 2H); 1.96-1.66(m, 8H); 1.20(t, J=7.5, 3H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example D.f 51: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From (3R)*,4R*) -3- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]Starting from tert-butyl-4-hydroxypyrrolidine-1-carboxylate (example d.e51), the title compound is obtained as a yellow solid.
MS(ESI): m/z=436(MH+, 100%)。
Example D.f 52: 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- [ ({4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (example d.e52), the title compound was obtained as a yellow solid.
MS(ESI): m/z=548(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.75(s, 1H, -NH), 8.95(s, 1H), 8.81(d, J =7.7, 1H, -NH), 7.47(d, J =2.4, 1H), 7.39(dd, J =8.6, 2.4, 1H), 7.08(d; J =8.6, 1H), 4.06(m, 1H), 3.87(d, J =6.8, 2H and m, 2H), 3.05(m, 2H), 2.94(sept, J =6.9, 1H), 2.77(s, 3H), 1.92(m, 2H), 1.45(m, 2H), 1.43(s, 9H), 1.22(d, J =6.9, 6H), 0.94(m, 1H), 0.36(m, 2H), 0.23(m, 2H).
Example D.f53N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (propan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e53), the title compound was obtained as a yellow solid.
MS(ESI): m/z=462(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.15(br.s, 1H,-NH); 9.02(s, 1H); 8.56(d, J=7.9, 1H,-NH); 8.06(br.d, J ~ 4.0, 3H,-NH3 +); 7.49(d, J=2.4, 1H); 7.45(dd, J=8.6, 2.4, 1H); 7.12(d; J=8.6, 1H); 3.89(d, J=6.9, 2H); 3.81(m, 1H); 3.10(m, 1H); 2.95(sept, J=6.9, 1H); 2.80(s, 3H); 2.04(m, 4H); 1.47(m, 4H); 1.22(d, J=6.9, 6H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example D.f54: N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5- (propan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e54), the title compound was obtained as a yellow solid.
MS(ESI): m/z=462(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.28(br.s, 1H,-NH); 9.15(s, 1H); 8.95(d, J=7.7, 1H,-NH); 8.19(br.s, 3H,-NH3 +); 7.51(d, J=2.4, 1H); 7.47(dd, J=8.6, 2.4, 1H); 7.14(d; J=8.6, 1H); 4.14(m, 1H); 3.90(d, J=6.9, 2H); 3.18(m, 1H); 2.96(sept, J=6.9, 1H); 2.82(s, 3H); 1.96-1.66(m, 8H); 1.23(d, J=6.9, 6H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example D.f 55: 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Tert-butyl 4- [ ({4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate from example D.e55 (1.77 g; 2.99 mmol) was dissolved in anhydrous acetone (30 mL). After addition of 4M HCl/dioxane (3 mL), the stirred mixture was gently refluxed until the starting material was consumed (according to LC-MS). The product is precipitated at room temperature by addition of methyl tert-butyl ether, isolated by suction filtration, washed with several portions of methyl tert-butyl ether and dried at 40 ℃ under high vacuum to give 1.40 g of the title compound as a pale yellow solid.
MS(ESI): m/z=448(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 12.18(s, 1H,-NH); 9.06(s, 1H); 8.99(br.s, 2H,-NH2 +); 8.73(d, J=7.5, 1H,-NH); 8.23(d, J=2.3, 1H); 8.17(dd, J=8.8, 2.3, 1H); 7.32(d, J=8.8, 1H); 4.10(m, 1H); 4.02(d, J=7.1, 2H); 3.31(m, 2H); 3.08(m, 2H); 2.81(s, 3H); 2.59(s, 3H); 2.13(m, 2H); 1.80(m, 2H); 0.99(m, 1H); 0.39(m, 2H); 0.29(m, 2H)。
Example D.f 56: 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- (trans-4-aminocyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e56), the title compound was obtained as a yellow solid as described in example d.f55 above.
MS(ESI): m/z=462(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 12.15(s, 1H,-NH); 9.03(s, 1H); 8.60(d, J=7.7, 1H,-NH); 8.23(d, J=2.2, 1H); 8.17(dd, J=8.8, 2.2, 1H); 8.08(br.s, 3H,-NH3 +); 7.31(d, J=8.8, 1H); 4.02(d, J=6.9, 2H); 3.80(m, 1H); 3.09(m, 1H); 2.81(s, 3H); 2.59(s, 3H); 2.05(m, 4H); 1.48(m, 4H); 0.99(m, 1H); 0.39(m, 2H); 0.28(m, 2H)。
Example D.f 57: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (example d.e57), the title compound was obtained as a colorless solid.
MS(ESI): m/z=434(MH+ , 100%)
1H-NMR(300 MHz, DMSO-d6, MeOH-d4): 7.49(d, J=2.0, 1H); 7.45(dd, J=8.6, 2.0, 1H); 7.15(d, J=8.6, 1H); 4.22-4.08(m, 1H); 3.90(d, J=6.9, 2H); 3.35-3.22(m, 2H); 3.16-3.00(m, 2H); 2.87(s, 3H); 2.83(s, 3H); 2.35(s, 3H); 2.20-2.07(m, 2H); 1.83(m, 2H); 0.96(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example D.f58: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (example d.e58), the title compound was obtained as a colorless solid.
MS(ESI): 468(MH+, 100%)
1H-NMR(300 MHz, DMSO-d6,MeOH-d4): 7.60(d, J=11.7, 1H); 6.98(d, J=7.1, 1H); 4.21-4.07(m, 1H); 4.03-3.94(m, 5H); 3.34-3.22(m, 2H); 3.18-3.00(m, 1H); 2.86(s, 3H); 2.83(s, 3H); 2.19-2.08(m, 2H); 1.91-1.74(m, 2H); 0.98(m, 1H); 0.40(m, 2H); 0.28(m, 2H)。
Example D.f59: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (example d.e59), the title compound was obtained as a colorless solid.
MS(ESI): m/z=468(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6, MeOH-d4) 7.49(d, J =9.5, 1H), 7.27(d, J =13.3, 1H), 4.16(m, 1H), 3.88(s, 3H and d, J =6.9, 2H), 3.35(m, 1H), 3.30(m, 1H), 3.14(m, 2H), 2.86(s, 3H), 2.83(s, 3H), 2.15(m, 2H), 1.81(m, 2H), 0.95(m, 1H), 0.39(m, 2H), 0.23(m, 2H).
Example D.f60: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl 4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylate (example d.e60), the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=456.2210([MH]+, C24H28F2N5O2 +Calculating the value: 456.2206).
Example D.f61N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate (example d.e61) the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=470.2347([MH]+, C25H30F2N5O2 +Calculating the value: 470.2362).
Example D.f62: N- [ (1S)*,3S*,4S*) -4-amino-3-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From { (1S)*,2S*,4S*) -4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]Starting from tert-butyl-2-fluorocyclohexyl } carbamate (example d.e62), the title compound was obtained as a colorless solid.
MS(ESI): m/z=488(MH+, 100%).
1H-NMR(300 MHz, DMSO-d6): 12.11(s, 1H,-NH); 9.01(s, 1H); 8.71(d, J=7.9, 1H,-NH); 8.45(br.d, J ~ 3.1, 3H,-NH3 +); 7.84(d, J=2.0, 1H); 7.76(dd, J=8.8, 2.0, 1H); 7.33(d, J=8.8, 1H); 7.09(t, J=55.9, 1H); 4.76(m, 1H); 4.01(m, 1H); 3.97(d, J=7.1, 2H); 3.33(m, 1H); 2.81(s, 3H); 2.46(m, 1H); 2.10(m, 1H); 2.00(m, 1H); 1.77(m, 1H); 1.54(m, 2H); 0.98(m, 1H); 0.38(m, 2H); 0.27(m, 2H)。
Example D.f63: N- [ (1S)*,2S*,4S*) -4-amino-2-methylcyclohexyl radical]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From { (1S)*,3S*,4S*) -4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]Starting from tert-butyl-3-methylcyclohexyl } carbamate (example d.e63), the title compound was obtained as a colorless solid.
1H-NMR(300 MHz, DMSO-d6): 12.00(s, 1H,-NH); 9.00(s, 1H); 8.59(d, J=8.6, 1H,-NH); 7.98(br.s, 3H,-NH3 +) 7.82(s, 1H), 7.76(d, J =8.7, 1H), 7.32(d, J =8.7, 1H), 7.10(t, J =55.8, 1H), 3.97(d, J =6.9, 2H), 3.56(m, 1H), 3.16(m, 1H), 2.80(s, 3H), 2.01(m, 3H), 1.69(m, 1H), 1.45(m, 2H), 1.24(m, 1H), 0.98(m, 1H and d, J =6.4, 3H), 0.39(m, 2H), 0.28(m, 2H).
Example D.f64N- [ (1S,3S) -3-aminocyclopentyl ] -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from tert-butyl { (1S,3S) -3- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclopentyl } carbamate (example d.e64) the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=456.2218([MH]+, C24H28F2N5O2 +Calculating the value: 456.2206).
Example D.f66: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- [ (3S,5S) -5-methylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride
Starting from (2S,4S) -4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] -2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (example d.e66), the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=456.2210([MH]+, C24H28F2N5O2 +Calculating the value: 456.2206).
Example D.f68: N- [ (1R)*,3S*,4S*) -3-amino-4-methylcyclopentyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From { (1S)*,2S*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl) ]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]Starting from tert-butyl-2-methylcyclopentyl } carbamate (example d.e68), the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=470.2363([MH]+, C25H30F2N5O2 +Calculating the value: 470.2362).
Example D.f70: N- [ (1S)*,3S*,4S*) -3-amino-4-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From { (1S)*,2S*,4S*) -4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]Starting from tert-butyl-2-fluorocyclopentyl } carbamate (example d.e70), the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=474.2117([MH]+, C24H27F3N5O2 +Calculating the value: 474.2111).
Example D.f72: N- [ (1S)*,3R*,4S*) -4-amino-3-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
From { (1S)*,2R*,4S*) -4- [ ({4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]Starting from tert-butyl-2-fluorocyclohexyl } carbamate (example d.e72), the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=488.2271([MH]+, C25H29F3N5O2 +Calculating the value: 488.2268).
Example D.f65: N- [ (1S) *,3S*,4S*) -4-amino-3-methylcyclohexyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride
Reacting N- [ (1S)*,3S*,4S*) -4-azido-3-methylcyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide (example D.e65; 1.3 g; 2.6 mmol) was dissolved in MeOH (25 mL) and reacted with Pd (OH) at room temperature and 20 bar2(20% on charcoal; 70.0 mg) was hydrogenated under pressure overnight. After filtration through a celite pad, the solvent was removed under reduced pressure. The residual amine was dissolved in dioxane (5 mL). At ice bath temperature, HCl (4M in dioxane; 0.7 mL) was added followed by tert-BuOMe (10 mL). The precipitate was collected by suction filtration, washed with several small portions of tert-BuOMe and dried under reduced pressure to give 1.3 g of the title compound as a pale yellow solid.
HR-MS(ESI): m/z=484.2525([MH]+, C26H32F2N5O2 +Calculating the value: 484.2519).
The following compounds were prepared in analogy to the procedure described in example d.f65 above. After pressure hydrogenation and removal of catalyst and solvent, the compound is obtained.
Example D.f67: N- [ (1R)*,2R*,4R*) -4-amino-2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1R)*,2R*,4R*) -4-azido-2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Starting from pyrimidine-7-carboxamide (example d.e67), the title compound (free base) was obtained as a colorless solid.
HR-MS(ESI): m/z=488.2265([MH]+, C25H29F3N5O2 +Calculating the value: 488.2268).
Example D.f 69: N- [ (1R)*,2R*,4S*) -4-amino-2-methylcyclopentyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1R)*,2R*,4S*) -4-azido-2-methylcyclopentyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Starting from pyrimidine-7-carboxamide (example d.e69), the title compound (free base) was obtained as a colorless solid.
HR-MS(ESI): m/z=470.2369([MH]+, C25H30F2N5O2 +Calculating the value: 470.2363).
Example D.f71: N- [ (1R)*,2R*,4R*) -4-amino-2-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxylic acidAmines as pesticides
From N- [ (1R)*,2R*,4R*) -4-azido-2-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Starting from pyrimidine-7-carboxamide (example d.e71), the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=474.2115([MH]+, C24H27F3N5O2 +Calculating the value: 474.2111).
Example D.f73: N- [ (1S) *,2R*,4S*) -4-amino-2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1S)*,2R*,4S*) -4-azido-2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Starting from pyrimidine-7-carboxamide (example d.e73), the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=488.2265([MH]+, C25H29F3N5O2 +Calculating the value: 488.2268).
Example D.g. 1: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Ethyl 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example D.a19; 52.73 g; 131.4 mmol) was dissolved in tert-BuOH (500.0 mL) and water (5.0 mL). After addition of commercially available KOtBu (73.70 g; 656.8 mmol), the reaction mixture was stirred at 100 ℃ overnight and cooled to room temperature. Water (1500 mL) was added and a 2M aqueous solution of citric acid was carefully added to adjust the pH to 6.0. The precipitated product was filtered, washed with several portions of water, and dried under reduced pressure to obtain 45.3 g of the title compound as an off-white solid.
1H-NMR(300 MHz, DMSO-d6): 12.22-11.77(br.s, 2H,-NH,-CO2H); 8.96(s, 1H); 7.82(d, J=2.0, 1H); 7.74(dd, J=8.6, 2.0, 1H); 7.31(d, J=8.6, 1H); 7.08(t, J=56.0, 1H); 3.96(d, J=6.9, 2H); 2.74(s, 3H); 0.98(m, 1H); 0.39(m, 2H); 0.26(m, 2H)。
Example D.g. 2: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid
Starting from ethyl 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylate (example d.a8), the title compound was obtained as an off-white solid following the procedure described in example d.g 1.
1H-NMR(300 MHz, DMSO-d6/MeOH-d4): 8.95(s, 1H); 7.89(d, J=2.1, 1H); 7.88(dd, J=8.4, 2.1, 1H); 7.37(d, J=8.4, 1H); 4.00(d, J=7.1, 2H); 2.74(s, 3H); 1.00(m, 1H); 0.40(m, 2H); 0.27(m, 2H)。
Example E1N- (1-acetylpiperidin-4-yl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride of example D.f. 1 (486 mg; 1.0 mmol) and DBU (2.5 mmol) were dissolved in anhydrous dichloromethane (5 mL). Acetyl chloride (1.1 mmol) was injected into the reaction mixture at ice bath temperature. After the addition, the mixture was stirred at room temperature overnight. Methanol (1 mL) was added and stirring was continued for two hours. The volatiles were evaporated. The residue was purified by reverse phase preparative HPLC. The collected product fractions were lyophilized to give the title compound as a colorless solid.
MS(ESI): m/z=492(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.00(s, 1H,-NH); 8.93(s, 1H); 8.76(d, J=7.8, 1H,-NH); 7.00(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H); 4.23-4.04(m, 2H); 3.80(m, 1H); 3.76(d, J=6.8, 2H); 3.28(m, 1H); 2.95(m, 1H); 2.77(s, 3H); 2.04(s, 3H); 1.95(m, 2H); 1.54(m, 1H); 1.38(m, 1H); 0.88(m, 1H); 0.31(m, 2H); 0.13(m, 2H)。
The following compounds were prepared in a manner analogous to that described above in example E1.
Example E2: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f1) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=506(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.00(s, 1H,-NH); 8.93(s, 1H); 8.75(d, J=7.7, 1H,-NH); 7.00(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H); 4.25-4.03(m, 2H); 3.79(m, 1H); 3.76(d, J=6.8, 2H); 3.25(m, 1H); 2.95(m, 1H); 2.77(s, 3H); 2.36(qu, J=7.5, 2H); 1.96(m, 2H); 1.52(m, 1H); 1.39(m, 1H); 1.01(t, J=7.5, 3H); 0.88(m, 1H); 0.31(m, 2H); 0.13(m, 2H)。
Example E3: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f1) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=522(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.00(s, 1H,-NH); 8.93(s, 1H); 8.75(d, J=7.7, 1H,-NH); 7.00(d, J=8.6, 1H); 6.55(d, J=8.6, 1H); 6.00(s, 2H); 4.22-4.03(m, 2H); 4.12(d, J=1.8, 2H); 3.76(d, J=6.8, 2H); 3.73(m, 1H); 3.31(s, 3H); 3.22(m, 1H); 2.98(m, 1H); 2.77(s, 3H); 1.97(m, 2H); 1.54(m, 1H); 1.41(m, 1H); 0.88(m, 1H); 0.31(m, 2H); 0.13(m, 2H)。
Example E4: 4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester
Starting from 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d. f1) and commercially available ethyl chloroformate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=522(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.99(s, 1H, -NH), 8.93(s, 1H), 8.75(d, J =7.7, 1H, -NH), 7.00(d, J =8.6, 1H), 6.56(d, J =8.6, 1H), 6.00(s, 2H), 4.06(m, 1H and qu, J =7.1, 2H), 3.88(m, 2H), 3.76(d, J =6.8, 2H), 3.11(m, 2H), 2.77(s, 3H), 1.94(m, 2H), 1.46(m, 2H), 1.20(t, J =7.1, 3H), 0.88(m, 1H), 0.31(m, 2H), 0.13(m, 2H).
Example E5N- (trans-4-acetamidocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f2) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=506(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.97(s, 1H,-NH); 8.93(s, 1H); 8.59(d, J=7.7, 1H,-NH); 7.72(d, J=7.9, 1H,-NH); 7.00(d, J=8.6, 1H); 6.55(d, J=8.6, 1H); 6.00(s, 2H); 3.80(m, 1H); 3.76(d, J=6.8, 2H); 3.58(m, 1H); 2.76(s, 3H); 2.00(m, 2H); 1.86(m, 2H); 1.79(s, 3H); 1.35(m, 4H); 0.88(m, 1H); 0.31(m, 2H); 0.13(m, 2H)。
Example E6: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f2) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=520(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.97(s, 1H,-NH); 8.93(s, 1H); 8.60(d, J=7.7, 1H,-NH); 7.62(d, J=7.9, 1H,-NH); 7.00(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H); 3.79(m, 1H); 3.76(d, J=6.8, 2H); 3.59(m, 1H); 2.76(s, 3H); 2.05(qu, J=7.6, 2H); 2.01(m, 2H); 1.86(m, 2H); 1.35(m, 4H); 0.99(t, J=7.6, 3H); 0.88(m, 1H); 0.30(m, 2H); 0.12(m, 2H)。
Example E7: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f2) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=536(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.97(s, 1H, -NH), 8.93(s, 1H), 8.59(d, J =7.7, 1H, -NH), 7.57(d, J =8.2, 1H, -NH), 7.00(d, J =8.6, 1H), 6.56(d, J =8.6, 1H), 6.00(s, 2H), 3.78(m, 1H and s, 2H), 3.76(d, J =6.8, 2H), 3.68(m, 1H), 3.31(s, 3H), 2.76(s, 3H), 2.01(m, 2H), 1.82(m, 2H), 1.43(m, 4H), 0.88(m, 1H), 0.30(m, 2H), 0.12(m, 2H).
Example E8 Ethyl { trans-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from N- (trans-4-aminocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d. f2) and commercially available ethyl chloroformate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=536(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.97(s, 1H, -NH), 8.93(s, 1H), 8.59(d, J =7.7, 1H, -NH), 7.00(d, J =6.8, 1H and d, J =8.6, 1H, -NH), 6.56(d, J =8.6, 1H), 6.00(s, 2H), 3.98(qu, J =6.9, 2H), 3.94(m, 1H), 3.76(m, 1H and d, J =6.8, 2H), 3.33(m, 1H), 2.76(s, 3H), 2.00(m, 2H), 1.87(m, 2H), 2H); 1.35(m, 4H); 1.16(t, J=6.9, 3H); 0.88(m, 1H); 0.30(m, 2H); 0.12(m, 2H)。
Example E9N- (cis-4-acetamidocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f. 3) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=506(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.98(s, 1H, -NH), 8.96(s, 1H), 8.87(d, J =7.5, 1H, -NH), 7.84(d, J =7.3, 1H, -NH), 7.01(d, J =8.6, 1H), 6.56(d, J =8.6, 1H), 6.00(s, 2H), 4.01(m, 1H), 3.77(m, 1H and d, J =6.8, 2H), 2.77(s, 3H), 1.83(s, 3H), 1.82-1.51(m,8H), 0.88(m, 1H), 0.31(m, 2H), 0.13(m, 2H).
Example E10: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f. 3) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=520(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.98(s, 1H,-NH); 8.96(s, 1H); 8.87(d, J=7.5, 1H,-NH); 7.75(d, J=7.5, 1H,-NH); 7.01(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H)4.01(m, 1H), 3.76(m, 1H and d, J =6.8, 2H), 2.77(s, 3H), 2.11(qu, J =7.5, 2H), 1.87-1.50(m,8H), 1.00(t, J =7.6, 3H), 0.88(m, 1H), 0.31(m, 2H), 0.13(m, 2H).
Example E11: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f3) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=536(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.98(s, 1H, -NH), 8.97(s, 1H), 8.91(d, J =7.3, 1H, -NH), 7.67(d, J =7.9, 1H, -NH), 7.01(d, J =8.6, 1H), 6.56(d, J =8.6, 1H), 6.00(s, 2H), 4.04(m, 1H), 3.81(s, 2H), 3.76(m, 1H and d, J =6.8, 2H), 3.31(s, 3H), 2.77(s, 3H), 1.87-1.57(m,8H), 0.89(m, 1H), 0.31(m, 2H), 0.13(m, 2H).
Example E12 Ethyl { cis-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from N- (cis-4-aminocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f3) and commercially available ethyl chloroformate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=536(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.97(s, 1H, -NH), 8.96(s, 1H), 8.91(d, J =7.9, 1H, -NH), 7.20(br.d, J-6.2, 1H, -NH), 7.01(d, J =8.6, 1H), 6.56(d, J =8.6, 1H), 6.00(s, 2H), 3.99(m, 1H and qu, J =7.1, 2H), 3.76(d, J =6.8, 2H), 3.48(m, 1H), 2.77(s, 3H), 1.85-1.54(m,8H), 1.17(t, J =7.1, 3H), 0.89(m, 1H), 0.31(m, 2H), 0.13(m, 2H).
Example E13N- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f4) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=478(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 12.03(s, 1H,-NH); 8.93(s, 1H);[8.88(d, J=7.0), 8.85(d, 6.7), 1H,-NH]; 7.00(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H);[4.59(m), 4.49(m), 1H];[3.84(m), 3.68-3.58(m), 2H]; 3.76(d, J=6.7, 2H); 3.56-3.27(m, 2H);[2.78(s), 2.77(s), 3H]; 2.34-2.16(m,1H); 2.08-1.87(m, 1H);[1.98(s), 1.96(s), 3H]; 0.88(m, 1H); 0.31(m, 2H); 0.12(m, 2H)。
Example E14: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f4) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=492(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 12.03(s, 1H,-NH); 8.92(s, 1H);[8.88(d, J=7.0), 8.85(d, 6.7), 1H,-NH]; 7.01(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H);[4.59(m), 4.49(m), 1H];[3.82(m), 3.69-3.57(m), 2H]; 3.76(d, J=6.7, 2H); 3.55-3.26(m, 2H);[2.78(s), 2.77(s), 3H]; 2.34-2.16(m,1H);[2.29(qu, J=7.5), 2.25(qu, J=7.5), 2H];[2.03(m), 1.92(m), 1H];[1.01(t, J=7.5), 0.99(t, J=7.5), 3H]; 0.88(m, 1H); 0.31(m, 2H); 0.12(m, 2H)。
Example E15: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f4) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=508(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 12.03(s, 1H,-NH);[8.93(s), 8.92(s), 1H]; [8.87(d, J=7.2), 8.85(d, 6.9), 1H,-NH]; 7.00(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H);[4.59(m), 4.49(m), 1H];[4.06(d, J=6.6), 4.01(d, J=2.2), 2H];[3.80(m), 3.68(m), 1H]; 3.76(d, J=6.7, 2H); 3.63-3.42(m, 2H); 3.39-3.26(m, 1H);[3.32(s), 3.30(s), 3H]; 2.77(s, 3H); 2.34-2.15(m,1H);[2.03(m), 1.91(m), 1H]; 0.88(m, 1H); 0.30(m, 2H); 0.12(m, 2H)。
Example E16: N- [ (3R)*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidines-7-carboxamides
From 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f. 5) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=494.2040([MH]+, C25H28N5O6 +Calculating the value: 494.2034).
Example E17: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f5) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=508.2191([MH]+, C26H30N5O6 +Calculating the value: 508.2191).
Example E18: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d. f5) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=524.2140([MH]+, C26H30N5O7 +Calculating the value: 524.2140).
Example E19N- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f. 6) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=466(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.80(s, 1H,-NH); 8.94(s. .1H); 8.81(d, J=7.7, 1H,-NH); 7.66(dd, J=8.4, 6.9, 1H); 7.08(dd, J=11.7, 2.4, 1H); 6.96(ddd, J=8.4, 8.4, 2.4, 1H); 4.23-4.04(m, 2H); 3.91(d, J=6.9, 2H); 3.78(m, 1H); 3.28(m, 1H); 2.95(m, 1H); 2.79(s, 3H); 2.04(s, 3H); 1.95(m, 2H); 1.54(m, 1H); 1.38(m, 1H); 0.96(m, 1H); 0.38(m, 2H): 0.25(m, 2H)。
Example E20: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f6) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=480(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.80(s, 1H,-NH); 8.94(s. .1H); 8.81(d, J=7.7, 1H,-NH); 7.66(dd, J=8.6, 7.1, 1H); 7.08(dd, J=11.7, 2.4, 1H); 6.96(ddd, J=8.6, 8.6, 2.4, 1H); 4.26-4.04(m, 2H); 3.91(d, J=6.9, 2H); 3.81(m, 1H); 3.25(m, 1H); 2.96(m, 1H); 2.78(s, 3H); 2.36(qu, J=7.5, 3H); 1.95(m, 2H); 1.51(m, 1H); 1.38(m, 1H); 1.01(t, J=7.5, 3H); 0.96(m, 1H); 0.38(m, 2H): 0.25(m, 2H)。
Example E21: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f6) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=496(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.80(s, 1H,-NH); 8.94(s. .1H); 8.81(d, J=7.7, 1H,-NH); 7.66(dd, J=8.6, 7.1, 1H); 7.09(dd, J=11.7, 2.4, 1H); 6.96(ddd, J=8.6, 8.6, 2.4, 1H); 4.24-4.04(m, 2H); 4.12(d, J=1.6, 2H); 3.91(d, J=7.1, 2H); 3.75(m, 1H); 3.31(s, 3H); 3.24(m, 1H); 2.98(m, 1H); 2.78(s, 3H); 1.96(m, 2H); 1.54(m, 1H); 1.41(m, 1H); 0.96(m, 1H); 0.38(m, 2H): 0.25(m, 2H)。
Example E22N- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f. 7) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=480(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.77(s, 1H,-NH); 8.94(s, 1H); 8.65(d, J=7.9, 1H,-NH); 7.72(d, J=7.7, 1H,-NH); 7.66(dd, 8.4, 7.1, 1H); 7.08(dd, 11.7, 2.4, 1H); 6.96(ddd, 8.4, 8.4, 2.4, 1H); 3.91(d, J=6.9, 2H); 3.80(m, 1H); 3.58(m, 1H); 2.78(s, 3H); 2.00(m, 2H); 1.86(m, 2H); 1.79(s, 3H); 1.35(m, 4H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example E23: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f7) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=494(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.77(s, 1H,-NH); 8.94(s, 1H); 8.65(d, J=7.7, 1H,-NH); 7.65(dd, 8.4, 7.1, 1H); 7.62(d, J=7.6, 1H,-NH); 7.08(dd, 11.7, 2.4, 1H); 6.96(ddd, 8.4, 8.4, 2.4, 1H); 3.91(d, J=6.9, 2H); 3.80(m, 1H); 3.59(m, 1H); 2.78(s, 3H); 2.06(qu, J=7.5, 2H); 2.01(m, 2H); 1.86(m, 2H); 1.35(m, 4H); 0.99(t, J=7.5, 3H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example E24: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f7) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.77(s, 1H, -NH), 8.94(s, 1H), 8.64(d, J =7.9, 1H, -NH), 7.66(dd, 8.4, 6.9, 1H), 7.57(d, J =8.4, 1H, -NH), 7.08(dd, 11.7, 2.4, 1H), 6.96(ddd, 8.4, 8.4, 2.4, 1H), 3.91(d, J =6.9, 2H), 3.78(s, 2H and m, 1H), 3.68(m, 1H), 3.31(s, 3H), 2.78(s, 3H), 2.01(m, 2H), 1.82(m, 2H), 1.43(m, 4H), 0.96(m, 1H), 0.38(m, 2H), 0.25(m, 2H).
Example E25N- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f8) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=480(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.78(s, 1H,-NH); 8.97(s, 1H); 8.93(d, J=7.5, 1H,-NH); 7.84(d, J=7.7, 1H,-NH); 7.66(dd, 8.4, 7.1, 1H); 7.09(dd, 11.7, 2.4, 1H); 6.96(ddd, 8.4, 8.4, 2.4, 1H); 4.02(m, 1H); 3.91(d, J=7.1, 2H); 3.75(m, 1H); 2.79(s, 3H); 1.84(s, 3H); 1.84-1.51(m, 8H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example E26: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f8) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=494(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.78(s, 1H,-NH); 8.97(s, 1H); 8.93(d, J=7.7, 1H,-NH); 7.75(d, J=7.7, 1H,-NH); 7.66(dd, 8.4, 6.9, 1H); 7.09(dd, 11.7, 2.4, 1H); 6.96(ddd, 8.4, 8.4, 2.4, 1H); 4.02(m, 1H); 3.92(d, J=7.1, 2H); 3.75(m, 1H); 2.79(s, 3H); 2.11(qu, J=7.5, 2H); 1.84-1.51(m, 8H); 1.00(t, J=7.5, 3H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example E27: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f8) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.78(s, 1H,-NH); 8.98(s, 1H); 8.96(d, J=7.5, 1H,-NH); 7.67(d, J=7.6, 1H,-NH); 7.66(dd, 8.4, 6.9, 1H); 7.09(dd, 11.5, 2.4, 1H); 6.96(ddd, 8.4, 8.4, 2.4, 1H); 4.05(m, 1H); 3.91(d, J=7.1, 2H); 3.82(s, 2H); 3.79(m, 1H); 3.31(s, 3H); 2.79(s, 3H); 1.86-1.58(m, 8H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example E28N- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f. 9) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=452(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.83(s, 1H,-NH); 8.94(s, 1H);[8.93(d, J=6.8), 8.90(d, J=6.9), 1H,-NH]; 7.66(ddd, J=8.4, 7.1, 1.1, 1H); 7.09(dd, J=11.5, 2.4, 1H); 6.96(ddd, J=8.4, 8.4, 2.4, 1H);[4.59(m), 4.49(m), 1H]; 3.91(d, J=7.1, 2H);[3.84(m), 3.69-3.58(m), 2H]; 3.56-3.27(m, 2H);[2.79(s), 2.78(s), 3H]; 2.35-2.16(m, 1H); 2.08-1.86(m, 1H);[1.98(s), 1.96(s), 3H]; 0.95(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example E29: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f9) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=466(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.83(s, 1H,-NH);[8.93(d, J=7.1), 8.90(d, J=6.8), 1H,-NH];[8.93(s), 8.92(s), 1H]; 7.66(ddd, J=8.4, 7.1, 0.7, 1H); 7.08(dd, J=11.7, 2.4, 1H); 6.96(ddd, J=8.4, 8.4, 2.4, 1H);[4.59(m), 4.49(m), 1H]; 3.91(d, J=7.1, 2H);[3.82(m), 3.70-3.58(m), 2H]; 3.55-3.27(m, 2H);[2.79(s), 2.78(s), 3H]; 2.34-2.15(m, 1H);[2.29(qu, J=7.5), 2.25(qu, J=7.5), 2H]; 2.08-1.86(m, 1H);[1.01(t, J=7.5), 0.99(t, J=7.5), 3H]; 0.95(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example E30: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f9) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=482(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.83(s, 1H,-NH);[8.94(s), 8.93(s), 1H];[8.92(d, J=7.1), 8.90(d, J=6.8), 1H,-NH]; 7.66(ddd, J=8.4, 6.9, 0.7, 1H); 7.09(dd, J=11.5, 2.4, 1H); 6.96(ddd, J=8.4, 8.4, 2.4, 1H);[4.59(m), 4.49(m), 1H];[4.06(d, J=4.0), 4.01(d, J=1.1), 2H]; 3.91(d, J=6.9, 2H);[3.79(m), 3.68(m), 1H]; 3.62-3.42(m, 2H); 3.38-3.27(m, 1H);[3.32(s), 3.29(s), 3H]; 2.79(s, 3H); 2.33-2.15(m, 1H);[2.03(m), 1.91(m), 1H]; 0.95(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example E31: N- [ (3R)*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-6-methyl-5H-pyrrolo [3,2-d ]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f10) and commercially available acetyl chloride gave the title compound as a colorless solid.
MS(ESI): m/z=468(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.84(s, 1H,-NH); 8.93(s, 1H);[8.88(d, J=7.2), 8.83(d, J=6.6), 1H,-NH]; 7.65(dd, J=8.4, 7.1, 1H); 7.09(dd, J=11.7, 2.0, 1H); 6.96(ddd, J=8.4, 8.4, 2.0, 1H);[5.56(d, J=3.2), 5.48(d, J=3.9), 1H,-OH];[4.36(m), 4.19(m), 1H]; 4.27(m, 1H); 3.91(d, 7.2, 2H);[3.76(m), 3.69(m), 3.58(m), 3.45(m), 2H]; 3.41-3.27(m, 2H); 2.79(s. .3H);[1.99(s), 1.98(s), 3H]; 0.95(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example E32: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f10) and commercially available propionyl chloride gave the title compound as a colorless solid.
MS(ESI): m/z=482(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.84(s, 1H,-NH); 8.91(s, 1H);[8.88(d, J=7.1), 8.82(d, J=6.8), 1H,-NH]; 7.65(dd, J=8.4, 7.1, 1H); 7.09(dd, J=11.7, 2.4, 1H); 6.96(ddd, J=8.4, 8.4, 2.4, 1H);[5.55(d, J=3.8), 5.47(d, J=4.0), 1H,-OH];[4.36(m), 4.19(m), 1H]; 4.27(m, 1H); 3.91(d, 6.9, 2H);[3.86(m), 3.59(m), 1H]; 3.72(m, 1H); 3.49-3.27(m, 2H); 2.78(s. .3H);[2.28(qu, J=7.5), 2.27(qu, J=7.5), 2H];[1.03(t, J=7.5), 1.01(t, J=7.5), 3H]; 0.95(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example E33: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d. f10) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
MS(ESI): m/z=498(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.85(s, 1H,-NH);[8.91(s), 8.90(s), 1H];[8.87(d, J=7.1), 8.83(d, J=6.6), 1H,-NH]; 7.65(dd, J=8.4, 7.3, 1H); 7.09(dd, J=11.7, 2.4, 1H); 6.96(ddd, J=8.4, 8.4, 2.4, 1H);[5.56(d, J=3.8), 5.50(d, J=4.0), 1H,-OH];[4.36(m), 4.19(m), 1H]; 4.27(m, 1H);[4.09(dd, J=14.6,3.5)4.02(d, J=14.6)2H]; 3.91(d, 6.9, 2H);[3.85(m), 3.62(m), 1H]; 3.73(m, 1H); 3.49-3.27(m, 2H);[3.34(s), 3.32(s), 3H]; 2.78(s. .3H); 0.95(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example E34: N- [ (3S)*,4S*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -4-fluorophenyl ]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4S*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f11) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=482.2196([MH]+, C25H29FN5O4 +Calculating the value: 482.2198).
Example E35: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-N-[(3S*,4S*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4S*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f11) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=496.2345([MH]+, C26H31FN5O4 +Calculating the value: 496.2355).
Example E36: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-N-[(3S*,4S*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4S*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d. f11) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=512.2288([MH]+, C26H31FN5O5 +Calculating the value: 512.2304).
Example E37: 4- (2-Cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (1-acetyl-piperidin-4-yl) -amide
Starting from 4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example d.f12) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=466(MH+, 100%), 356, 302。
1H-NMR(300 MHz, DMSO-d6): 11.84(br.s, 1H,-NH); 8.96(s, 1H); 8.80(d, J=7.7, 1H,-NH); 7.43(dd, J=9.0, 3.3, 1H); 7.37(ddd, J=9.1, 8.3, 3.3, 1H); 7.19(dd, J=9.1, 4.4, 1H); 4.22-4.06(m, 2H); 3.87(d, J=6.9, 2H); 3.78(m, 1H); 3.27(m, 1H); 2.95(m, 1H); 2.79(s, 3H); 2.04(s, 3H); 1.96(m, 2H); 1.54(m, 1H); 1.39(m, 1H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example E38: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example d.f12) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=480(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.84(s, 1H,-NH); 8.96(s, 1H); 8.80(d, J=7.7, 1H,-NH); 7.42(dd, J=9.0, 3.2, 1H); 7.36(ddd, J=9.1, 8.3, 3.2, 1H); 7.19(dd, J=9.1, 4.4, 1H); 4.25-4.04(m, 2H); 3.87(d, J=6.9, 2H); 3.81(m, 1H); 3.27(m, 1H); 2.96(m, 1H); 2.79(s, 3H); 2.36(qu, J=7.5, 2H); 1.96(m, 2H); 1.52(m, 1H); 1.39(m, 1H); 1.01(t, J=7.5, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example E39: 4- (2-Cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid [1- (2-methoxy-acetyl) -piperidin-4-yl ] -amide
Starting from 4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example d.f12) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=496(MH+, 100%), 356, 302。
1H-NMR(300 MHz, DMSO-d6): 11.84(br.s, 1H,-NH); 8.96(s, 1H); 8.80(d, J=7.7, 1H,-NH); 7.43(dd, J=9.0, 3.3, 1H); 7.37(ddd, J=9.1, 8.3, 3.3, 1H); 7.19(dd, J=9.1, 4.4, 1H); 4.23-4.07(m, 2H); 4.12(d, J=1.6, 2H); 3.87(d, J=6.9, 2H); 3.75(m, 1H); 3.31(s, 3H); 3.22(m, 1H); 2.98(m, 1H); 2.79(s, 3H); 1.97(m, 2H); 1.54(m, 1H); 1.41(m, 1H); 0.87(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example E40: 4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester
Starting from 4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example d.f12) and commercially available ethyl chloroformate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=496(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.84(s, 1H, -NH), 8.97(s, 1H), 8.80(d, J =7.7, 1H, -NH), 7.42(dd, J =9.1, 3.3, 1H), 7.37(ddd, J =9.1, 8.2, 3.3, 1H), 7.19(dd, J =9.1, 4.4, 1H), 4.06(qu, J =7.2, 2H and m, 1H), 3.87(d, J =6.9, 2H and m, 2H), 3.11(m, 2H), 2.79(s, 3H), 1.94(m, 2H), 1.46(m, 2H), 1.20(t, J =7.2, 3H), 0.94(m, 1H), 0.36(m, 2H), 0.22(m, 2H).
Example E41N- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f13) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=480(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.81(s, 1H,-NH); 8.97(s, 1H); 8.67(d, J=7.7, 1H,-NH); 7.72(d, J=7.7, 1H,-NH); 7.42(dd, J=8.9, 3.2, 1H); 7.36(ddd, J=9.1, 8.4, 3.2, 1H); 7.18(dd, J=9.1, 4.4, 1H); 3.87(d, J=6.9, 2H); 3.80(m, 1H); 3.58(m, 1H); 2.78(s, 3H); 2.00(m, 2H); 1.86(m, 2H); 1.79(s, 3H); 1.35(m, 4H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example E42: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f13) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=494(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.81(s, 1H,-NH); 8.97(s, 1H); 8.64(d, J=7.7, 1H,-NH); 7.62(d, J=7.7, 1H,-NH); 7.42(dd, J=8.9, 3.3, 1H); 7.36(ddd, J=9.1, 8.2, 3.3, 1H); 7.18(dd, J=9.1, 4.4, 1H); 3.87(d, J=6.9, 2H); 3.80(m, 1H); 3.60(m, 1H); 2.78(s, 3H); 2.06(m, 2H); 1.86(m, 2H); 1.79(s, 3H); 1.35(m, 4H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example E43: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f13) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.81(s, 1H,-NH); 8.97(s, 1H); 8.63(d, J=7.7, 1H,-NH); 7.57(d, J=8.2, 1H,-NH); 7.42(dd, J=8.9, 3.3, 1H); 7.36(ddd, J=8.9, 8.2, 3.3, 1H), 7.18(dd, J =8.9, 4.4, 1H), 3.87(d, J =6.9, 2H), 3.78(s, 2H and m, 1H), 3.69(m, 1H), 3.31(s, 3H), 2.78(s, 3H), 2.01(m, 2H), 1.82(m, 2H), 1.43(m, 4H), 0.94(m, 1H), 0.36(m, 2H), 0.22(m, 2H).
Example E44 Ethyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f13) and commercially available ethyl chloroformate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.81(s, 1H,-NH); 8.96(s, 1H); 8.63(d, J=7.7, 1H,-NH); 7.42(dd, J=8.9, 3.3, 1H); 7.36(ddd, J=9.1, 8.3, 3.3, 1H); 7.18(dd, J=9.1, 4.4, 1H); 7.01(d, J=7.3, 1H,-NH); 3.98(qu, J=7.1, 2H); 3.87(d, J=6.9, 2H); 3.77(m, 1H); 3.34(m, 1H); 2.78(s, 3H); 2.00(m, 2H); 1.87(m, 2H); 1.36(m, 4H); 1.16(d, J=6.7, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example E45N- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f14) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=480(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.83(s, 1H,-NH); 9.00(s, 1H); 8.92(d, J=7.5, 1H,-NH); 7.85(d, J=7.7, 1H,-NH); 7.43(dd, J=8.9, 3.3, 1H); 7.38(ddd, J=8.9, 8.2, 3.3, 1H); 7.19(dd, J=8.9, 4.4, 1H); 4.03(m, 1H); 3.88(d, J=6.8, 2H); 3.75(m, 1H); 2.79(s, 3H); 1.84(s, 3H); 1.82-1.52(m, 8H); 0.94(m, 1H); 0.37(m, 2H); 0.23(m, 2H)。
Example E46N- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f15) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=452(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.88(s, 1H,-NH); 8.97(s, 1H);[8.93(d, J=6.9), 8.89(d, J=6.9), 1H,-NH]; 7.43(dd, J=8.9, 3.2, 1H); 7.38(ddd, J=9.0, 8.6, 3.2, 1H); 7.19(dd, J=9.0, 4.4, 1H);[4.59(m), 4.49(m), 1H]; 3.88(d, J=6.9, 2H);[3.84(m), 3.65(m), 1H]; 3.62(m, 1H); 3.55-3.26(m, 2H);[2.80(s); 2.79(s), 3H]; 2.35-2.16(m, 1H); 2.09-1.87(m, 1H);[1.98(s), 1.96(s), 3H]; 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example E47: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f15) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=466(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.87(s, 1H,-NH); 8.96(s, 1H);[8.92(d, J=7.1), 8.89(d, J=6.8), 1H,-NH]; 7.42(dd, J=8.9, 3.3, 1H); 7.38(ddd, J=9.1, 8.4, 3.3, 1H); 7.19(dd, J=9.1, 4.4, 1H);[4.59(m), 4.49(m), 1H]; 3.87(d, J=6.9, 2H);[3.82(m), 3.66(m), 1H]; 3.61(m, 1H); 3.55-3.26(m, 2H);[2.80(s); 2.79(s), 3H]; 2.34-2.15(m, 1H);[2.29(qu, J=7.5), 2.25(qu, J=7.5), 2H];[2.03(m), 1.92(m), 1H];[1.01(t, J=7.5), 1.00(t, J=7.5), 3H]; 0.93(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example E48: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f15) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=482(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.88(s, 1H,-NH); 8.96(s, 1H);[8.91(d, J=7.1), 8.89(d, J=6.8), 1H,-NH]; 7.42(ddd, J=8.9, 3.3, 0.6, 1H); 7.38(ddd, J=9.1, 8.4, 3.3, 1H); 7.19(dd, J=9.1, 4.4, 1H);[4.59(m), 4.50(m), 1H];[4.06(d, J=4.0), 4.01(d, J=1.1), 2H]; 3.87(d, J=6.9, 2H);[3.80(m), 3.68(m), 1H]; 3.63-3.42(m, 2H); 3.36(m, 1H);[3.32(s), 3.30(s), 3H]; 2.79(s, 3H); 2.34-2.13(m, 1H);[2.03(m), 1.92(m), 1H]; 0.93(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example E49: N- [ (3R)*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f16) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=482.2199([MH]+, C25H29FN5O4 +Calculating the value: 482.2198).
Example E50: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl)]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f16) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=496.2359([MH]+, C26H31FN5O4 +Calculating the value: 496.2355).
Example E51: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl)]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl ]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f16) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=512.2294([MH]+, C26H31FN5O5 +Calculating the value: 512.2304).
Example E52N- (1-acetylpiperidin-4-yl) -4- (2-ethoxy-5-fluorophenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- (2-ethoxy-5-fluorophenyl) -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide (example d.f17) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=440(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.87(s, 1H,-NH); 8.95(s, 1H); 8.79(d, J=7.7, 1H,-NH); 7.42(ddd, J=9.1, 8.9, 3.2, 1H); 7.38(dd, J=8.2, 3.2, 1H); 7.22(dd, J=9.1, 4.4, 1H); 4.22-4.06(m, 2H); 4.08(qu, J=7.0, 2H); 3.78(m, 1H); 3.27(m, 1H); 2.95(m, 2H); 2.79(s, 3H); 2.04(s, 3H); 1.95(m, 2H); 1.54(m, 1H); 1.38(m, 1H); 1.10(t, J=7.0, 3H)。
Example E53: 4- (2-ethoxy-5-fluorophenyl) -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- (2-ethoxy-5-fluorophenyl) -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide (example d.f17) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=454(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6, MeOH-d4): 11.87(s, 1H,-NH); 8.95(s, 1H); 8.79(d, J=7.7, 1H,-NH); 7.42(ddd, J=9.1, 8.9, 3.2, 1H); 7.38(dd, J=8.2, 3.2, 1H); 7.22(dd, J=9.1, 4.4, 1H); 4.25-4.03(m, 2H); 4.08(qu, J=6.9, 2H); 3.81(m, 1H); 3.25(m, 1H); 2.96(m, 2H); 2.78(s, 3H); 2.36(qu, J=7.3, 2H); 1.95(m, 2H); 1.52(m, 1H); 1.38(m, 1H); 1.11(t, J=6.9, 3H); 1.01(t, J=7.3, 3H)。
Example E54: 4- (2-ethoxy-5-fluorophenyl) -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- (2-ethoxy-5-fluorophenyl) -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide (example d.f17) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=470(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.87(s, 1H,-NH); 8.95(s, 1H); 8.79(d, J=7.7, 1H,-NH); 7.42(ddd, J=9.1, 8.9, 3.2, 1H); 7.38(dd, J=8.3, 3.2, 1H); 7.22(dd, J=9.1, 4.4, 1H); 4.21-4.06(m, 2H); 4.12(d, J=3.0, 2H); 4.08(qu, J=7.0, 2H); 3.75(m, 1H); 3.31(s, 3H); 3.22(m, 1H); 2.98(m, 1H); 2.78(s, 3H); 1.97(m, 2H); 1.53(m, 1H); 1.41(m, 1H); 1.11(t, J=6.9, 3H)。
Example E55N- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f18) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=478(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.68(s, 1H,-NH); 8.90(s, 1H); 8.84(d, J=7.7, 1H,-NH); 7.59(d, J=8.4, 1H); 6.72(dd, J=8.4, 2.2, 2H); 6.69(d, J=2.2, 1H); 4.21-4.04(m, 2H); 3.91(d, J=6.9, 2H); 3.86(s, 3H); 3.78(m, 1H); 3.27(m, 1H); 2.95(m, 1H); 2.78(s, 3H); 2.04(s, 3H); 1.95(m, 2H); 1.54(m, 1H); 1.38(m, 1H); 0.96(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example E56: 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f18) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=492(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.68(s, 1H,-NH); 8.90(s, 1H); 8.84(d, J=7.8, 1H,-NH); 7.59(d, J=8.4, 1H); 6.72(dd, J=8.4, 2.2, 2H); 6.69(d, J=2.2, 1H); 4.25-4.03(m, 2H); 3.90(d, J=6.9, 2H); 3.86(s, 3H); 3.81(m, 1H); 3.25(m, 1H); 2.96(m, 1H); 2.78(s, 3H); 2.36(qu, J=7.3, 2H); 1.95(m, 2H); 1.51(m, 1H); 1.38(m, 1H); 1.01(t, J=7.3, 3H); 0.96(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example E57: 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f18) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=508(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.68(s, 1H,-NH); 8.90(s, 1H); 8.84(d, J=7.7, 1H,-NH); 7.59(d, J=8.4, 1H); 6.72(dd, J=8.4, 2.2, 2H); 6.69(d, J=2.2, 1H); 4.21-4.06(m, 2H); 4.12(d, J=1.5, 2H); 3.90(d, J=6.8, 2H); 3.86(s, 3H); 3.75(m, 1H); 3.31(s, 3H); 3.22(m, 1H); 2.99(m, 1H); 2.78(s, 3H); 1.96(m, 2H); 1.53(m, 1H); 1.41(m, 1H); 0.96(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example E58N- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f19) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=492(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.66(s, 1H,-NH); 8.91(s, 1H); 8.67(d, J=7.9, 1H,-NH); 7.72(d, J=7.9, 1H,-NH); 7.58(d, J=8.4, 1H); 6.72(dd, J=8.4, 2.2, 1H); 6.68(d, J=2.2, 1H); 3.90(d , J=6.9, 2H); 3.86(s, 3H); 3.80(m, 1H); 3.58(m, 1H); 2.77(s, 3H); 2.00(m, 2H); 1.86(m, 2H); 1.79(s, 3H); 1.35(m, 4H); 0.96(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example E59N- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f. 20) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=492(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.66(s, 1H,-NH); 8.95(d, J=6.9, 1H,-NH); 8.94(s, 1H); 7.84(d, J=7.5, 1H,-NH); 7.59(d, J=8.4, 1H); 6.72(dd, J=8.4, 2.2, 2H); 6.69(d, J=2.2, 1H); 4.02(m, 1H); 3.91(d , J=6.8, 2H); 3.86(s, 3H); 3.75(m, 1H); 2.78(s, 3H); 1.84(s, 3H); 1.81-1.51(m, 8H); 0.96(m, 1H); 0.38(m, 2H); 0.27(m, 2H)。
Example E60N- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f21) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=464(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(br.s, 1H,-NH);[8.96(d, J=6.8), 8.93(d, J=6.8), 1H,-NH]; 8.91(s, 1H); 7.59(dd, J=8.4, 0.9, 1H); 6.72(dd, J=8.4, 2.2, 1H); 6.69(d, J=2.2, 1H);[4.58(m), 4.49(m), 1H]; 3.90(d , J=6.9, 2H); 3.86(s, 3H);[3.83(m), 3.65(m), 1H]; 3.62(m, 1H); 3.55-3.27(m, 2H);[2.78(s), 2.77(s), 3H]; 2.34-2.15(m 1H); 2.08-1.86(m, 1H);[1.98(s), 1.96(s), 3H]; 0.95(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example E61: 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f21) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=478(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.71(br.s, 1H,-NH);[8.96(d, J=6.8), 8.93(d, J=6.8), 1H,-NH];[8.90(s), 8.89(s), 1H]; 7.59(dd, J=8.4, 0.7, 1H); 6.72(dd, J=8.4, 2.2, 1H); 6.69(d, J=2.2, 1H);[4.58(m), 4.48(m), 1H]; 3.90(d , J=6.9, 2H); 3.86(s, 3H);[3.81(m), 3.67(m), 1H]; 3.60(m, 1H); 3.55-3.26(m, 2H);[2.79(s), 2.78(s), 3H]; 2.34-2.15(m 1H);[2.28(qu, J=7.5), 2.25(qu, J=7.5), 2H];[2.03(m), 1.91(m), 1H];[1.01(t, J=7.5), 0.99(t, J=7.5), 3H]; 0.95(m, 1H); 0.37(m, 2H); 0.26(m, 2H)。
Example E62: 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f21) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=494(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.71(br.s, 1H,-NH);[8.95(d, J=6.8), 8.93(d, J=6.8), 1H,-NH];[8.90(s), 8.89(s), 1H]; 7.59(dd, J=8.4, 0.7, 1H); 6.72(dd, J=8.4, 2.2, 1H); 6.69(d, J=2.2, 1H);[4.58(m), 4.49(m), 1H];[4.06(d, J=3.8), 4.01(d, J=1.1), 2H]; 3.90(d , J=6.9, 2H); 3.86(s, 3H);[3.79(m), 3.68(m), 1H]; 3.62-3.42(m, 2H); 3.38-3.27(m, 1H);[3.32(s), 3.29(s), 3H]; 2.78(s, 3H); 2.33-2.14(m 1H);[2.03(m), 1.90(m), 1H]; 0.95(m, 1H); 0.37(m, 2H); 0.26(m, 2H)。
Example E63: N- [ (3R)*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f22) and commercially available acetyl chloride gave the title compound as a colorless solid.
MS(ESI): m/z=480(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.74(br.s, 1H,-NH);[8.91(d, J=7.1), 8.85(d, J=6.8), 1H,-NH]; 8.89(s, 1H); 7.59(dd, J=8.4, 0.7, 1H); 6.72(dd, J=8.4, 2.2, 1H); 6.69(d, J=2.2, 1H); 5.50(br.s, 1H,-OH);[4.35(m), 4.19(m), 1H]; 4.27(m, 1H); 3.90(d , J=6.9, 2H); 3.86(s, 3H); 3.79-3.65(m, 1H); 3.62-3.53(m, 1H); 3.48-3.32(m, 2H); 2.78(s, 3H);[1.99(s); 1.98(s), 3H]; 0.95(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example E64: 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f22) and commercially available propionyl chloride gave the title compound as a colorless solid.
MS(ESI): m/z=494(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(br.s, 1H,-NH);[8.90(d, J=7.1), 8.85(d, J=6.6), 1H,-NH]; 8.87(s, 1H); 7.58(d, J=8.4, 1H); 6.72(dd, J=8.4, 2.2, 1H); 6.69(d, J=2.2, 1H);[5.54(br.s), 5.46(br.s), 1H,-OH];[4.35(m), 4.18(m), 1H]; 4.27(m, 1H); 3.91(d , J=7.1, 2H); 3.86(s, 3H); 3.79-3.66(m, 1H); 3.63-3.55(m, 1H); 3.48-3.32(m, 2H); 2.78(s, 3H);[2.28(qu, J=7.5), 2.27(qu, J=7.5), 2H]; [1.03(d, J=7.5); 1.01(d, J=7.5), 3H]; 0.95(m, 1H); 0.37(m, 2H); 0.26(m, 2H)。
Example E65: 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f22) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
MS(ESI): m/z=510(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.74(br.s, 1H,-NH);[8.90(d, J=7.1), 8.85(d, J=6.6), 1H,-NH];[8.87(s), 8.86(s), 1H]; 7.58(d, J=8.4, 1H); 6.72(dd, J=8.4, 2.2, 1H); 6.69(d, J=2.2, 1H); 5.68-5.36(br.s, 1H,-OH);[4.36(m), 4.19(m), 1H]; 4.27(m, 1H);[4.09(dd, J=14.6, 3.5), 4.01[d, J=14.6), 2H]; 3.90(d , J=6.9, 2H); 3.86(s, 3H); 3.78-3.68(m, 1H); 3.66-3.58(m, 1H); 3.48-3.32(m, 2H);[3.33(s), 3.31(s), 3H]; 2.78(s, 3H); 0.95(m, 1H); 0.37(m, 2H); 0.26(m, 2H)。
Example E66N- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f23) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=478(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.77(s, 1H,-NH); 8.95(s, 1H), 8.82(d, J =7.7, 1H, -NH), 7.18(t, J =1.8, 1H), 7.11(d, J =1.8, 2H), 4.22-3.93(m, 2H), 3.82(d, J =6.8, 2H), 3.77(s, 3H and m, 1H), 3.27(m, 1H), 2.95(m, 1H), 2.79(s, 3H), 2.04(s, 3H), 1.95(m, 2H), 1.54(m, 1H), 1.39(m, 1H), 0.92(m, 1H), 0.34(m, 2H), 0.19(m, 2H).
Example E67: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f23) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=492(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.76(s, 1H,-NH); 8.95(s, 1H); 8.82(d, J=7.7, 1H,-NH); 7.17(t, J=1.8, 1H); 7.11(d, J=1.8, 1H); 4.25-4.05(m, 2H); 3.82(d, J=6.9, 2H); 3.79(m, 1H); 3.77(s, 3H); 3.25(m, 1H); 2.96(m, 1H); 2.79(s, 3H); 2.36(qu, J=7.5, 2H); 1.96(m, 2H); 1.52(m, 1H); 1.38(m, 1H); 1.01(t, J=7.5, 3H); 0.92(m, 1H); 0.34(m, 2H); 0.20(m, 2H)。
Example E68: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f23) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=508(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.77(s, 1H,-NH); 8.95(s, 1H); 8.82(d, J=7.7, 1H,-NH); 7.17(t, J=1.8, 1H); 7.11(d, J=1.8, 2H); 4.21-4.06(m, 2H); 4.12(d, J=1.6, 2H); 3.82(d, J=6.8, 2H); 3.77(s, 3H); 3.73(m, 1H); 3.31(s, 3H); 3.22(m, 1H); 2.98(m, 1H); 2.79(s, 3H); 1.97(m, 2H); 1.54(m, 1H); 1.41(m, 1H); 0.92(m, 1H); 0.34(m, 2H); 0.20(m, 2H)。
Example E69N- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f24) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=492(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.74(s, 1H, -NH), 8.96(s, 1H), 8.65(d, J =7.7, 1H, -NH), 7.72(d, J =7.7, 1H, -NH), 7.17(t, J =1.8, 1H), 7.10(d, J =1.8, 2H), 3.82(d, J =6.8, 2H), 3.77(s, 3H and m, 1H), 3.59(m, 1H), 2.78(s, 3H), 2.01(m, 2H), 1.86(m, 2H), 1.79(s, 3H), 1.35(m, 4H), 0.92(m, 1H), 0.34(m, 2H), 0.19(m, 2H).
Example E70: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f24) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=506(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.74(s, 1H,-NH); 8.96(s, 1H); 8.66(d, J=7.7, 1H,-NH); 7.62(d, J=7.7, 1H,-NH); 7.17(t, J=1.8, 1H); 7.10(d, J=1.8, 2H); 3.82(d, J=6.8, 2H); 3.79(m, 1H); 3.77(s, 3H); 3.59(m, 1H); 2.78(s, 3H); 2.06(qu, J=7.5, 2H); 2.01(m, 2H); 1.86(m, 2H); 1.35(m, 4H); 0.99(t, J=7.5, 3H); 0.92(m, 1H); 0.34(m, 2H); 0.19(m, 2H)。
Example E71: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f24) and the commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=522(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.74(s, 1H, -NH), 8.96(s, 1H), 8.65(d, J =7.7, 1H, -NH), 7.57(d, J =8.2, 1H, -NH), 7.17(t, J =1.8, 1H), 7.10(d, J =1.8, 2H), 3.82(d, J =6.8, 2H), 3.78(s, 2H), 3.77(s, 3H and m, 1H), 3.69(m, 1H), 3.31(s, 3H), 2.78(s, 3H), 2.01(m, 2H), 1.82(m, 2H), 1.43(m, 4H), 0.92(m, 1H), 0.34(m, 2H), 0.19(m, 2H).
Example E72N- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f25) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=492(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.76(s, 1H,-NH); 8.99(s, 1H); 8.93(d, J=7.5, 1H,-NH); 7.85(d, J=7.3, 1H,-NH); 7.18(t, J=1.8, 1H); 7.11(d, J=1.8, 2H); 4.02(m, 1H); 3.83(d, J=6.8, 2H); 3.77(s, 3H); 3.75(m, 1H); 2.79(s, 3H); 1.84(s, 3H); 1.81-1.52(m, 8H); 0.92(m, 1H); 0.35(m, 2H); 0.20(m, 2H)。
Example E73: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f25) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=506(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.76(s, 1H,-NH); 8.99(s, 1H); 8.92(d, J=7.7, 1H,-NH); 7.75(d, J=7.7, 1H,-NH); 7.18(t, J=1.8, 1H); 7.11(d, J=1.8, 2H); 4.02(m, 1H); 3.83(d, J=6.9, 2H); 3.77(s, 3H); 3.75(m, 1H); 2.79(s, 3H); 2.11(qu, J=7.5, 2H); 1.86-1.50(m, 8H); 1.00(t, J=7.5, 3H); 0.92(m, 1H); 0.35(m, 2H); 0.20(m, 2H)。
Example E74: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f25) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=522(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.75(s, 1H, -NH), 8.99(s, 1H), 8.96(d, J =7.5, 1H, -NH), 7.67(d, J =7.7, 1H, -NH), 7.18(t, J =1.8, 1H), 7.11(d, J =1.8, 2H), 4.05(m, 1H), 3.83(d, J =6.7, 2H), 3.80(s, 2H and m, 1H), 3.77(s, 3H), 3.31(s, 3H), 2.79(s, 3H), 1.87-1.58(m, 8H), 0.92(m, 1H), 0.35(m, 2H), 0.20(m, 2H).
Example E75N- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f26) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=464.2290([MH]+, C25H30N5O4 +Calculating the value: 464.2292).
Example E76: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f26) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=478.2450([MH]+, C26H32N5O4+, calculated: 478.2449).
Example E77: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f26) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=494.2393([MH]+, C26H32N5O5 +Calculating the value: 494.2398).
Example E78: N- [ (3R)*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f27) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=494.2405([MH]+, C26H32N5O5 +Calculating the value: 494.2398).
Example E79: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f27) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=508.2551([MH]+, C27H34N5O5 +Calculating the value: 508.2554).
Example E80: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f27) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=524.2501([MH]+, C27H34N5O6 +Calculating the value: 524.2504).
Example E81N- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f28) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=420(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.25(br.s, 1H,-NH); 9.11(br.s, 2H,-NH2 +); 9.06(s, 1H); 7.47(d, J=2.1, 1H); 7.39(dd, J=8.4, 2.1, 1H); 7.10(d, J=8.6, 1H); 4.12(m, 1H); 3.88(d, J=6.9, 2H); 3.31(m, 2H); 3.08(m, 2H); 2.81(s, 3H); 2.34(s, 3H); 2.13(m, 2H); 1.79(m, 2H); 0.93(m, 1H); 0.36(m, 2H); 0.25(m, 2H)。
Example E82: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f28) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=476(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.68(br.s, 1H,-NH); 8.93(s, 1H); 8.82(d, J=7.7, 1H,-NH); 7.43(d, J=1.8, 1H); 7.32(dd, J=8.4, 1.8, 1H); 7.05(d, J=8.4, 1H); 4.26-4.05(m, 2H); 3.86(d, J=6.9, 2H); 3.81(m, 1H); 3.25(m, 1H); 2.96(m, 1H); 2.78(s, 3H); 2.36(qu, J=7.3, 2H); 2.33(s, 3H); 1.96(m, 2H); 1.51(m, 1H); 1.39(m, 1H); 1.01(t, J=7.3, 3H); 0.94(m, 1H); 0.35(m, 2H); 0.22(m, 2H)。
Example E83: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f28) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=492(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.67(br.s, 1H,-NH); 8.92(s, 1H); 8.83(d, J=7.7, 1H,-NH); 7.42(d, J=1.8, 1H); 7.32(dd, J=8.4, 1.8, 1H); 7.06(d, J=8.4, 1H); 4.23-4.04(m, 2H); 4.12(d, J=1.8, 2H); 3.86(d, J=6.8, 2H); 3.75(m, 1H); 3.31(s, 3H); 3.22(m, 1H); 2.99(m, 1H); 2.77(s, 3H); 2.33(s, 3H); 1.97(m, 2H); 1.53(m, 1H); 1.40(m, 1H); 0.94(m, 1H); 0.35(m, 2H); 0.22(m, 2H)。
Example E84N- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f29) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=434(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.25(br.s, 1H,-NH); 9.03(s, 1H); 8.55(d, J=7.9, 1H,-NH); 8.09(br.d, J=4.2, 3H,-NH3 +); 7.46(d, J=2.1, 1H); 7.39(dd, J=8.4, 2.1, 1H); 7.11(d, J=8.6, 1H); 3.88(d, J=6.9, 2H); 3.82(m, 1H); 3.09(m, 1H); 2.81(s, 3H); 2.34(s, 3H); 2.04(m, 4H); 1.47(m, 4H); 0.93(m, 1H); 0.36(m, 2H); 0.24(m, 2H)。
Example E85: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f29) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=490(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.71(s, 1H,-NH); 8.94(s, 1H); 8.67(d, J=7.7, 1H,-NH); 7.62(d, J=7.9, 1H,-NH); 7.43(d, J=2.0, 1H); 7.32(dd, J=8.4, 2.0, 1H); 7.06(d, J=8.4, 1H); 3.86(d, J=6.9, 2H); 3.80(m, 1H); 3.59(m, 1H); 2.77(s, 3H); 2.33(s, 3H); 2.05(qu, J=7.5, 2H); 2.01(m, 2H); 1.86(m, 2H); 1.35(m, 4H); 0.99(t, J=7.5, 3H); 0.94(m, 1H); 0.35(m, 2H); 0.22(m, 2H)。
Example E86: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f29) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=506(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.71(s, 1H, -NH), 8.94(s, 1H), 8.66(d, J =7.7, 1H, -NH), 7.57(d, J =8.4, 1H, -NH), 7.43(d, J =2.1, 1H), 7.32(dd, J =8.4, 2.1, 1H), 7.06(d, J =8.4, 1H), 5.40(t, J =5.9, 1H, -OH), 3.86(d, J =6.9, 2H), 3.78(s, 2H and m, 1H), 3.69(m, 1H), 3.31(s, 3H), 2.77(s, 3H), 2.33(s, 3H), 2.01(m, 2H), 1.82(m, 2H), 1.34(m, 4H), 0.94(m, 1H), 0.22(m, 2H), 2H) In that respect
Example E87N- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f30) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=476(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(s, 1H,-NH); 8.97(s, 1H); 8.94(d, J=7.7, 1H,-NH); 7.85(d, J=7.7, 1H,-NH); 7.44(d, J=1.8, 1H); 7.33(dd, J=8.4, 1.8, 1H); 7.06(d, J=8.4, 1H); 4.02(m, 1H); 3.86(d, J=6.9, 2H); 3.75(m, 1H); 2.78(s, 3H); 2.33(s, 3H); 1.84(s, 3H); 1.81-1.51(m, 8H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example E88: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f30) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=490(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(s, 1H,-NH); 8.97(s, 1H); 8.94(d, J=7.5, 1H,-NH); 7.75(d, J=7.7, 1H,-NH); 7.44(d, J=1.8, 1H); 7.33(dd, J=8.4, 1.8, 1H); 7.06(d, J=8.4, 1H); 4.02(m, 1H); 3.86(d, J=6.9, 2H); 3.75(m, 1H); 2.78(s, 3H); 2.33(s, 3H); 2.11(qu, J=7.7, 2H); 1.83-1.53(m, 8H); 1.00(t, J=7.7, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example E89: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f30) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=506(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.72(s, 1H, -NH), 8.97(s, 1H and d, J =7.5, 1H, -NH), 7.67(d, J =7.7, 1H, -NH), 7.44(d, J =2.1, 1H), 7.33(dd, J =8.4, 2.1, 1H), 7.06(d, J =8.4, 1H), 4.05(m, 1H), 3.86(d, J =6.9, 2H), 3.82(s, 2H), 3.79(m, 1H), 3.31(s, 3H), 2.78(s, 3H), 2.33(s, 3H), 1.84-1.61(m, 8H), 0.94(m, 1H), 0.36(m, 2H), 0.22(m, 2H).
Example E90N- (1-Acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f31) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=516(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.90(s, 1H,-NH); 8.99(s, 1H); 8.80(d, J=7.9, 1H,-NH); 7.91(d, J=2.0, 1H); 7.89(dd, J=8.8, 2.0, 1H); 7.38(d, J=8.8, 1H); 4.23-4.05(m, 2H); 4.00(d, J=7.0, 2H); 3.79(m, 1H); 3.28(m, 1H); 2.95(m, 1H); 2.80(s, 3H); 2.04(s, 3H); 1.96(m, 2H); 1.55(m, 1H); 1.39(m, 1H); 0.99(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example E91: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f31) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=530(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.90(s, 1H,-NH); 8.99(s, 1H); 8.80(d, J=7.7, 1H,-NH); 7.91(d, J=2.0, 1H); 7.89(dd, J=8.8, 2.0, 1H); 7.38(d, J=8.8, 1H); 4.26-4.06(m, 2H); 4.00(d, J=6.9, 2H); 3.82(m, 1H); 3.28(m, 1H); 2.96(m, 1H); 2.79(s, 3H); 2.36(qu, J=7.4, 2H); 1.96(m, 2H); 1.52(m, 1H); 1.39(m, 1H); 1.01(t, J=7.4, 3H); 0.99(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example E92: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f31) and commercially available methoxy-methyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=546(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.90(s, 1H,-NH); 8.99(s, 1H); 8.80(d, J=7.7, 1H,-NH); 7.91(d, J=2.0, 1H); 7.89(dd, J=8.8, 2.0, 1H); 7.38(d, J=8.8, 1H); 4.24-4.06(m, 2H); 4.12(s, 2H); 4.00(d, J=6.9, 2H); 3.75(m, 1H); 3.31(s, 3H); 3.23(m, 1H); 2.99(m, 1H); 2.79(s, 3H); 1.97(m, 2H); 1.54(m, 1H); 1.41(m, 1H); 0.98(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example E93N- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f32) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=530(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.87(s, 1H,-NH); 8.99(s, 1H); 8.64(d, J=7.7, 1H,-NH); 7.91(d, J=2.0, 1H); 7.89(dd, J=8.8, 2.0, 1H); 7.72(d, J=7.7, 1H,-NH); 7.38(d, J=8.8, 1H); 4.00(d, J=6.9, 2H); 3.81(m, 1H); 3.59(m, 1H); 2.79(s, 3H); 2.01(m, 2H); 1.86(m, 2H); 1.79(s, 3H); 1.36(m, 4H); 0.98(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example E94: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f32) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
Alternatively, the solid obtained above was recrystallized from a glycol/water mixture (5/1).
MS(ESI): m/z=544(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.87(s, 1H, -NH), 8.99(s, 1H), 8.64(d, J =7.7, 1H, -NH), 7.90(d, J =2.0, 1H), 7.89(dd, J =8.8, 2.0, 1H), 7.63(d, J =7.8, 1H, -NH), 7.38(d, J =8.8, 1H), 3.99(d, J =6.9, 2H), 3.80(m, 1H), 3.59(m, 1H), 2.79(s, 3H), 2.06(qu, J =7.5, 2H), 2.01(m, 2H), 1.86(m, 2H), 1.36(m, 4H), 0.98(t, J =7.5, 3H and m, 1H), 0.39(m, 2H), and 0.27(m, 2H).
Example E95: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f32) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=560(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.87(s, 1H, -NH), 8.99(s, 1H), 8.63(d, J =7.7, 1H, -NH), 7.91(d, J =2.0, 1H), 7.89(dd, J =8.8, 2.0, 1H), 7.57(d, J =8.2, 1H, -NH), 7.38(d, J =8.8, 1H), 4.00(d, J =7.0, 2H), 3.78(s, 2H and m, 1H), 3.70(m, 1H), 3.31(s, 3H), 2.79(s, 3H), 2.01(m, 2H), 1.82(m, 2H), 1.44(m, 4H), 0.98(m, 1H), 0.39(m, 2H), 0.27(m, 2H).
Example E96N- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f33) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=530(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.88(br.s, 1H,-NH); 9.02(s, 1H); 8.92(d, J=7.5, 1H,-NH); 7.91(s, 1H); 7.88(d, J=8.2, 1H); 7.85(d, J=7.6, 1H,-NH); 7.38(d, J=8.2, 1H); 4.04(m, 1H); 4.00(d, J=6.9, 2H); 3.75(m, 1H); 2.80(s, 3H); 1.84(s, 3H); 1.81-1.52(m, 8H); 0.99(m, 1H); 0.40(m, 2H); 0.28(m, 2H)。
Example E97: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f33) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=544(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.88(br.s, 1H,-NH); 9.01(s, 1H); 8.92(d, J=7.3, 1H,-NH); 7.91(s, 1H); 7.89(d, J=8.7, 1H); 7.79(d, J=7.6, 1H,-NH); 7.38(d, J=8.7, 1H); 4.03(m, 1H); 4.00(d, J=7.0, 2H); 3.75(m, 1H); 2.79(s, 3H); 2.12(qu, J=7.6, 2H); 1.83-1.52(m, 8H); 1.00(t, J=7.6, 3H); 0.98(m, 1H); 0.40(m, 2H); 0.28(m, 2H)。
Example E98: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f33) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=560(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.91(s, 1H,-NH); 9.03(s, 1H); 8.96(d, J=7.3, 1H,-NH); 7.91(s, 1H); 7.90(d, J=8.8, 1H); 7.72(d, J=7.8, 1H,-NH); 7.39(d, J=8.8, 1H); 4.06(m, 1H); 4.00(d, J=7.0, 2H); 3.82(s, 2H); 3.79(m, 1H); 3.31(s, 3H); 2.80(s, 3H); 1.85-1.60(m, 8H); 0.98(m, 1H); 0.40(m, 2H); 0.28(m, 2H)。
Example E99N- (1-acetylpiperidin-4-yl) -4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f34) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=490(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.92(br.s, 1H,-NH); 8.98(s, 1H); 8.79(d, J=7.7, 1H,-NH); 7.92(d, J=2.2, 1H); 7.91(dd, J=9.4, 2.2, 1H); 7.43(d, J=9.4, 1H); 4.21(qu, J=7.0, 2H); 4.18-4.07(m, 2H); 3.78(m, 1H); 3.28(m, 1H); 2.95(m, 1H); 2.79(s, 3H); 2.04(s, 3H); 1.96(m, 2H); 1.54(m, 1H); 1.39(m, 1H); 1.16(t, J=7.0, 3H)。
Example E100: 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f34) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=504(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.93(br.s, 1H,-NH); 8.98(s, 1H); 8.79(d, J=7.7, 1H,-NH); 7.92(d, J=2.2, 1H); 7.91(dd, J=9.4, 2.2, 1H); 7.42(d, J=9.4, 1H); 4.21(qu, J=7.0, 2H); 4.17-4.07(m, 2H); 3.82(m, 1H); 3.26(m, 1H); 2.96(m, 1H); 2.79(s, 3H); 2.36(qu, J=7.1, 2H); 1.96(m, 2H); 1.52(m, 1H); 1.38(m, 1H); 1.16(t, J=7.0, 3H); 1.01(t, J=7.1, 3H)。
Example E101: 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f34) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=520(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.93(br.s, 1H,-NH); 8.98(s, 1H); 8.79(d, J=7.7, 1H,-NH); 7.92(d, J=2.2, 1H); 7.91(dd, J=9.5, 2.2, 1H); 7.42(d, J=9.5, 1H); 4.21(qu, J=7.0, 2H); 4.17-4.06(m, 2H); 4.12(d, J=2.8, 2H); 3.75(m, 1H); 3.31(s, 3H); 3.23(m, 1H); 2.99(m, 1H); 2.79(s, 3H); 1.97(m, 2H); 1.54(m, 1H); 1.41(m, 1H); 1.16(t, J=7.0, 3H)。
Example E102N- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f35) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=496(MH+, 100 %)。
1H-NMR (300 MHz, 11.76(s, 1H, -NH), 8.95(s, 1H), 8.81(d, J =7.7, 1H, -NH), 7.39(d, J =9.9, 1H), 7.18(d, J =13.3, 1H), 4.23-4.05(m, 2H), 3.84(s, 3H and d, J =6.8, 2H), 3.78(m, 1H), 3.28(m, 1H), 2.95(m, 1H), 2.79(s, 3H), 2.04(s, 3H), 1.96(m, 2H), 1.54(m, 1H), 1.38(m, 1H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example E103: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f35) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.76(s, 1H, -NH), 8.95(s, 1H), 8.81(d, J =7.7, 1H, -NH), 7.39(d, J =9.9, 1H), 7.18(d, J =13.3, 1H), 4.25-4.05(m, 2H), 3.84(s, 3H and d, J =6.8, 2H), 3.79(m, 1H), 3.26(m, 1H), 2.96(m, 1H), 2.79(s, 3H), 2.36(qu J =7.4, 2H), 1.96(m, 2H), 1.52(m, 1H), 1.38(m, 1H), 1.01(t, J =7.4, 3H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example E104: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f35) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=526(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.76(s, 1H, -NH), 8.96(s, 1H), 8.81(d, J =7.7, 1H, -NH), 7.39(d, J =9.9, 1H), 7.18(d, J =13.3, 1H), 4.22-4.05(m, 2H), 4.11(s, 2H), 3.84(s, 3H and d, J =6.9, 2H), 3.75(m, 1H), 3.24(m, 1H), 2.98(m, 1H), 2.79(s, 3H), 1.97(m, 2H), 1.54(m, 1H), 1.41(m, 1H), 0.93(m,1H); 0.36(m, 2H); 0.21(m, 2H)。
example E105: 4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f35) and commercially available ethyl chloroformate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=526(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.76(s, 1H, -NH), 8.96(s, 1H), 8.80(d, J =7.7, 1H, -NH), 7.39(d, J =9.9, 1H), 7.18(d, J =13.3, 1H), 4.06(qu, J =7.1, 2H and m, 1H), 3.88(m, 2H), 3.84(s, 3H and d, J =6.8, 2H), 3.11(m, 2H), 2.78(s, 3H), 1.94(m, 2H), 1.46(m, 1H), 1.20(t, J =7.1, 3H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example E106N- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f36) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.73(s, 1H, -NH), 8.96(s, 1H), 8.65(s, J =7.7, 1H, -NH), 7.72(d, J =7.7, 1H, -NH), 7.40(d, J =9.9, 1H), 7.18(d, J =13.3, 1H), 3.84(s, 3H and d, J =6.8, 2H), 3.80(m, 1H), 3.58(m, 1H), 2.78(s, 3H), 2.01(m, 2H), 1.86(m, 2H); 1.79(s, 3H); 1.35(m, 4H); 0.93(m, 1H); 0.36(m, 2H); 0.21(m, 2H)。
Example E107: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f36) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=524(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.74(s, 1H, -NH), 8.96(s, 1H), 8.65(d, J =7.7, 1H, -NH), 7.62(d, J =7.7, 1H, -NH), 7.39(d, J =9.9, 1H), 7.18(d, J =13.3, 1H), 3.84(s, 3H and d, J =6.8, 2H), 3.80(m, 1H), 3.59(m, 1H), 2.78(s, 3H), 2.06(qu, J =7.6, 2H), 2.01(m, 2H), 1.86(m, 2H), 1.35(m, 4H), 0.99(t, J =7.6, 3H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example E108: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f36) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=540(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.74(s, 1H,-NH); 8.96(s, 1H); 8.64(s, J=7.7, 1H,-NH); 7.56(d, J=8.2, 1H,-NH); 7.39(d, J=9.9,1H) 7.18(d, J =13.3, 1H), 3.84(s, 3H), 3.83(d, J =6.8, 2H), 3.78(s, 2H and m, 1H), 3.69(m, 1H), 3.31(s, 3H), 2.78(s, 3H), 2.01(m, 2H), 1.82(m, 2H), 1.43(m, 4H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example E109 Ethyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f36) and commercial ethyl chloroformate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=540(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.73(s, 1H, -NH), 8.96(s, 1H), 8.64(d, J =7.7, 1H, -NH), 7.39(d, J =9.9, 1H), 7.18(d, J =13.3, 1H), 7.01(d, J =7.1, 1H, -NH), 3.98(qu, J =7.0, 2H), 3.84(s, 3H and d, J =6.8, 2H), 3.76(m, 1H), 3.33(m, 1H), 2.78(s, 3H), 2.00(m, 2H), 1.87(m, 2H), 1.36(m, 4H), 1.16(t, J =7.0, 3H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example E110N- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f37) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.75(s, 1H, -NH), 8.99(s, 1H), 8.91(d, J =7.5, 1H, -NH), 7.84(d, J =7.3, 1H, -NH), 7.40(d, J =9.9, 1H), 7.18(d, J =13.3, 1H), 4.02(m, 1H), 3.85(s, 3H and d, J =6.7, 2H), 3.75(m, 1H), 2.79(s, 3H), 1.84(s, 3H), 1.82-1.51(m, 8H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example E111: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f37) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=524(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.75(s, 1H, -NH), 8.99(s, 1H), 8.91(d, J =7.5, 1H, -NH), 7.75(d, J =7.3, 1H, -NH), 7.40(d, J =9.9, 1H), 7.19(d, J =13.3, 1H), 4.02(m, 1H), 3.85(s, 3H and d, J =6.9, 2H), 3.75(m, 1H), 2.79(s, 3H), 2.11(qu, J =7.7, 2H), 1.85-1.51(m, 8H), 1.00(t, J =7.7, 3H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example E112: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f37) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=540(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.74(s, 1H, -NH), 8.99(s, 1H), 8.95(d, J =7.3, 1H, -NH), 7.66(d, J =7.7, 1H, -NH), 7.39(d, J =9.7, 1H), 7.19(d, J =13.5, 1H), 4.05(m, 1H), 3.85(s, 3H and d, J =6.9, 2H), 3.82(s, 2H), 3.79(m, 1H), 3.29(s, 3H), 2.79(s, 3H), 1.86-1.58(m, 8H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example E113: N- [ (3R)*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f38) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=512.2310([MH]+, C26H31FN5O4 +Calculating the value: 512.2304).
Example E114: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f38) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=526.2462([MH]+, C27H33FN5O4 +Calculating the value: 526.2460).
Example E115: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f38) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=542.2399([MH]+, C27H33FN5O6 +Calculating the value: 542.2409).
Example E116: N- [ (3S)*,4S*) -1-acetyl-4-hydroxypiperidin-3-yl]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ]-N-[(3S*,4S*) -4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f39) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=512.2302([MH]+, C26H31FN5O4 +Calculating the value: 512.2304).
Example E117: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -4-hydroxy-1-propionylpiperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -4-hydroxypiperPyridin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f39) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=526.2462([MH]+, C27H33FN5O4 +Calculating the value: 526.2460).
Example E118: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -4-hydroxy-1- (methoxyacetyl) piperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f39) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=542.2401([MH]+, C27H33FN5O6 +Calculating the value: 542.2409).
Example E119: N- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f40) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=554(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.75(s, 1H,-NH); 8.93(s, 1H); 8.82(d, J=7.7, 1H,-NH); 7.54(d, J=9.1, 1H); 7.04(d, J=12.0, 1H); 4.22-4.05(m, 2H); 3.87(d, J=6.9, 2H); 3.78(m, 1H); 3.28(m, 1H); 2.95(m, 1H); 2.78(s, 3H); 2.25(d, J=1.1, 3H); 2.04(s, 3H); 1.95(m, 2H); 1.54(m, 1H); 1.38(m, 1H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example E120: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f40) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=494(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.75(s, 1H,-NH); 8.93(s, 1H); 8.81(d, J=7.9, 1H,-NH); 7.54(d, J=9.1, 1H); 7.04(d, J=12.0, 1H); 4.25-4.05(m, 2H); 3.87(d, J=6.9, 2H); 3.81(m, 1H); 3.26(m, 1H); 2.96(m, 1H); 2.78(s, 3H); 2.36(qu, J=7.5, 2H); 2.24(d, J=1.1, 3H); 1.95(m, 2H); 1.51(m, 1H); 1.38(m, 1H); 1.01(t, J=7.5, 3H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example E121: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f40) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.75(s, 1H,-NH); 8.93(s, 1H); 8.81(d, J=7.7, 1H,-NH); 7.54(d, J=9.1, 1H); 7.04(d, J=12.0, 1H); 4.22-4.06(m, 2H); 4.12(d, J=1.6, 2H); 3.87(d, J=6.9, 2H); 3.75(m, 1H); 3.31(s, 3H); 3.22(m, 1H); 2.98(m, 1H); 2.78(s, 3H); 2.24(d, J=1.1, 3H); 1.96(m, 2H); 1.53(m, 1H); 1.41(m, 1H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example E122N- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f41) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=494(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(s, 1H,-NH); 8.93(s, 1H); 8.65(d, J=7.7, 1H,-NH); 7.72(d, J=7.7, 1H,-NH); 7.54(d, J=9.1, 1H); 7.03(d, J=12.0, 1H); 3.87(d, J=6.9, 2H); 3.80(m, 1H); 3.58(m, 1H); 2.77(s, 3H); 2.25(d, J=1.1, 3H); 2.00(m, 2H); 1.86(m, 2H); 1.79(s, 3H); 1.35(m, 4H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example E123: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f41) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=508(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(s, 1H,-NH); 8.93(s, 1H); 8.65(d, J=7.7, 1H,-NH); 7.62(d, J=7.7, 1H,-NH); 7.54(d, J=9.1, 1H); 7.03(d, J=12.0, 1H); 3.87(d, J=6.9, 2H); 3.80(m, 1H); 3.59(m, 1H); 2.77(s, 3H); 2.25(d, J=0.9, 3H); 2.05(qu, J=7.7, 2H); 2.01(m, 2H); 1.85(m, 2H); 1.35(m, 4H); 0.99(t, J=7.7, 3H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example E124: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f41) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=524(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.72(s, 1H, -NH), 8.93(s, 1H), 8.64(d, J =7.7, 1H, -NH), 7.57(d, J =7.7, 1H, -NH), 7.54(d, J =9.1, 1H), 7.03(d, J =12.0, 1H), 3.87(d, J =6.9, 2H), 3.78(m, 1H and s, 2H), 3.68(m, 1H), 3.31(s, 3H), 2.77(s, 3H), 2.25(d, J =1.1, 3H), 2.01(m, 2H), 1.82(m, 2H), 1.43(m, 4H), 0.95(m, 1H), 0.37(m, 2H), 0.24(m, 2H).
Example E125N- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f42) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=494(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 8.96(s, 1H); 8.93(d, J=7.7, 1H,-NH); 7.84(d, J=7.7, 1H,-NH); 7.54(d, J=9.1, 1H); 7.04(d, J=12.0, 1H); 4.03(m, 1H); 3.88(d, J=6.9, 2H); 3.75(m, 1H); 2.78(s, 3H); 2.25(d, J=1.1, 3H); 1.84(s, 3H); 1.84-1.51(m, 8H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example E126: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f42) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=508(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 8.96(s, 1H); 8.93(d, J=7.5, 1H,-NH); 7.75(d, J=7.5, 1H,-NH); 7.54(d, J=9.1, 1H); 7.04(d, J=12.2, 1H); 4.03(m, 1H); 3.88(d, J=7.1, 2H); 3.75(m, 1H); 2.78(s, 3H); 2.25(d, J=1.1, 3H); 2.11(qu, J=7.5, 2H); 1.84-1.51(m, 8H); 1.00(t, J=7.5, 3H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example E127: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f42) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=524(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 8.97(s, 1H); 8.96(d, J=7.8, 1H,-NH); 7.66(d, J=7.8, 1H,-NH); 7.54(d, J=9.1, 1H); 7.04(d, J=12.2, 1H); 4.05(m, 1H); 3.88(d, J=6.9, 2H); 3.82(s, 2H); 3.79(m, 1H); 3.31(s 3H); 2.78(s, 3H); 2.25(d, J=1.1, 3H); 1.86-1.59(m, 8H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example E128: N- [ (3R)*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f43) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=496.2373([MH]+, C26H31FN5O4 +Calculating the value: 496.2355).
Example E129: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f43) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=510.2534([MH]+, C27H33FN5O4 +Calculating the value: 510.2511).
Example E130: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d ]Pyrimidine-7-carboxamide hydrochloride (example d.f43) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=526.2474([MH]+, C27H33FN5O5 +Calculating the value: 526.2460).
Example E131N- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f44) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=496(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(br.s, 1H,-NH); 8.92(s, 1H); 8.82(d, J=7.7, 1H,-NH); 7.47(d, J=11.9, 1H); 6.93(d, J=7.3, 1H); 4.22-4.04(m, 2H); 3.97(s, 3H); 3.94(d, J=6.9, 2H); 3.78(m, 1H); 3.27(m, 1H); 2.95(m, 1H); 2.79(s, 3H); 2.04(s, 3H); 1.95(m, 2H); 1.54(m, 1H); 1.38(m, 1H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example E132: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f44) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(br.s, 1H,-NH); 8.91(s, 1H); 8.82(d, J=7.7, 1H,-NH); 7.47(d, J=11.9, 1H); 6.92(d, J=7.3, 1H); 4.19(m, 1H); 4.12(m, 1H); 3.97(s, 3H); 3.94(d, J=6.9, 2H); 3.81(m, 1H); 3.25(m, 1H); 2.96(m, 1H); 2.79(s, 3H); 2.36(qu, J=7.3, 2H); 1.95(m,2H); 1.51(m, 1H); 1.38(m, 1H); 1.01(t, J=7.3, 3H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example E133: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f44) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=526(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.73(br.s, 1H, -NH), 8.92(s, 1H), 8.82(d, J =7.7, 1H, -NH), 7.47(d, J =11.9, 1H), 6.92(d, J =7.3, 1H), 4.22-4.06(s, 2H and m, 2H), 3.97(s, 3H), 3.94(d, J =6.9, 2H), 3.75(m, 1H), 3.31(m, 1H), 3.22(m, 1H), 2.98(m, 1H), 2.79(s, 3H), 1.96(m, 2H), 1.53(m, 1H), 1.40(m, 1H), 0.96(m, 1H), 0.38(m, 2H), 0.25(m,2H)。
example E134: 4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester
Starting from 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f44) and commercially available ethyl chloroformate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=526(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.72(br.s, 1H, -NH), 8.92(s, 1H), 8.82(d, J =7.7, 1H, -NH), 7.47(d, J =11.9, 1H), 6.93(d, J =7.3, 1H), 4.06(qu, J =7.1, 2H and m, 1H), 3.97(s, 3H), 3.94(d, J =7.1, 2H), 3.88(m, 2H), 3.11(m, 2H), 2.79(s, 3H), 1.94(m, 2H), 1.45(m, 1H), 1.20(t, J =7.1, 3H), 0.96(m, 1H), 0.39(m, 2H), 0.25(m, 2H).
Example E135N- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f45) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=468(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.32(br.s, 1H,-NH); 9.01(s, 1H); 8.51(d, J=7.7, 1H,-NH); 8.18(br.d, J=4.6, 3H,-NH3 +); 7.54(d, J=11.7, 1H); 6.96(d, J=7.3, 1H); 3.99(s, 3H); 3.97(d, J=7.4, 2H); 3.81(m, 1H); 3.07(m, 1H); 2.83(s, 3H); 2.05(m, 4H); 1.48(m, 4H); 0.97(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example E136: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f45) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=524(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.70(s, 1H,-NH); 8.92(s, 1H); 8.66(d, J=7.7, 1H,-NH); 7.62(d, J=7.7, 1H,-NH); 7.47(d, J=11.8, 1H); 6.92(d, J=7.5, 1H); 3.97(s, 3H); 3.94(d, J=6.9, 2H); 3.80(m,1H); 3.59(m, 1H); 2.78(s, 3H); 2.05(qu, J=7.7, 2H); 2.00(m, 2H); 1.86(m, 2H); 1.35(m, 4H); 0.99(t, J=7.7, 3H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example E137: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f45) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=540(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.70(s, 1H,-NH); 8.92(s, 1H); 8.65(d, J=7.7, 1H,-NH); 7.56(d, J=8.2, 1H,-NH); 7.47(d, J=11.7, 1H); 6.92(d, J =7.3, 1H), 3.97(s, 3H), 3.94(d, J =6.9, 2H), 3.78(s, 2H and m,1H), 3.69(m, 1H), 3.31(s, 3H), 2.78(s, 3H), 2.01(m, 2H), 1.82(m, 2H), 1.43(m, 4H), 0.96(m, 1H), 0.38(m, 2H), 0.25(m, 2H).
Example E138N- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f46) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.71(s, 1H,-NH); 8.95(s, 1H); 8.94(d, J=7.7, 1H,-NH); 7.84(d, J=7.5, 1H,-NH); 7.48(d, J=11.9, 1H); 6.93(d, J=7.3, 1H); 4.02(m, 1H); 3.97(s, 3H); 3.95(d, J=6.9, 2H); 3.75(m,1H); 2.79(s, 3H); 1.84(s, 3H); 1.80-1.52(m, 8H); 0.96(m, 1H); 0.39(m, 2H); 0.25(m, 2H)。
Example E139: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f46) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=524(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.71(s, 1H,-NH); 8.95(s, 1H); 8.93(d, J=7.7, 1H,-NH); 7.75(d, J=7.5, 1H,-NH); 7.47(d, J=11.9, 1H); 6.93(d, J=7.3, 1H); 4.02(m, 1H); 3.97(s, 3H); 3.94(d, J=6.9, 2H); 3.75(m,1H); 2.79(s, 3H); 2.11(qu, J=7.6, 2H); 1.83-1.52(m, 8H); 1.00(t, J=7.6, 1H); 0.96(m, 1H); 0.39(m, 2H); 0.25(m, 2H)。
Example E140: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f46) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=540(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.70(s, 1H,-NH); 8.97(d, J=7.7, 1H,-NH); 8.96(s, 1H); 7.67(d, J=7.7, 1H,-NH); 7.47(d, J=11.9, 1H); 6.93(d, J=7.3, 1H); 4.05(m, 1H); 3.97(s, 3H); 3.94(d, J=7.1, 2H); 3.82(s, 2H); 3.79(m,1H); 3.31(s, 3H); 2.79(s, 3H); 1.85-1.59(m, 8H); 0.96(m, 1H); 0.39(m, 2H); 0.25(m, 2H)。
Example E141 Ethyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f46) and commercial ethyl chloroformate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=540(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.69(s, 1H,-NH); 8.98(d, J=7.7, 1H,-NH); 8.95(s, 1H); 7.47(d, J=11.9, 1H); 7.21(br.d, J=6.0, 1H,-NH); 6.93(d, J=7.3, 1H); 4.03(m, 1H); 3.99(qu, J=7.1, 2H); 3.97(s, 3H); 3.94(d, J=7.1, 2H); 3.48(m, 1H); 2.78(s, 3H); 1.85-1.54(m, 8H); 1.17(t, J=7.1, 3H); 0.96(m, 1H); 0.39(m, 2H); 0.25(m, 2H)。
Example E142: N- [ (3R)*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f47) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=512.2301([MH]+, C26H31FN5O5 +Calculating the value: 512.2304).
Example E143: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d ]Pyrimidine-7-carboxamide hydrochloride (example d.f47) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=HR-MS(ESI): m/z=526.2454([MH]+, C27H33FN5O5 +Calculating the value: 526.2460).
Example E144: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f47) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=542.2398([MH]+, C27H33FN5O6 +Calculating the value: 542.2409).
Example E145N- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f48) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=476(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.76(s, 1H,-NH); 8.95(s, 1H); 8.83(d, J=7.7, 1H,-NH); 7.45(d, J=2.2, 1H); 7.36(dd, J=8.6, 2.2, 1H); 7.08(d, J=8.6, 1H); 4.22-4.04(m, 2H); 3.87(d, J=6.9, 2H); 3.78(m, 1H); 3.28(m, 1H); 2.95(m, 1H); 2.78(s, 3H); 2.64(qu, J=7.5, 2H); 2.04(s, 3H); 1.96(m, 2H); 1.54(m, 1H); 1.39(m, 1H); 1.18(t, J=7.5, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.25(m, 2H)。
Example E146: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f48) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=490(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.76(s, 1H,-NH); 8.94(s, 1H); 8.82(d, J=7.7, 1H,-NH); 7.45(d, J=2.4, 1H); 7.36(dd, J=8.6, 2.4, 1H); 7.08(d, J=8.6, 1H); 4.25-4.04(m, 2H); 3.87(d, J=6.9, 2H); 3.82(m, 1H); 3.25(m, 1H); 2.97(m, 1H); 2.78(s, 3H); 2.64(qu, J=7.5, 2H); 2.36(qu, J=7.5, 2H); 1.96(m, 2H); 1.52(m, 1H); 1.38(m, 1H); 1.18(t, J=7.5, 3H); 1.01(t, J=7.5, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example E147: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f48) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=506(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.76(s, 1H,-NH); 8.95(s, 1H); 8.82(d, J=7.7, 1H,-NH); 7.45(d, J=2.4, 1H); 7.36(dd, J=8.6, 2.4, 1H); 7.08(d, J=8.6, 1H); 4.22-4.04(m, 2H); 4.12(d, J=1.6, 2H); 3.87(d, J=6.9, 2H); 3.75(m, 1H); 3.31(s, 3H); 3.22(m, 1H); 2.99(m, 1H); 2.78(s, 3H); 2.64(qu, J=7.5, 2H); 1.96(m, 2H); 1.54(m, 1H); 1.41(m, 1H); 1.18(t, J=7.5, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
EXAMPLE E148N- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f49) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=490(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(s, 1H,-NH); 8.95(s, 1H); 8.66(d, J=7.7, 1H,-NH); 7.72(d, J=7.7, 1H,-NH); 7.45(d, J=2.2, 1H); 7.35(dd, J=8.6, 2.2, 1H); 7.08(d, J=8.6, 1H); 3.86(d, J=6.9, 2H); 3.80(m, 1H); 3.58(m, 1H); 2.77(s, 3H); 2.64(qu, J=7.5, 2H); 2.00(m, 2H); 1.87(m, 2H); 1.79(s, 3H); 1.35(m, 4H); 1.18(t, J=7.5, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example E149: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f49) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=504(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(s, 1H,-NH); 8.95(s, 1H); 8.67(d, J=7.7, 1H,-NH); 7.62(d, J=7.7, 1H,-NH); 7.45(d, J=2.2, 1H); 7.36(dd, J=8.6, 2.2, 1H); 7.08(d, J=8.6, 1H); 3.86(d, J=6.9, 2H); 3.80(m, 1H); 3.58(m, 1H); 2.77(s, 3H); 2.64(qu, J=7.5, 2H); 2.06(qu, J=7.7, 2H); 2.01(m, 2H); 1.86(m, 2H); 1.35(m, 4H); 1.18(t, J=7.5, 3H); 0.99(t, J=7.5, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example E150: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f49) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=504(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.86(br.s, 1H, -NH), 8.93(s, 1H), 8.66(d, J =7.7, 1H, -NH), 7.57(d, J =8.2, 1H, -NH), 7.44(d, J =2.4, 1H), 7.35(dd, J =8.6, 2.4, 1H), 7.07(d, J =8.6, 1H), 3.86(d, J =6.9, 2H), 3.78(s, 2H and m, 1H), 3.69(m, 1H), 3.31(s, 3H), 2.77(s, 3H), 2.63(qu, J =7.5, 2H), 2.01(m, 2H), 1.82(m, 2H), 1.43(m, 4H), 1.18(t =7.5, 0.94(m, 0.22H), 2H) In that respect
Example E151N- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f50) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=490(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 8.98(s, 1H); 8.94(d, J=7.7, 1H,-NH); 7.85(d, J=7.5, 1H,-NH); 7.45(d, J=2.4, 1H); 7.36(dd, J=8.6, 2.4, 1H); 7.08(d, J=8.6, 1H); 4.03(m, 1H); 3.87(d, J=6.9, 2H); 3.75(m, 1H); 2.78(s, 3H); 2.64(qu, J=7.5, 2H); 1.84(s, 3H); 1.82-1.51(m, 8H); 1.19(t, J=7.5, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example E152: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f50) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=504(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 8.98(s, 1H); 8.94(d, J=7.5, 1H,-NH); 7.75(d, J=7.5, 1H,-NH); 7.45(d, J=2.2, 1H); 7.36(dd, J=8.6, 2.2, 1H); 7.08(d, J=8.6, 1H); 4.02(m, 1H); 3.87(d, J=6.8, 2H); 3.75(m, 1H); 2.78(s, 3H); 2.64(qu, J=7.5, 2H); 2.11(qu, J=7.5, 2H); 1.89-1.52(m, 8H); 1.19(t, J=7.5, 3H); 1.00(t, J=7.5, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example E153: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f50) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=504(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 8.98(s, 1H); 8.97(d, J=7.5, 1H,-NH); 7.67(d, J=7.5, 1H,-NH); 7.45(d, J=2.2, 1H); 7.36(dd, J=8.6, 2.2, 1H); 7.08(d, J=8.6, 1H); 4.06(m, 1H); 3.87(d, J=6.8, 2H); 3.82(s, 2H); 3.79(m, 1H); 3.31(s, 3H); 2.78(s, 3H); 2.64(qu, J=7.6, 2H); 1.89-1.55(m, 8H); 1.19(t, J=7.6, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example E154: N- [ (3R)*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f51) and commercially available acetyl chloride gave the title compound as a colorless solid.
MS(ESI): m/z=478(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.80(s, 1H,-NH); 8.93(s, 1H);[8.90(d, J=7.1), 8.84(d, J=6.6), 1H,-NH]; 7.45(d, J=2.4, 1H); 7.36(dd, J=8.4, 2.4, 1H); 7.08(d, J=8.4, 1H);[5.56(d, J=3.8), 5.48(J=4.0), 1H,-OH];[4.36(m), 4.19(m), 1H]; 4.27(m, 1H); 3.86(d, J=6.9, 2H); 3.80-3.65(m, 1H);[3.58(m), 3.45(m), 1H]; 3.41-3.27(m, 2H);[2.78(s), 2.77(s), 3H]; 2.63(qu, J=7.6, 2H);[1.99(s)-1.98(s), 3H]; 1.18(t, J=7.6, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example E155: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy)-5-ethylphenyl radical]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f51) and commercially available propionyl chloride gave the title compound as a colorless solid.
MS(ESI): m/z=492(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.79(s, 1H,-NH); 8.91(s, 1H);[8.88(d, J=7.1), 8.84(d, J=6.6), 1H,-NH]; 7.44(d, J=2.4, 1H); 7.36(dd, J=8.6, 2.4, 1H); 7.08(d, J=8.6, 1H);[5.55(d, J=3.7), 5.47(d, J=3.9), 1H,-OH];[4.36(m), 4.19(m), 1H]; 4.27(m, 1H); 3.86(d, J=6.8, 2H); 3.73(m, 1H);[3.59(m), 3.45(m), 1H]; 3.42-3.27(m, 2H); 2.78(s, 3H); 2.63(qu, J=7.6, 2H);[2.29(qu, J=7.5), 2.28(qu, J=7.5), 2H]; 1.18(t, J=7.6, 3H);[1.03(t, J=7.5), 1.01(t, J=7.5), 3H]; 0.93(m, 1H); 0.35(m, 2H); 0.22(m, 2H)。
Example E156: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f51) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
MS(ESI): m/z=508(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.77(s, 1H,-NH);[8.91(s), 8.90(s), 1H];[8.88(d, J=7.1), 8.84(d, J=6.6), 1H,-NH]; 7.44(d, J=2.4, 1H); 7.36(dd, J=8.4, 2.4, 1H); 7.08(d, J=8.4, 1H);[5.57(d, J=3.7), 5.50(d, J=3.9), 1H,-OH];[4.36(m), 4.19(m), 1H]; 4.27(m, 1H);[4.07(d, J=3.5), 4.04(s), 2H]; 3.86(d, J=6.9, 2H); 3.73(m, 1H);[3.62(m), 3.46(m), 1H]; 3.44-3.27(m, 2H);[3.34(s), 3.32(s), 3H]; 2.78(s, 3H); 2.63(qu, J=7.6, 2H); 1.18(t, J=7.6, 3H); 0.93(m, 1H); 0.35(m, 2H); 0.22(m, 2H)。
Example E157N- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f52) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=490(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.76(s, 1H, -NH), 8.95(s, 1H), 8.83(d, J =7.7, 1H, -NH), 7.47(d, J =2.4, 1H), 7.39(dd, J =8.6, 2.4, 1H), 7.09(d; J =8.6, 1H), 4.23-4.05(m, 2H), 3.87(d, J =6.9, 2H), 3.78(m, 1H), 3.28(m, 1H), 2.94(m, 1H and sept, J =6.9, 1H), 2.78(s, 3H), 2.04(s, 3H), 1.96(m, 2H), 1.54(m, 1H), 1.39(m, 1H), 1.22(d, J =6.9, 6H), 0.94(m, 0.23H), 0.23(m, 0.23H), 2H) In that respect
Example E158: 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f52) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=520(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.76(s, 1H,-NH); 8.95(s, 1H); 8.82(d, J=7.9, 1H,-NH); 7.47(d, J=2.4, 1H); 7.39(dd, J=8.6, 2.4, 1H);7.09(d; J =8.6, 1H), 4.21-4.05(m, 2H), 4.12(d, J =1.6, 2H), 3.87(d, J =6.9, 2H), 3.75(m, 1H), 3.31(s, 3H), 3.22(m, 1H), 2.94(m, 1H and sept, J =6.9, 1H), 2.78(s, 3H), 1.96(m, 2H), 1.54(m, 1H), 1.41(m, 1H), 1.22(d, J =6.9, 6H), 0.94(m, 1H), 0.36(m, 2H), 0.23(m, 2H).
Example E159N- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f53) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=504(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 8.96(s, 1H); 8.66(d, J=7.7, 1H,-NH); 7.72(d, J=7.7, 1H,-NH); 7.47(d, J=2.4, 1H); 7.39(dd, J=8.6, 2.4, 1H); 7.08(d; J=8.6, 1H); 3.87(d, J=6.9, 2H); 3.80(m, 1H); 3.58(m, 1H); 2.94(sept, J=6.9, 1H); 2.77(s, 3H); 2.01(m, 2H); 1.87(m, 2H); 1.79(s, 3H); 1.35(m, 4H); 1.22(d, J=6.9, 6H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example E160: 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f53) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=534(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.73(s, 1H, -NH), 8.95(s, 1H), 8.66(d, J =7.7, 1H, -NH), 7.57(d, J =8.2, 1H, -NH), 7.47(d, J =2.4, 1H), 7.39(dd, J =8.6, 2.4, 1H), 7.08(d; J =8.6, 1H), 3.87(d, J =6.9, 2H), 3.78(s, 2H and m, 1H), 3.69(m, 1H), 3.31(s, 3H), 2.94(sept, J =6.9, 1H), 2.77(s, 3H), 2.01(m, 2H), 1.82(m, 2H), 1.43(m, 4H), 1.22(d, J =6.9, 6H), 0.94(m, 0.36H), 0.36(m, 22H), 2H) In that respect
Example E161N- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f54) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=504(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.74(s, 1H,-NH); 8.98(s, 1H); 8.93(d, J=7.5, 1H,-NH); 7.85(d, J=7.7, 1H,-NH); 7.47(d, J=2.4, 1H); 7.40(dd, J=8.6, 2.4, 1H); 7.09(d; J=8.6, 1H); 4.02(m, 1H); 3.87(d, J=6.9, 2H); 3.75(m, 1H); 2.94(sept, J=6.8, 1H); 2.78(s, 3H); 1.84(s, 3H); 1.81-1.51(m, 8H); 1.22(d, J=6.8, 6H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example E162: 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f54) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=534(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 8.99(s, 1H); 8.97(d, J=7.3, 1H,-NH); 7.67(d, J=7.7, 1H,-NH); 7.47(d, J=2.4, 1H); 7.40(dd, J=8.6, 2.4, 1H); 7.09(d; J=8.6, 1H); 4.06(m, 1H); 3.86(d, J=6.9, 2H); 3.82(s, 2H); 3.79(m, 1H); 3.31(s, 3H); 2.95(sept, J=6.9, 1H); 2.78(s, 3H); 1.86-1.61(m, 8H); 1.22(d, J=6.9, 6H); 0.94(m, 1H); 0.36(m, 2H); 0.24(m, 2H)。
Example E163: 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- (1-acetylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f55) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=490(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.88(s, 1H,-NH); 8.99(s, 1H); 8.92(d, J=7.7, 1H,-NH); 8.21(d, J=2.3, 1H); 8.15(dd, J=8.8, 2.3, 1H); 7.30(d, J=8.8, 1H); 4.22-4.07(m, 2H); 4.01(d, J=7.1, 2H); 3.79(m, 1H); 3.28(m, 1H); 2.95(m, 1H); 2.79(s, 3H); 2.58(s, 3H); 2.04(s, 3H); 1.96(m, 2H); 1.55(m, 1H); 1.40(m, 1H); 0.99(m, 1H); 0.39(m, 2H); 0.28(m, 2H)。
Example E164: 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f55) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=504(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.88(s, 1H,-NH); 8.99(s, 1H); 8.81(d, J=7.7, 1H,-NH); 8.21(d, J=2.2, 1H); 8.15(dd, J=8.8, 2.2, 1H); 7.30(d, J=8.8, 1H); 4.20(m, 1H); 4.13(m, 1H); 4.01(d, J=7.0, 2H); 3.82(m, 1H); 3.27(m, 1H); 2.96(m, 1H); 2.79(s, 3H); 2.58(s, 3H); 2.36(dqu, J=7.5, 1.3, 2H); 1.96(m, 2H); 1.53(m, 1H); 1.39(m, 1H); 1.01(t, J=7.5, 3H); 0.99(m, 1H); 0.39(m, 2H); 0.28(m, 2H)。
Example E165: 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f55) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=520(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.88(s, 1H,-NH); 8.99(s, 1H); 8.81(d, J=7.7, 1H,-NH); 8.21(d, J=2.3, 1H); 8.15(dd, J=8.8, 2.3, 1H); 7.30(d, J=8.8, 1H); 4.22-4.07(m, 2H); 4.12(d, J=3.0, 2H); 4.01(d, J=7.0, 2H); 3.75(m, 1H); 3.31(s, 3H); 3.23(m, 1H); 2.98(m, 1H); 2.79(s, 3H); 2.58(s, 3H); 1.97(m, 2H); 1.55(m, 1H); 1.42(m, 1H); 0.99(m, 1H); 0.39(m, 2H); 0.28(m, 2H)。
Example E166N- [ trans-4- (acetylamino) cyclohexyl ] -4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- (trans-4-aminocyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f56) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=504(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.23(br.s, 1H,-NH); 8.97(s, 1H); 8.65(d, J=7.7, 1H,-NH); 8.20(d, J=2.2, 1H); 8.14(dd, J=8.8, 2.2, 1H); 7.73(d, J=7.7, 1H,-NH); 7.29(d, J=8.8, 1H); 4.01(d, J=7.0, 2H); 3.80(m, 1H); 3.59(m, 1H); 2.77(s, 3H); 2.58(s, 3H); 2.01(m, 2H); 1.86(m, 2H); 1.79(s, 3H); 1.35(m, 4H); 0.99(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example E167: 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- (trans-4-aminocyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f56) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=518(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.78(br.s, 1H, -NH); 8.98(s, 1H); 8.65(d, J =7.7, 1H, -NH); 8.20(d, J =2.3, 1H); 8.14(dd, J =8.9, 2.3, 1H); 7.62(d, J =7.7, 1H, -NH); 7.29(d, J =8.9, 1H); 4.01(d, J =7.0, 2H); 3.80(m, 1H); 3.59(m, 1H); 2.78(s, 3H); 2.58(s, 3H); 2.05(qu, J =7.7, 2H); 2.01(m, 2H); 1.86(m, 2H); 1.36(m, 4H); 0.99(t, J =7.7, 3H and m, 1H); 0.39(m, 2H); 0.27(m, 2H).
Example E168: 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- (trans-4-aminocyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f56) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=534(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.84(br.s, 1H,-NH); 8.99(s, 1H); 8.64(d, J=7.8, 1H,-NH); 8.21(d, J=2.3, 1H); 8.14(dd, J=8.8, 2.3, 1H); 7.57(d, J=8.2, 1H,-NH); 7.30(d, J=8.8, 1H); 4.01(d, J=7.0, 2H); 3.81(m, 1H); 3.78(s, 2H); 3.70(m, 1H); 3.31(s, 3H); 2.78(s, 3H); 2.58(s, 3H); 2.02(m, 2H); 1.82(m, 2H); 1.44(m, 4H); 0.99(m, 1H); 0.39(m, 2H); 0.28(m, 2H)。
Example E169N- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f57) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=476(MH+ , 100%)
1H-NMR(300 MHz, DMSO-d6): 11.59(s, 1H,-NH); 9.05(d, J=7.7, 1H,-NH); 7.39(d, J=1.8, 1H); 7.31(dd, J=8.4, 1.8, 1H); 7.04(d, J=8.4, 1H); 4.18-4.03(m, 2H); 3.85(d, J=6.9, 2H); 3.77(m, 1H); 3.40-3.23(m, 1H); 3.06(m, 1H); 2.75(s, 3H); 2.72(s, 3H); 2.33(s, 3H); 2.04(s, 3H); 1.95(m, 2H); 1.63-1.33(m, 2H); 0.93(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example E170: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f57) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=490(MH+ , 100%)
1H-NMR(300 MHz, DMSO-d6): 11.58(s, 1H,-NH); 9.05(d, J=7.7, 1H,-NH); 7.39(d, J=2.0, 1H); 7.31(dd, J=8.4, 2.0, 1H); 7.04(d, J=8.4, 1H); 4.18-4.03(m, 2H); 3.85(d, J=6.9, 2H); 3.77(m, 1H); 3.37-3.22(m, 1H); 3.07(m, 1H); 2.75(s, 3H); 2.72(s, 3H); 2.36(qu, J=7.3, 2H); 2.33(s, 3H); 1.95(m, 2H); 1.60-1.34(m, 2H); 1.01(t, J=7.3, 3H); 0.92(m, 1H); 0.35(m, 2H); 0.22(m, 2H)。
Example E171: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f57) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=506(MH+ , 100%)
1H-NMR(300 MHz, DMSO-d6): 11.58(s, 1H,-NH); 9.05(d, J=7.7, 1H,-NH); 7.39(d, J=1.8, 1H); 7.31(dd, J=8.6, 1.8, 1H); 7.04(d, J=8.6, 1H); 4.20-4.02(m, 2H); 4.12(d, J=0.9, 2H); 3.85(d, J=6.9, 2H); 3.72(m, 1H); 3.31(s, 3H); 3.27(m, 1H); 3.09(m, 1H); 2.75(s, 3H); 2.72(s, 3H); 2.33(s, 3H); 1.97(m, 2H); 1.63-1.35(m, 2H); 0.93(m, 1H); 0.35(m, 2H); 0.21(m, 2H)。
Example E172N- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f58) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100%)
1H-NMR(300 MHz, DMSO-d6): 11.56(s, 1H,-NH); 9.04(d, J=7.7, 1H,-NH); 7.43(d, J=11.9, 1H); 6.91(d, J=7.3, 1H); 4.18-4.03(m, 2H); 3.96(s, 3H); 3.93(d, J=6.9, 2H); 3.81-3.70(m, 1H); 3.38-3.25(m, 1H); 3.06(m, 1H); 2.76(s, 3H); 2.71(s, 3H); 2.04(s, 3H); 1.94(m, 2H); 1.62-1.33(m, 2H); 0.95(m, 1H); 0.39(m, 2H); 0.25(m, 2H)。
Example E173N- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f59) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.59(br.s, 1H,-NH); 9.02(d, J=7.7, 1H,-NH); 7.33(d, J=9.9, 1H); 7.16(d, J=13.5, 1H); 4.19-4.03(m, 2H); 3.84(s, 3H); 3.82(d, J=6.8, 2H); 3.76(m, 2H); 3.34(m, 1H); 3.05(m, 1H); 2.75(s, 3H); 2.73(s, 3H); 2.04(s, 3H); 1.95(m, 2H); 1.54(m, 1H); 1.41(m, 1H); 0.92(m, 1H); 0.35(m, 2H); 0.19(m, 2H)。
Example E174: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f59) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=524(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.60(br.s, 1H,-NH); 9.02(d, J=7.7, 1H,-NH); 7.33(d, J=9.9, 1H); 7.16(d, J=13.3, 1H); 4.19-4.03(m, 2H); 3.84(s, 3H); 3.83(d, J=6.8, 2H); 3.77(m, 2H); 3.28(m, 1H); 3.07(m, 1H); 2.75(s, 3H); 2.73(s, 3H); 2.36(qu, J=7.3, 2H); 1.95(m, 2H); 1.52(m, 1H); 1.41(m, 1H); 1.01(t, J=7.3, 3H); 0.92(m, 1H); 0.35(m, 2H); 0.19(m, 2H)。
Example E175: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f59) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
MS(ESI): m/z=540(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.60(br.s, 1H,-NH); 9.02(d, J=7.7, 1H,-NH); 7.33(d, J=9.9, 1H); 7.16(d, J=13.5, 1H); 4.20-4.01(m, 2H); 4.12(s, 2H); 3.84(s, 3H); 3.83(d, J=6.8, 2H); 3.72(m, 1H); 3.31(s, 3H); 3.24(m, 1H); 3.08(m, 1H); 2.75(s, 3H); 2.73(s, 3H); 1.96(m, 2H); 1.63-1.33(m, 2H); 0.92(m, 1H); 0.35(m, 2H); 0.20(m, 2H)。
Example E176: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1S,2S) -2-hydroxycyclopentyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1S,2S) -2-hydroxycyclopentyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide (example D.d60), the title compound was obtained as a colorless solid.
MS(ESI): m/z=421(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(s, 1H,-NH); 8.94(s, 1H); 8.78(d, J=7.1, 1H,-NH); 7.44(d, J=2.2, 1H); 7.33(dd, J=8.6, 2.2, 1H); 7.06(d, J=8.6, 1H); 4.92(d, J=4.0, 1H;-OH); 4.07(m, 1H); 3.99(m, 1H); 3.86(d, J=6.9, 2H); 2.78(s, 3H); 2.33(s, 3H); 2.12(m, 1H); 1.91(m, 1H); 1.74(m, 2H); 1.53(m, 2H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example E177: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1S,2R) -2-hydroxycyclopentyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1S,2R) -2-hydroxycyclopentyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide (example D.d61), the title compound was obtained as a colorless solid.
MS(ESI): m/z=421(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.66(s, 1H,-NH); 8.99(d, J=7.1, 1H,-NH); 8.92(s, 1H); 7.43(d, J=2.0, 1H); 7.32(dd, J=8.6, 2.0, 1H); 7.06(d, J=8.6, 1H); 4.882(d, J=4.2, 1H;-OH); 4.16(m, 1H); 4.02(m, 1H); 3.86(d, J=6.9, 2H); 2.79(s, 3H); 2.33(s, 3H); 2.01-1.73(m, 3H); 1.70-1.46(m, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example E178: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1R,2R) -2-hydroxycyclopentyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1R,2R) -2-hydroxycyclopentyl ] -6-methyl-5- { [2- (trimethylsilyl) ethoxy ] methyl } -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide (example D.d62), the title compound was obtained as a colorless solid.
MS(ESI): m/z=421(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(s, 1H,-NH); 8.93(s, 1H); 8.77(d, J=7.1, 1H,-NH); 7.44(d, J=2.2, 1H); 7.32(dd, J=8.6, 2.2, 1H); 7.05(d, J=8.6, 1H); 4.92(d, J=4.0, 1H;-OH); 4.07(m, 1H); 3.98(m, 1H); 3.85(d, J=6.9, 2H); 2.78(s, 3H); 2.33(s, 3H); 2.11(m, 1H); 1.91(m, 1H); 1.74(m, 2H); 1.53(m, 2H); 0.94(m, 1H); 0.35(m, 2H); 0.22(m, 2H)。
Example E179N- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
MS(ESI): m/z=482(MH+, 100 %)。
1H-NMR (300 MHz, DMSO-d6): 11.69(s, 1H, -NH), [ 8.93(s, 1H) ], [8.92(d, J =6.9), 8.89(d, J =6.7), 1H, -NH ]; 7.39(d, J =9.9, 1H), [ 7.18(d, J =13.5, 1H) ], [4.58(m),4.49(m), 1H ]; 3.84(d, J =6.8, 2H and s, 3H); 3.68-3.57(m, 1H); 3.55-3.35(m, 2H); 3.32-3.21(m, 1H); 2.77(s, 3H); 2.34-2.16(m, 1H); [2.04(m), 1.91(m), 1H ], [ 1.96(s, 3H) ], [ 1.96 (m), 0.93 (m), 0.35 (m), 2H) 0.20(m, 2H).
Example E180: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
MS(ESI): m/z=496(MH+, 100 %)。
1H-NMR (300 MHz, DMSO-d6): 11.70(s, 1H, -NH), [ 8.93(s, 1H), [8.92(d, J =6.9), 8.89(d, J =6.9), 1H, -NH ]; 7.39(d, J =9.9, 1H), [ 7.18(d, J =13.5, 1H), [4.58(m),4.49(m), 1H ]; 3.84(d, J =6.9, 2H and s, 3H); 3.69-3.57(m, 1H); 3.55-3.42(m, 1H); 3.40-3.22(m, 2H); 2.78(s, 3H); 2.34-2.15(m, 1H); [2.29 (J, J =7.4), [ 2.25 (m, 2H) ], 2.91.01 ]; 1H ]; 1.1H ]; 1.7.4, 1H ]; 2.5 (m, 1H ]; 1H ], j =7.4), 0.99(t, J =7.4), 3H ]; 0.93(m, 1H), 0.36(m, 2H), 0.20(m, 2H).
Example E181: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
MS(ESI): m/z=512(MH+, 100 %)。
1H-NMR (300 MHz, DMSO-d6): 11.78(s, 1H, -NH), [ 8.94(s, 1H) ], [8.92(d, J =7.4), 8.90(d, J =7.9, 1H, -NH), [ 7.39(d, J =9.7, 1H) ], 7.18(d, J =13.4, 1H) ], [4.58(m),4.49(m), 1H ], [4.06(d, J =4.2), 4.01(d, J =1.3), 2H ], [ 3.84(d, J =6.9, 2H and s, 3H) ], [3.80(m), 3.68(m), 1H ], [ 3.62-3.43(m, 2H) ], 3.36(m, 1H), [ 3.32(s, 3H) ], 2.78(s, 3H), 2.78(s, 3.15 (m), 2H ], [ 1H ], (m, 15H ], 1H, 0.92(m, 1H), 0.36(m, 2H), 0.20(m, 2H).
Example E182 Ethyl (3R) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylate
MS(ESI): m/z=512(MH+, 100 %)。
1H-NMR (300 MHz, DMSO-d6): 11.80(s, 1H, -NH), 8.95(s, 1H), 8.91(d, J =6.7, 1H, -NH), 7.40(d, J =9.9, 1H), 7.19(d, J =13.5, 1H), 4.51(m, 1H), 4.05(qu, J =6.9, 2H), 3.84(d, J =6.9, 2H and s, 3H), 3.66(m, 1H), 3.47(m, 2H), 3.27(m, 1H), 2.78(s, 3H), 2.23(m, 1H), 1.91(m, 1H), 1.19(t, J =6.9, 3H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example E183: N- [ (3R)*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
MS(ESI): m/z=498(MH+, 100 %)。
1H-NMR (300 MHz, DMSO-d6): 11.75(br.s, 1H, -NH), 8.93(s, 1H); [8.88(d, J =7.1), 8.82(d, J =6.6), 1H, -NH ]; 7.39(d, J =9.9, 1H); 7.18(d, J =13.5, 1H); [5.56(d, J =3.8), 5.49(d, J =4.0), 1H, -OH ]; 4.39-4.16(m, 2H); 3.91(m, 1H); 3.83(d, J =6.9, 2H and s, 3H); 3.73(m, 1H); 3.47-3.22(m, 2H); 2.78(s, 3H); 1.99(s), 1.98(s), 2H); 3.0 (m, 0H); 2.36 (m, 0H); 2H); 2.21H, 2H) In that respect
Example E184: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
MS(ESI): m/z=512(MH+, 100 %)。
1H-NMR (300 MHz, DMSO-d6): 11.69(br.s, 1H, -NH), 8.90(s, 1H); 8.87(d, J =7.1), 8.82(d, J =6.6), 1H, -NH ]; 7.38(d, J =9.9, 1H), 7.18(d, J =13.5, 1H); 5.56(d, J =3.5), 5.47(d, J =3.8), 1H, -OH ]; 4.39-4.14(m, 2H); 3.88(m, 1H); 3.84(d, J =6.9, 2H and s, 3H); 3.72(m, 1H); 3.63-3.20(m, 2H); 2.78(s, 3H); 2.28(m, 2H); 1.03, t = 7.01), 7.7.7, 7.7, 7H ]; 7.01, 1H) 0.36(m, 2H) and 0.20(m, 2H).
Example E185: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
MS(ESI): m/z=528(MH+, 100 %)。
1H-NMR (300 MHz, DMSO-d6): 11.68(br.s, 1H, -NH), [8.90(s), 8.89(s), 1H ], [8.86(d, J =7.1), 8.82(d, J =6.8), 1H, -NH ], [ 7.38(d, J =9.9, 1H), [ 7.18(d, J =13.3, 1H ], [5.57(d, J =2.4), 5.50(d, J =3.7), 1H, -OH ], [ 4.40-4.15(m, 2H), [4.06(d, J =3.3), 4.04(s), 2H ], [ 3.86(m, 1H), [ 3.84(d, J =6.8, 2H and s, 3H ], [ 3.73(m, 1H ], [ 3.65-3.22.7 ] s, 3.77, 3H ], [ 3.77 ], [ 3.31H ],31, 3H) 0.92(m, 1H), 0.36(m, 2H), 0.20(m, 2H).
Example E186: N- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
MS(ESI): m/z=482(MH+, 100%)。
Example E187: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
MS(ESI): m/z=496(MH+, 100%)。
Example E188: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
MS(ESI): m/z=512(MH+, 100%)。
Example E189: N- [ (3R) *,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
MS(ESI): m/z=498(MH+, 100%)。
Example E190: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
MS(ESI): m/z=512(MH+, 100%)。
Example E191: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
MS(ESI): m/z=528(MH+, 100%)。
Example E192: N- [ (3R)*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
MS(ESI): m/z=480(MH+, 100%)。
Example E193: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
MS(ESI): m/z=494(MH+, 100%)。
Example E194: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
MS(ESI): m/z=510(MH+, 100%)。
Example E195: N- [ (1R)*,3S*,4S*) -3- (acetylamino) -4-methylcyclopentyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1R)*,3S*,4S*) -3-amino-4-methylcyclopentyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f68) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=512.2463([MH]+, C27H32F2N5O3 +Calculating the value: 512.2468).
Example E196: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-N- [ (1R)*,3S*,4S*) -3-methyl-4- (propionylamino) cyclopentyl]-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1R)*,3S*,4S*) -3-amino-4-methylcyclopentyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f68) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=526.2624([MH]+, C28H34F2N5O3 +Calculating the value: 526.2624).
Example E197: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1R*,3S*,4S*) -3- [ (methoxyacetyl) amino]-4-methylcyclopentyl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1R)*,3S*,4S*) -3-amino-4-methylcyclopentyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f68) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=542.2570([MH]+, C28H34F2N5O4 +Calculating the value: 542.2573).
Example E198: N- [ (1R)*,2R*,4S*) -4- (acetylamino) -2-methylcyclopentyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1R)*,2R*,4S*) -4-amino-2-methylcyclopentyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide (example d.f69) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=512.2475([MH]+, C27H32F2N5O3 +Calculating the value: 512.2468).
Example E199: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-N- [ (1R)*,2R*,4S*) -2-methyl-4- (propionylamino) cyclopentyl]-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1R)*,2R*,4S*) -4-amino-2-methylcyclopentyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide (example d.f69) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=526.2622([MH]+, C28H34F2N5O3 +Calculating the value: 526.2624).
Example E200: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1R*,2R*,4S*) -4- [ (methoxyacetyl) amino]-2-methylcyclopentyl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1R)*,2R*,4S*) -4-amino-2-methylcyclopentyl ]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide (example d.f69) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=542.2575([MH]+, C28H34F2N5O4 +Calculating the value: 542.2573).
Example E201: N- [ (1S)*,3S*,4S*) -3- (acetylamino) -4-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1S)*,3S*,4S*) -3-amino-4-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-methylAmide hydrochloride (example d.f70) and commercial acetyl chloride to afford the title compound as a colorless solid.
HR-MS(ESI): m/z=516.2215([MH]+, C26H29F3N5O3 +Calculating the value: 516.2217).
Example E202: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-[(1S*,3S*,4S*) -3-fluoro-4- (propionylamino) cyclopentyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1S)*,3S*,4S*) -3-amino-4-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f70) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=530.2382([MH]+, C27H31F3N5O3 +Calculating the value: 530.2374).
Example E203: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1S*,3S*,4S*) -3-fluoro-4- [ (methoxyacetyl) amino]Cyclopentyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamides
From N- [ (1S)*,3S*,4S*) -3-amino-4-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f70) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=546.2323([MH]+, C27H31F3N5O4 +Calculating the value: .546.2323).
Example F1: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- (1-glycolylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride of example D.f.1 (486 mg; 1.0 mmol) was dissolved in anhydrous dichloromethane (5 mL) and DBU (2.5 mmol). Commercial 2-chloro-2-oxoethyl acetate (1.1 mmol) was injected into the reaction mixture at ice bath temperature. After the addition, stirring was continued at room temperature overnight. Methanol (1 mL) was added and stirring was continued for two hours. The volatiles were evaporated.
The residue was dissolved in methanol (5 mL), treated with 5M KOH (1.5 mmol), and stirred at room temperature overnight. The pH of the reaction mixture was adjusted to 6-7 by the addition of 2M citric acid. The volatiles were evaporated. The residue was purified by reverse phase preparative HPLC. The collected product fractions were lyophilized to give the title compound as a colorless solid.
MS(ESI): m/z=508(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.00(s, 1H,-NH); 8.93(s, 1H); 8.76(d, J=7.7, 1H,-NH); 7.00(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H); 4.50(t, J=5.3, 1H,-OH); 4.25-4.03(m, 2H); 4.12(m, 2H); 3.76(d, J=6.8, 2H); 3.67(m, 1H); 3.19(m, 1H); 3.02(m, 1H); 2.77(s, 3H); 1.97(m, 2H); 1.54(m, 1H); 1.42(m, 1H); 0.88(m, 1H); 0.31(m, 2H); 0.13(m, 2H)。
The following compounds were prepared in a manner analogous to that described above in example F1.
Example F2: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f1) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=522(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 12.00(s, 1H,-NH); 8.93(s, 1H); 8.76(d, J=7.5, 1H,-NH); 7.01(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H); 4.86(d, J=6.8, 1H,-OH); 4.46(m, 1H); 4.28-4.07(m, 2H); 3.95(m, 1H); 3.76(d, J=6.8, 2H); 3.26(m, 1H); 2.99(m, 1H); 2.77(s, 3H); 1.98(m, 2H); 1.54(m, 1H); 1.42(m, 1H); 1.21(br.s, 3H); 0.88(m, 1H); 0.31(m, 2H); 0.13(m, 2H)。
Example F3: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f. 2) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=522(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.97(s, 1H, -NH), 8.94(s, 1H), 8.60(d, J =7.7, 1H, -NH), 7.47(d, J =8.2, 1H, -NH), 7.00(d, J =8.6, 1H), 6.56(d, J =8.6, 1H), 6.00(s, 2H), 5.40(t, J =5.8, 1H, -OH), 3.79(m, 1H and d, J =5.8, 2H), 3.76(d, J =6.8, 2H), 3.68(m, 1H), 2.76(s, 3H), 2.00(m, 2H), 1.83(m, 2H), 1.44(m, 4H), 0.88(m, 1H), 0.30(m, 2H), 0.12(m, 2H).
Example F4: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f2) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=536(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.97(s, 1H,-NH); 8.94(s, 1H); 8.59(d, J=7.7, 1H,-NH); 7.42(d, J=8.2, 1H,-NH); 7.00(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H); 5.40(d, J=5.1, 1H,-OH); 3.94(m, 1H); 3.80(m, 1H); 3.76(d, J=6.8, 2H); 3.63(m, 1H); 2.76(s, 3H); 2.00(m, 2H); 1.83(m, 2H); 1.42(m, 4H); 1.21(d, J=6.8, 3H); 0.88(m, 1H); 0.30(m, 2H); 0.12(m, 2H)。
Example F5: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f. 3) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=522(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.97(s, 1H,-NH); 8.97(s, 1H); 8.90(d, J=7.5, 1H,-NH); 7.53(d, J=7.9, 1H,-NH); 7.01(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H); 5.32(t, J=5.81H, -OH), 4.05(m, 1H), 3.82(d, J =5.8, 2H), 3.76(m, 1H and d, J =6.8, 2H), 2.77(s, 3H), 1.85-1.57(m,8H), 0.89(m, 1H), 0.31(m, 2H), 0.13(m, 2H).
Example F6: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f. 3) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=536(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.98(s, 1H, -NH), 8.97(s, 1H), 8.89(d, J =7.3, 1H, -NH), 7.48(d, J =7.9, 1H, -NH), 7.00(d, J =8.6, 1H), 6.56(d, J =8.6, 1H), 6.00(s, 2H), 5.36(d, J =5.5, 1H, -OH), 4.05(m, 1H), 3.98(m, 1H), 3.76(m, 1H and d, J =6.8, 2H), 2.77(s, 3H), 1.83-1.57(m,8H), 1.22(d, J =6.8, 3H), 0.89(m, 1H), 0.31(m, 2H), 0.13(m, 2H).
Example F7: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ (3R) -1-ethanoylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f4) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=494(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 12.03(s, 1H,-NH); 8.93(s, 1H); [8.87(d, J=7.0), 8.84(d, 6.7), 1H,-NH]; 7.00(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H);[4.60(m), 4.49(m), 1H]; 4.55(t, J=5.6, 1H,-OH);[4.05(d, J=5.6), 4.01(d, J=5.6), 2H]; 3.79-3.69(m, 1H), 3.76(d, J=6.7, 2H); 3.61-3.45(m, 2H); 3.40-3.27(m, 1H); 2.77(s, 3H); 2.33-2.16(m,1H);[2.04(m), 1.92(m), 1H]; 0.88(m, 1H); 0.31(m, 2H); 0.12(m, 2H)。
Example F8: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f4) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=508(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 12.03(s, 1H,-NH);[8.92(s), 8.89(s), 1H]; [8.88(d, J=6.9), 8.87(d, 6.6), 1H,-NH]; 7.00(d, J=8.6, 1H); 6.56(d, J=8.6, 1H); 6.00(s, 2H);[4.91(d, J=6.8), 4.84(d, J=6.8), 1H,-OH];[4.58(m), 4.51(m), 1H];[4.33(m), 4.25(m), 1H];[3.84(m), 3.78(m), 1H], 3.76(d, J=6.6, 2H); 3.71-3.53(m, 2H); 3.46(m), 3.36(m), 1H]; 2.77(s, 3H);[2.27(m), 2.20(m),1H];[2.04(m), 1.92(m), 1H];[1.23(d, J=6.5), 1.20(d, J=6.5), 3H]; 0.88(m, 1H); 0.31(m, 2H); 0.12(m, 2H)。
Example F9: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d. f5) and commercially available 2-chloro-2-oxoethyl acetate gave the title compound as a colorless solid.
HR-MS(ESI): m/z=510.1963([MH]+, C26H30N5O7 +Calculating the value: 510.1983).
Example F10: 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide and 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3, diastereomer mixtures of 2-d pyrimidine-7-carboxamides
From 4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Starting from pyrimidine-7-carboxamide hydrochloride (example d. f5) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=524.2123([MH]+, C26H30N5O7 +Calculating the value: 524.2140).
Example F11: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- (1-glycolylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f. 6) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=482(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.80(s, 1H,-NH); 8.94(s. .1H); 8.81(d, J=7.7, 1H,-NH); 7.66(dd, J=8.4, 6.9, 1H); 7.08(dd, J=11.7, 2.4, 1H); 6.96(ddd, J=8.4, 8.4, 2.4, 1H); 4.51(t, J=5.3, 1H,-OH); 4.25-4.04(m, 2H); 4.13(dd, J=5.3, 4.9, 2H); 3.91(d, J=6.9, 2H); 3.68(m, 1H); 3.20(m, 1H); 3.02(m, 1H); 2.79(s, 3H); 1.97(m, 2H); 1.54(m, 1H); 1.42(m, 1H); 0.96(m, 1H); 0.38(m, 2H): 0.25(m, 2H)。
Example F12: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f6) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=496(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.80(s, 1H,-NH); 8.94(s. .1H); 8.81(d, J=5.9, 1H,-NH); 7.65(dd, J=8.4, 7.1, 1H); 7.08(dd, J=11.5, 2.3, 1H); 6.96(ddd, J=8.4, 8.4, 2.3, 1H); 4.88(d, J=6.7, 1H,-OH); 4.47(m, 1H); 4.28-4.09(m, 2H); 3.96(m, 1H); 3.91(d, J=6.9, 2H); 3.27(m, 1H); 3.00(m, 1H); 2.79(s, 3H); 1.97(m, 2H); 1.53(m, 1H); 1.41(m, 1H); 1.21(br.s, 3H); 0.96(m, 1H); 0.38(m, 2H): 0.25(m, 2H)。
Example F13: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f. 7) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=496(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.77(s, 1H, -NH); 8.95(s, 1H); 8.65(d, J =7.9, 1H, -NH); 7.66(dd, 8.4, 6.9, 1H); 7.48(d, J =8.2, 1H, -NH); 7.08(dd, 11.7, 2.4, 1H); 6.96(ddd, 8.4, 8.4, 2.4, 1H); 5.40(t, J =5.7, 1H, -OH); 3.91(d, J =7.1, 2H); 3.79(d, J =5.7, 2H and m, 1H); 3.68(m, 1H); 2.78(s, 3H); 2.01(m, 2H); 1.83(m, 2H); 1.44(m, 4H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H).
Example F14: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f7) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.77(s, 1H,-NH); 8.95(s, 1H); 8.64(d, J=7.7, 1H,-NH); 7.66(dd, 8.4, 7.1, 1H); 7.42(d, J=8.2, 1H,-NH); 7.08(dd, 11.7, 2.4, 1H); 6.95(ddd, 8.4, 8.4, 2.4, 1H); 5.40(d, J=5.1, 1H,-OH); 3.94(m, 1H); 3.91(d, J=6.9, 2H); 3.81(m, 1H); 3.63(m, 1H); 2.78(s, 3H); 1.99(m, 2H); 1.82(m, 2H); 1.42(m, 4H); 1.21(d, J=6.8, 3H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example F15: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ cis-4- (glycolylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f8) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=496(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.78(s, 1H,-NH); 8.98(s, 1H); 8.96(d, J=7.6, 1H,-NH); 7.66(dd, 8.4, 6.9, 1H); 7.53(d, J=7.7, 1H,-NH); 7.09(dd, 11.7, 2.4, 1H); 6.96(ddd, 8.4, 8.4, 2.4, 1H); 5.33(t, J=5.8, 1H,-OH); 4.06(m, 1H); 3.91(d, J=6.9, 2H); 3.82(d, J=5.8, 2H); 3.80(m, 1H); 2.79(s, 3H); 1.82-1.58(m, 8H); 0.96(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example F16: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f8) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.78(s, 1H,-NH); 8.98(s, 1H); 8.95(d, J=7.3, 1H,-NH); 7.66(dd, 8.4, 7.1, 1H); 7.48(d, J=7.9, 1H,-NH); 7.09(dd, 11.5, 2.4, 1H); 6.96(ddd, 8.4, 8.4, 2.4, 1H); 5.37(d, J=5.5, 1H,-OH); 4.06(m, 1H); 3.99(m, 1H); 3.92(d, J=6.9, 2H); 3.74(m, 1H); 2.79(s, 3H); 1.83-1.56(m, 8H); 1.22(d, J=6.8, 3H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example F17: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ (3R) -1- (hydroxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f9) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=468(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.83(s, 1H,-NH); 8.94(s, 1H);[8.93(d, J=7.1), 8.90(d, J=7.0), 1H,-NH]; 7.66(dd, J=8.4, 7.1, 1H); 7.09(dd, J=11.7, 2.4, 1H); 6.96(ddd, J=8.4, 8.4, 2.4, 1H);[4.60(m), 4.50(m), 1H]; 4.56(t, J=5.7, 1H,-OH);[4.06(d, J=5.7), 4.01(d, J=5.7), 2H]; 3.91(d, J=6.9, 2H); 3.80-3.68(m, 1H); 3.62-3.43(m, 2H); 3.40-3.27(m, 1H); 2.79(s, 3H); 2.34-2.16(m, 1H);[2.05(m), 1.92(m), 1H]; 0.95(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example F18: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f9) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=498.2129([MH]+, C25H29FN5O4 +Calculating the value: 498.2147).
Example F19: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-N-[(3R*,4R*) -4-hydroxy-1- (hydroxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d. f10) and commercially available 2-chloro-2-oxoethyl acetate gave the title compound as a colorless solid.
MS(ESI): m/z=484(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6): 11.75(br.s, 1H,-NH);[8.93(s), 8.92(s), 1H];[8.87(d, J=7.1), 8.82(d, J=6.8), 1H,-NH]; 7.65(dd, J=8.4, 7.0, 1H); 7.09(dd, J=11.5, 2.4, 1H); 6.96(ddd, J=8.4, 8.4, 2.4, 1H);[5.57(br.s), 5.51(br.s), 1H,-OH]; 4.60(m, 1H,-OH);[4.37(m), 4.20(m), 1H]; 4.28(m, 1H); 4.05(br.d, J ~ 2.0, 2H); 3.91(d, 6.9, 2H); 3.87-3.59(m, 2H); 3.48-3.27(m, 2H); 2.78(s. .3H); 0.95(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example F20 diastereomer mixture of 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide and 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide.
From 4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl ]-6-methyl-5H-pyrrolo [3,2-d]Starting from pyrimidine-7-carboxamide hydrochloride (example d. f10) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=482.2178([MH]+, C25H29FN5O4 +Calculating the value: 482.2198).
Example F21: 4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-N-[(3S*,4S*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4S*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d. f11) and commercially available 2-chloro-2-oxoethyl acetate gave the title compound as a colorless solid.
HR-MS(ESI): m/z=498.2134([MH]+, C25H28FN5O5 +Calculating the value: 498.2147).
Example F22 diastereomer mixture of 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide and 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide.
From 4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4S*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Starting from pyrimidine-7-carboxamide hydrochloride (example d. f11) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=512.2293([MH]+, C26H31FN5O5 +Calculating the value: 512.2304).
Example F23: 4- (2-Cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid [1- (2-hydroxy-acetyl) -piperidin-4-yl ] -amide
Starting from 4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example d.f12) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=482(MH+, 100%), 356, 302。
1H-NMR(300 MHz, DMSO-d6): 11.84(br.s, 1H,-NH); 8.96(s, 1H); 8.80(d, J=7.7, 1H,-NH); 7.42(dd, J=9.0, 3.2, 1H); 7.37(ddd, J=9.1, 8.3, 3.2, 1H); 7.19(dd, J=9.1, 4.4, 1H); 4.50(br.s, 1H,-OH); 4.25-4.03(m, 2H); 4.13(br.s, 2H); 3.87(d, J=6.9, 2H); 3.68(m, 1H); 3.20(m, 1H); 3.02(m, 1H); 2.79(s, 3H); 1.97(m, 2H); 1.55(m, 1H); 1.42(m, 1H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example F24: 4- (2-Cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid [1- ((S) -2-hydroxy-propionyl) -piperidin-4-yl ] -amide
Starting from 4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example d.f12) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=496(MH+, 100%), 356, 302。
1H-NMR(300 MHz, DMSO-d6): 11.84(br.s, 1H,-NH); 8.97(s, 1H); 8.80(d, J=7.7, 1H,-NH); 7.42(dd, J=9.0, 3.2, 1H); 7.37(ddd, J=9.1, 8.3, 3.2, 1H); 7.19(dd, J=9.1, 4.4, 1H); 5.01-4.58(s, 1H,-OH); 4.28-4.07(m, 2H); 3.95(m, 1H); 3.87(d, J=6.9, 2H); 3.29(m, 1H); 3.01(m, 1H); 2.79(s, 3H); 1.98(m, 2H); 1.54(m, 1H); 1.42(m, 1H); 1.22(br.s, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example F25: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f13) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=496(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.81(s, 1H,-NH); 8.97(s, 1H); 8.64(d, J=7.9, 1H,-NH); 7.47(d, J=8.4, 1H,-NH); 7.42(dd, J=8.9, 3.3, 1H); 7.36(ddd, J=9.1, 8.2, 3.3, 1H); 7.18(dd, J=9.1, 4.4, 1H); 5.40(t, J=5.7, 1H,-OH); 3.87(d, J=6.8, 2H); 3.82(m, 1H); 3.79(d, J=5.7, 2H); 3.68(m, 1H); 2.79(s, 3H); 2.01(m, 2H); 1.83(m, 2H); 1.44(m, 4H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example F26: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f13) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.81(s, 1H, -NH), 8.97(s, 1H), 8.64(d, J =7.7, 1H, -NH), 7.42(dd, J =8.9, 3.3, 1H and d, J =8.4, 1H, -NH), 7.36(ddd, J =9.1, 8.4, 3.3, 1H), 7.18(dd, J=9.1, 4.4, 1H); 5.40(d, J=5.3, 1H,-OH); 3.94(m, 1H); 3.87(d, J=6.9, 2H); 3.82(m, 1H); 3.63(m, 1H); 2.78(s, 3H); 2.01(m, 2H); 1.82(m, 2H); 1.43(m, 4H); 1.21(d, J=6.7, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example F27: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f14) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.82(s, 1H,-NH); 9.00(s, 1H); 8.94(d, J=7.7, 1H,-NH); 7.48(d, J=7.9, 1H,-NH); 7.43(dd, J=9.1, 3.3, 1H); 7.38(ddd, J=8.9, 8.4, 3.3, 1H); 7.19(dd, J=8.9, 4.4, 1H); 5.37(d, J=5.5, 1H,-OH); 4.05(m, 1H); 3.99(td, J=6.8, 5.5, 1H); 3.88(d, J=6.8, 2H); 3.75(m, 1H); 2.79(s, 3H); 1.81-1.58(m, 8H); 1.22(d, J=6.8, 3H); 0.94(m, 1H); 0.37(m, 2H); 0.23(m, 2H)。
Example F28: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- [ (3R) -1- (hydroxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f15) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=468.2039([MH]+, C24H26FN5O4+, calculated: 468.2042).
Example F29: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f15) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=482.2199([MH]+, C24H26FN5O4 +Calculating the value: 482.2198).
Example F30: 4- [2- (cyclopropylmethoxy) -5-fluorophenyl)]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d. f16) and commercially available 2-chloro-2-oxoethyl acetate gave the title compound as a colorless solid.
HR-MS(ESI): m/z=498.2142([MH]+, C25H29FN5O5 +Calculating the value: 498.2147).
Example F31 diastereomer mixture of 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide and 4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide.
From 4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Starting from pyrimidine-7-carboxamide hydrochloride (example d.f16) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=512.2298([MH]+, C26H31FN5O5 +Calculating the value: 512.2304).
Example F32: 4- (2-ethoxy-5-fluorophenyl) -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- (2-ethoxy-5-fluorophenyl) -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f17) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=456(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.87(s, 1H,-NH); 8.95(s, 1H); 8.79(d, J=7.7, 1H,-NH); 7.42(ddd, J=9.1, 8.9, 3.2, 1H); 7.38(dd, J=8.3, 3.2, 1H); 7.22(dd, J=9.1, 4.4, 1H); 4.50(t, J=5.5, 1H,-OH); 4.23-4.06(m, 2H); 4.13(d, J=5.5, 2H); 4.08(qu, J=6.9, 2H); 3.68(m, 1H); 3.20(m, 1H); 3.02(m, 1H); 2.78(s, 3H); 1.97(m, 2H); 1.53(m, 1H); 1.42(m, 1H); 1.11(t, J=6.9, 3H)。
Example F33: 4- (2-ethoxy-5-fluorophenyl) -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- (2-ethoxy-5-fluorophenyl) -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f17) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=470(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.87(s, 1H,-NH); 8.96(s, 1H); 8.79(d, J=6.7, 1H,-NH); 7.42(ddd, J=9.1, 8.9, 3.3, 1H); 7.38(dd, J=8.3, 3.3, 1H); 7.22(dd, J=9.1, 4.4, 1H); 4.86(d, J=6.7, 1H,-OH); 4.47(m, 1H); 4.26-4.11(m, 2H); 4.08(qu, J=6.9, 2H); 3.95(m, 1H); 3.27(m, 1H); 3.00(m, 1H); 2.79(s, 3H); 1.98(m, 2H); 1.53(m, 1H); 1.41(m, 1H); 1.21(br.s, 3H); 1.11(t, J=6.9, 3H)。
Example F34: 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- (1-glycolylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f18) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=494(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.68(s, 1H,-NH); 8.90(s, 1H); 8.84(d, J=7.7, 1H,-NH); 7.58(d, J=8.4, 1H); 6.72(dd, J=8.4, 2.2, 2H); 6.69(d, J=2.2, 1H); 4.50(t, J=5.5, 1H,-OH); 4.24-4.02(m, 2H); 4.13(m, 2H); 3.90(d, J=6.9, 2H); 3.86(s, 3H); 3.67(m, 1H); 3.20(m, 1H); 3.02(m, 1H); 2.78(s, 3H); 1.96(m, 2H); 1.54(m, 1H); 1.41(m, 1H); 0.96(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example F35: 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide (example d.f18) and the commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=508(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.68(s, 1H,-NH); 8.91(s, 1H); 8.84(d, J=7.5, 1H,-NH); 7.59(d, J=8.4, 1H); 6.79(d, J=2.2, 1H); 6.72(dd, J=8.4, 2.2, 1H); 4.86(t, J=6.9, 1H,-OH); 4.46(m, 1H); 4.28-4.06(m, 2H); 3.96(m, 1H); 3.90(d, J=6.9, 2H); 3.86(s, 3H); 3.26(m, 1H); 3.00(m, 1H); 2.78(s, 3H); 1.97(m, 2H); 1.53(m, 1H); 1.41(m, 1H); 1.21(br.s, 3H); 0.96(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example F36: 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f19) and the commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=522(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.65(s, 1H,-NH); 8.91(s, 1H); 8.67(d, J=7.9, 1H,-NH); 7.59(d, J=8.4, 1H); 7.42(d, J=8.4, 1H,-NH); 6.72(dd, J=8.4, 2.2, 2H); 6.68(d, J=2.2, 1H); 5.40(d, J=5.3, 1H,-OH); 3.94(m, 1H); 3.90(d , J=6.9, 2H); 3.86(s, 3H); 3.80(m, 1H); 3.63(m, 1H); 2.77(s, 3H); 2.01(m, 2H); 1.82(m, 2H); 1.42(m, 4H); 1.21(d, J=6.8, 3H); 0.96(m, 1H); 0.38(m, 2H); 0.26(m, 2H)。
Example F37: 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f21) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=480(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.71(br.s, 1H,-NH);[8.95(d, J=7.6), 8.93(d, J=7.6), 1H,-NH]; 8.90(s, 1H); 7.59(d, J=8.4, 1H); 6.72(dd, J=8.4, 2.2, 1H); 6.69(d, J=2.2, 1H);[4.59(m), 4.49(m), 1H]; 4.55(t, J=5.8, 1H,-OH);[4.06(d, J=5.8), 4.01(d, J=5.8), 1H]; 3.90(d , J=6.9, 2H); 3.86(s, 3H); 3.79-3.68(m, 1H); 3.62-3.43(m, 1H); 3.39-3.27(m, 1H); 2.78(s, 3H); 2.34-2.15(m 1H); 2.09-1.86(m, 1H); 0.95(m, 1H); 0.37(m, 2H); 0.26(m, 2H)。
Example F38: 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f21) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=494.2402([MH]+, C26H32N5O5 +Calculating the value: 494.2389).
Example F39: 4- [2- (cyclopropylmethoxy)Yl) -4-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f22) and commercially available 2-chloro-2-oxoethyl acetate gave the title compound as a colorless solid.
MS(ESI): m/z=496(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(br.s, 1H,-NH);[8.90(d, J=7.1), 8.85(d, J=6.6), 1H,-NH];[8.89(s), 8.88(s), 1H]; 7.58(d, J=8.4, 1H); 6.72(dd, J=8.4, 2.2, 1H); 6.69(d, J=2.2, 1H);[5.56(d, J=4.0), 5.50(d, J=4.2), 1H,-OH];[4.63(t, J=5.7), 4.60(t, J=5.7), 1H,-OH];[4.37(m), 4.19(m), 1H]; 4.28(m, 1H);[4.05(d, J=5.7), 4.04[d, J=5.7), 2H]; 3.90(d , J=6.9, 2H); 3.86(s, 3H); 3.84-3.69(m, 1H); 3.68-3.59(m, 1H); 3.46-3.32(m, 2H); 2.78(s, 3H); 0.95(m, 1H); 0.37(m, 2H); 0.26(m, 2H)。
Example F40 diastereomer mixture of 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide and 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide.
From 4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Starting from pyrimidine-7-carboxamide hydrochloride (example d.f22) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=510.2352([MH]+, C26H32N5O5 +Calculating the value: 510.2347).
Example F41: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- (1-glycolylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f23) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=494(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.77(s, 1H,-NH); 8.95(s, 1H); 8.82(d, J=7.7, 1H,-NH); 7.17(t, J=1.8, 1H); 7.11(d, J=1.8, 2H); 4.50(t, J=5.5, 1H,-OH); 4.24-4.04(m, 2H); 4.13(m, 2H); 3.82(d, J=6.9, 2H); 3.77(s, 3H); 3.68(m, 1H); 3.19(m, 1H); 3.02(m, 1H); 2.79(s, 3H); 1.97(m, 2H); 1.55(m, 1H); 1.42(m, 1H); 0.92(m, 1H); 0.34(m, 2H); 0.19(m, 2H)。
Example F42: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f23) and the commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=494(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.77(s, 1H,-NH); 8.96(s, 1H); 8.82(d, J=7.7, 1H,-NH); 7.17(t, J=1.8, 1H); 7.11(d, J=1.8, 2H); 4.86(d, J=6.9, 1H,-OH); 4.47(m, 1H); 4.27-4.06(m, 2H); 3.95(m, 1H); 3.82(d, J=6.9, 2H); 3.77(s, 3H); 3.27(m, 1H); 3.00(m, 1H); 2.79(s, 3H); 1.99(m, 2H); 1.63-1.31(m, 2H); 1.22(br.s, 3H); 0.92(m, 1H); 0.34(m, 2H); 0.19(m, 2H)。
Example F43: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f24) and the commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=508(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.74(s, 1H, -NH), 8.96(s, 1H), 8.65(d, J =7.8, 1H, -NH), 7.47(d, J =8.2, 1H, -NH), 7.17(t, J =1.8, 1H), 7.10(d, J =1.8, 2H), 5.50(t, J =5.8, 1H, -OH), 3.82(d, J =6.9, 2H), 3.79(d, J =5.8, 2H), 3.77(s, 3H and m, 1H), 3.69(m, 1H), 2.78(s, 3H), 2.01(m, 2H), 1.83(m, 2H), 1.44(m, 4H), 0.92(m, 1H), 0.34(m, 2H), 0.19(m, 2H).
Example F44: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f24) and the commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=522(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.74(s, 1H, -NH), 8.96(s, 1H), 8.65(d, J =7.9, 1H, -NH), 7.42(d, J =8.2, 1H, -NH), 7.18(t, J =1.8, 1H), 7.10(d, J =1.8, 2H), 5.40(d, J =5.1, 1H, -OH), 3.94(m, 1H), 3.82(d, J =6.9, 2H and m, 1H), 3.77(s, 3H), 3.63(m, 1H), 2.78(s, 3H), 2.01(m, 2H), 1.82(m, 2H), 1.43(m, 4H), 1.21(d, J =6.8, 3H), 0.92(m, 1H), 0.34(m, 2H), 0.19(m, 2H).
Example F45: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f25) and the commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=508.2558([MH]+, C27H34N5O5 +Calculating the value: 508.2554).
Example F46: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f25) and the commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=522.2710([MH]+, C28H36N5O5 +Calculating the value: 522.2711).
Example F47: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f26) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=480.2243([MH]+, C25H30N5O5 +Calculating the value: 480.2241).
Example F48: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ (3R) -pyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f26) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=494.2399([MH]+, C26H32N5O5 +Calculating the value: 494.2398).
Example F49: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f27) and commercially available 2-chloro-2-oxoethyl acetate gave the title compound as a colorless solid.
HR-MS(ESI): m/z=510.2349([MH]+, C26H32N5O6 +Calculating the value: 510.2347).
Example F50 diastereomer mixture of 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide and 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide.
From 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Starting from pyrimidine-7-carboxamide hydrochloride (example d.f27) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=524.2495([MH]+, C27H34N5O6 +Calculating the value: 514.2504).
Example F51: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f28) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=478(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.74(br.s, 1H,-NH); 8.93(s, 1H); 8.83(d, J=7.7, 1H,-NH); 7.43(d, J=1.8, 1H); 7.33(dd, J=8.4, 1.8, 1H); 7.06(d, J=8.4, 1H); 4.51(t, J=5.3, 1H,-OH); 4.24-4.05(m, 2H); 4.13(m, 2H); 3.86(d, J=6.9, 2H); 3.68(m, 1H); 3.20(m, 1H); 3.03(m, 1H); 2.78(s, 3H); 2.33(s, 3H); 1.97(m, 2H); 1.54(m, 1H); 1.42(m, 1H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example F52: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f28) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=492(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.74(br.s, 1H,-NH); 8.94(s, 1H); 8.83(d, J=7.7, 1H,-NH); 7.43(d, J=1.8, 1H); 7.33(dd, J=8.6, 1.8, 1H); 7.06(d, J=8.6, 1H); 4.86(d, J=6.9, 1H,-OH); 4.47(m, 1H); 4.24-4.08(m, 2H); 4.95(m, 1H); 3.86(d, J=6.8, 2H); 3.27(m, 1H); 3.00(m, 1H); 2.78(s, 3H); 2.33(s, 3H); 1.98(m, 2H); 1.63-1.32(m, 2H); 1.21(br.s, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example F53: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f29) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=492(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.71(s, 1H, -NH), 8.94(s, 1H), 8.66(d, J =7.7, 1H, -NH), 7.47(d, J =8.4, 1H, -NH), 7.43(d, J =2.1, 1H), 7.32(dd, J =8.4, 2.1, 1H), 7.06(d, J =8.4, 1H), 5.40(t, J =5.9, 1H, -OH), 3.86(d, J =6.8, 2H), 3.79(d, J =5.9, 2H and m, 1H), 3.68(m, 1H), 2.77(s, 3H), 2.33(s, 3H), 2.01(m, 2H), 1.83(m, 2H), 1.44(m, 4H), 0.94(m, 1H), 0.35(m, 22H), 2H) In that respect
Example F54: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f29) and the commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=506(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.71(s, 1H,-NH); 8.94(s, 1H); 8.66(d, J=7.7, 1H,-NH); 7.43(d, J=2.0, 1H); 7.42(d, J=7.8, 1H,-NH); 7.33(dd, J=8.4, 2.0, 1H); 7.06(d, J=8.4, 1H); 5.40(d, J=5.3, 1H,-OH); 3.94(m, 1H); 3.86(d, J=6.8, 2H); 3.80(m, 1H); 3.63(m, 1H); 2.77(s, 3H); 2.33(s, 3H); 2.01(m, 2H); 1.83(m, 2H); 1.43(m, 4H); 1.21(d, J=6.8, 3H); 0.94(m, 1H); 0.35(m, 2H); 0.22(m, 2H)。
Example F55: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f30) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=492(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.72(s, 1H, -NH), 8.97(s, 1H and d, J =7.5, 1H, -NH), 7.53(d, J =7.7, 1H, -NH), 7.44(d, J =2.0, 1H), 7.33(dd, J =8.4, 2.0, 1H), 7.06(d, J =8.4, 1H), 5.33(t, J =5.8, 1H, -OH), 4.06(m, 1H), 3.86(d, J =6.9, 2H), 3.83(d, J =5.8, 3H), 3.80(m, 1H), 2.76(s, 3H), 2.33(s, 3H), 1.81-1.61(m, 8H), 0.94(m, 1H), 0.36(m, 2H), 0.23(m, 2H).
Example F56: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f30) and the commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=520(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(s, 1H,-NH); 8.97(s, 1H); 8.96(d, J=6.4, 1H,-NH); 7.48(d, J=7.9, 1H,-NH); 7.44(d, J=1.8, 1H); 7.33(dd, J=8.6, 1.8, 1H); 7.06(d, J=8.6, 1H); 5.37(d, J=5.5, 1H,-OH); 4.05(m, 1H); 3.99(m, 1H); 3.86(d, J=6.9, 2H); 3.75(m, 1H); 2.78(s, 3H); 2.33(s, 3H); 1.81-1.57(m, 8H); 1.22(d, J=6.8, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example F57: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f31) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=532(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.90(s, 1H,-NH); 8.99(s, 1H); 8.80(d, J=7.7, 1H,-NH); 7.91(d, J=2.0, 1H); 7.89(dd, J=8.8, 2.0, 1H); 7.38(d, J=8.8, 1H); 4.51(t, J=5.5, 1H,-OH); 4.25-4.06(m, 2H); 4.13(m, 2H); 4.00(d, J=6.9, 2H); 3.69(m, 1H); 3.20(m, 1H); 3.03(m, 1H); 2.79(s, 3H); 1.97(m, 2H); 1.55(m, 1H); 1.43(m, 1H); 0.98(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example F58: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f31) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=546(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.90(s, 1H,-NH); 8.99(s, 1H); 8.80(d, J=7.5, 1H,-NH); 7.91(d, J=2.0, 1H); 7.89(dd, J=8.8, 2.0, 1H); 7.38(d, J=8.8, 1H); 4.87(d, J=6.9, 1H,-OH); 4.47(m, 1H); 4.28-4.07(m, 2H); 3.99(d, J=6.9, 2H); 3.93(m, 1H); 3.28(m, 1H); 3.01(m, 1H); 2.80(s, 3H); 1.98(m, 2H); 1.64-1.31(m, 2H); 1.22(br.s, 3H); 0.98(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example F59: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f32) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=546(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.87(s, 1H,-NH); 8.99(s, 1H); 8.63(d, J=7.7, 1H,-NH); 7.91(d, J=2.0, 1H); 7.89(dd, J=8.8, 2.0, 1H); 7.48(d, J=8.2, 1H,-NH); 7.38(d, J=8.8, 1H); 5.40(t, J=5.9, 1H,-OH); 3.99(d, J=6.9, 2H); 3.82(m, 1H); 3.79(d, J=5.9, 2H); 3.69(m, 1H); 2.79(s, 3H); 2.02(m, 2H); 1.83(m, 2H); 1.44(m, 4H); 0.98(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example F60: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f32) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=560(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.87(s, 1H,-NH); 8.99(s, 1H); 8.64(d, J=7.8, 1H,-NH); 7.91(d, J=2.0, 1H); 7.89(dd, J=8.8, 2.0, 1H); 7.42(d, J=8.2, 1H,-NH); 7.38(d, J=8.8, 1H); 5.40(d, J=5.1, 1H,-OH); 4.00(d, J=6.9, 2H); 3.94(m, 1H); 3.81(m, 1H); 3.63(m, 1H); 2.79(s, 3H); 2.02(m, 2H); 1.83(m, 2H); 1.43(m, 4H); 1.21(d, J=6.8, 3H); 0.98(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example F61: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f33) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=546(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.91(s, 1H,-NH); 9.03(s, 1H); 8.96(d, J=7.3, 1H,-NH); 7.91(s, 1H); 7.90(d, J=8.8, 1H); 7.58(d, J=7.8, 1H,-NH); 7.39(d, J=8.8, 1H); 5.37(t, J=5.9, 1H,-OH); 4.07(m, 1H); 4.00(d, J=7.0, 2H); 3.83(d, J=5.9, 2H); 3.80(m, 1H); 2.80(s, 3H); 1.83-1.59(m, 8H); 0.98(m, 1H); 0.40(m, 2H); 0.28(m, 2H)。
Example F62: 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f33) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=560(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.91(s, 1H,-NH); 9.03(s, 1H); 8.95(d, J=7.3, 1H,-NH); 7.91(s, 1H) 7.90(d, J =8.8, 1H), 7.52(d, J =7.6, 1H, -NH), 7.39(d, J =8.8, 1H), 5.40(d, J =5.5, 1H, -OH), 4.06(m, 1H), 4.00(d, J =7.0, 2H and m, 1H), 3.75(m, 1H), 2.80(s, 3H), 1.83-1.57(m, 8H), 1.22(d, J =6.8, 3H), 0.98(m, 1H), 0.40(m, 2H), 0.28(m, 2H).
Example F63: 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f34) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=506(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.93(br.s, 1H,-NH); 8.98(s, 1H); 8.79(d, J=7.7, 1H,-NH); 7.92(d, J=2.2, 1H); 7.91(dd, J=9.4, 2.2, 1H); 7.42(d, J=9.4, 1H); 4.50(t, J=5.4, 1H,-OH); 4.21(qu, J=7.0, 2H); 4.18-4.07(m, 4H); 3.68(m, 1H); 3.20(m, 1H); 3.03(m, 1H); 2.79(s, 3H); 1.97(m, 2H); 1.55(m, 1H); 1.42(m, 1H); 1.16(t, J=7.0, 3H)。
Example F64: 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f34) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=520(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.93(br.s, 1H,-NH); 8.98(s, 1H); 8.79(d, J=7.8, 1H,-NH); 7.92(d, J=2.2, 1H); 7.91(dd, J=9.5, 2.2, 1H); 7.42(d, J=9.5, 1H); 4.86(d, J=6.6, 1H,-OH); 4.46(m, 1H); 4.21(qu, J=7.0, 2H); 4.18-4.09(m, 2H); 3.95(m, 1H); 3.28(m, 1H); 3.00(m, 1H); 2.79(s, 3H); 1.98(m, 2H); 1.54(m, 1H); 1.42(m, 1H); 1.21(br.s, 3H); 1.16(t, J=7.0, 3H)。
Example F65: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- (1-glycolylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f35) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=512(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.77(s, 1H, -NH), 8.96(s, 1H), 8.81(d, J =7.5, 1H, -NH), 7.39(d, J =9.9, 1H), 7.18(d, J =13.3, 1H), 4.50(t, J =5.5, 1H, -OH), 4.24-4.04(m, 2H), 4.13(m, 2H), 3.84(s, 3H and d, J =6.8, 2H), 3.68(m, 1H), 3.20(m, 1H), 3.02(m, 1H), 2.79(s, 3H), 1.97(m, 2H), 1.54(m, 1H), 1.42(m, 1H), 0.93(m, 1H), 0.36(m, 2H), and 0.21(m, 2H).
Example F66: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f35) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=526(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.75(s, 1H, -NH), 8.96(s, 1H), 8.81(d, J =7.5, 1H, -NH), 7.39(d, J =9.9, 1H), 7.18(d, J =13.3, 1H), 4.86(d, J =6.9, 1H, -OH), 4.47(m, 1H), 4.27-4.06(m, 2H), 3.95 (m.1H), 3.84(s, 3H and d, J =6.9, 2H), 3.28(m, 1H), 3.00(m, 1H), 2.79(s, 3H), 1.98(m, 2H), 1.53(m, 1H), 1.42(m, 1H), 1.21(br.s, 3H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example F67: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f36) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=526(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.73(s, 1H, -NH), 8.96(s, 1H), 8.64(s, J =7.7, 1H, -NH), 7.47(d, J =8.2, 1H, -NH), 7.39(d, J =9.9, 1H), 7.18(d, J =13.3, 1H), 5.40(t, J =5.8, 1H, -OH), 3.84(s, 3H and d, J =6.8, 2H), 3.79(d, J =5.8, 2H and m, 1H), 3.68(m, 1H), 2.78(s, 3H), 2.01(m, 2H), 1.83(m, 2H), 1.44(m, 4H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example F68: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f36) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=540(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.73(s, 1H, -NH), 8.96(s, 1H), 8.64(d, J =7.7, 1H, -NH), 7.42(d, J =8.1, 1H, -NH), 7.39(d, J =9.9, 1H), 7.18(d, J =13.3, 1H), 5.40(d, J =5.1, 1H, -OH), 3.94(m, 1H), 3.84(s, 3H and d, J =6.8, 2H), 3.79(d, J =5.8, 2H and m, 1H), 3.63(m, 1H), 2.78(s, 3H), 2.01(m, 2H), 1.82(m, 2H), 1.43(m, 4H), 1.21(d, J =6.7, 3H), 0.93(m, 1H), 0.36(m, 0.21H), 2H) In that respect
Example F69: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f37) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=526(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.74(s, 1H, -NH), 8.99(s, 1H), 8.95(d, J =7.5, 1H, -NH), 7.52(d, J =7.7, 1H, -NH), 7.43(d, J =9.9, 1H), 7.19(d, J =13.3, 1H), 5.33(t, J =5.1, 1H, -OH), 4.06(m, 1H), 3.85(s, 3H and d, J =6.9, 2H), 3.82(d, J =5.1, 2H and m, 1H), 2.79(s, 3H), 1.72(m, 8H), 0.93(m, 1H), 0.37(m, 2H), 0.22(m, 2H).
Example F70: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f37) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=540(MH+, 100 %)。
1H-NMR(300 MHz, DMSO-d6) 11.74(s, 1H, -NH), 8.99(s, 1H), 8.94(d, J =7.5, 1H, -NH), 7.47(d, J =7.8, 1H, -NH), 7.40(d, J =9.9, 1H), 7.18(d, J =13.3, 1H), 5.36(d, J =5.5, 1H, -OH), 4.04(m, 1H), 3.99(m, 1H), 3.85(s, 3H and d, J =6.9, 2H), 3.75(m, 1H), 2.79(s, 3H), 1.71(m, 8H), 1.22(d, J =6.7, 3H), 0.93(m, 1H), 0.36(m, 2H), 0.21(m, 2H).
Example F71: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f38) and commercially available 2-chloro-2-oxoethyl acetate gave the title compound as a colorless solid.
HR-MS(ESI): m/z=528.2258([MH]+, C26H31FN5O6 +Calculating the value: 528.2253).
Example F72: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac. -3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide and 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac. -3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3, diastereomer mixtures of 2-d pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Starting from pyrimidine-7-carboxamide hydrochloride (example d.f38) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=542.2410([MH]+, C27H33FN5O6 +Calculating the value: 542.2409).
Example F73: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -1-glycolyl-4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f39) and commercially available 2-chloro-2-oxoethyl acetate gave the title compound as a colorless solid.
HR-MS(ESI): m/z=528.2252([MH]+, C26H31FN5O6 +Calculating the value: 528.2253).
Example F74: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac. -3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide and 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac. -3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-3-yl } -6-methyl-5H-pyrrolo [3, diastereomer mixtures of 2-d pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethyl)Oxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Starting from pyrimidine-7-carboxamide hydrochloride (example d.f39) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=542.2393([MH]+, C27H33FN5O6 +Calculating the value: 542.2409).
Example F75: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f40) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=496(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.75(s, 1H, -NH), 8.93(s, 1H), 8.81(d, J =7.7, 1H, -NH), 7.53(d, J =9.0, 1H), 7.03(d, J =12.0, 1H), 4.50(t, J =5.5, 1H, -OH), 4.25-4.05(m, 2H and m, 2H), 3.87(d, J =6.9, 2H), 3.68(m, 1H), 3.20(m, 1H), 3.02(m, 1H), 2.78(s, 3H), 2.25(d, J =1.3, 3H), 1.97(m, 2H), 1.53(m, 1H), 1.42(m, 1H), 0.95(m, 1H), 0.37(m, 2H), 0.24(m, 2H).
Example F76: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f40) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.75(s, 1H,-NH); 8.93(s, 1H); 8.81(d, J=7.7, 1H,-NH); 7.54(dd, J=9.1, 0.6, 1H); 7.03(d, J=12.0, 1H); 4.86(d, J=6.9, 1H,-OH); 4.46(m, 1H); 4.27-4.07(m, 2H); 3.95(m, 1H); 3.87(d, J=6.9, 2H); 3.27(m, 1H); 3.00(m, 1H); 2.78(s, 3H); 2.25(d, J=1.3, 3H); 1.98(m, 2H); 1.62-1.31(m, 2H); 1.22(br.s, 3H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example F77: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f41) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.72(s, 1H, -NH), 8.93(s, 1H), 8.65(d, J =7.7, 1H, -NH), 7.53(d, J =9.1, 1H), 7.47(d, J =8.2, 1H, -NH), 7.03(d, J =12.2, 1H), 5.40(t, J =5.7, 1H, -OH), 3.87(d, J =6.9, 2H), 3.79(m, 1H and d, J =5.7, 2H), 3.68(m, 1H), 2.77(s, 3H), 2.25(d, J =1.1, 3H), 2.01(m, 2H), 1.82(m, 2H), 1.44(m, 4H), 0.95(m, 1H), 0.37(m, 2H), 0.24(m, 2H).
Example F78: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f41) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=524(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(s, 1H,-NH); 8.94(s, 1H); 8.65(d, J=7.7, 1H,-NH); 7.54(d, J=9.1, 1H); 7.42(d, J=8.4, 1H,-NH); 7.03(d, J=12.2, 1H); 5.40(d, J=5.2, 1H,-OH); 3.94(dt, J=6.8, 5.2, 2H); 3.87(d, J=6.9, 2H); 3.80(m, 1H); 3.63(m, 1H); 2.77(s, 3H); 2.25(d, J=1.1, 3H); 2.01(m, 2H); 1.82(m, 2H); 1.42(m, 4H); 1.21(d, J=6.8, 3H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example F79: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f42) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=510(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.73(s, 1H, -NH), 8.97(s, 1H), 8.96(d, J =7.3, 1H, -NH), 7.54(d, J =9.1, 1H and d, J =7.5, 1H, -NH), 7.04(d, J =12.2, 1H), 5.33(t, J =5.8, 1H, -OH), 4.06(m, 1H), 3.88(d, J =6.9, 2H), 3.82(d, J =5.8, 2H), 3.80(m, 1H), 2.78(s, 3H), 2.25(d, J =0.9, 3H), 1.81-1.59(m, 8H), 0.95(m, 1H), 0.37(m, 2H), 0.24(m, 2H).
Example F80: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f42) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=524(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 8.97(s, 1H); 8.95(d, J=7.8, 1H,-NH); 7.54(d, J=9.1, 1H); 7.48(d, J=7.8, 1H,-NH); 7.04(d, J=12.2, 1H); 5.36(d, J=5.5, 1H,-OH); 4.05(m, 1H); 3.99(dt, J=6.8, 5.5, 1H); 3.88(d, J=6.9, 2H); 3.75(m, 1H); 2.78(s, 3H); 2.25(d, J=0.9, 3H); 1.80-1.59(m, 8H); 1.22(d, J=6.8, 3H); 0.95(m, 1H); 0.37(m, 2H); 0.24(m, 2H)。
Example F81: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d. f43) and commercially available 2-chloro-2-oxoethyl acetate gave the title compound as a colorless solid.
HR-MS(ESI): m/z=512.2324([MH]+, C26H31FN5O5 +Calculating the value: 512.2304).
Example F82: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide and 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3, diastereomer mixtures of 2-d pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Starting from pyrimidine-7-carboxamide hydrochloride (example d.f43) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=526.2470([MH]+, C27H33FN5O5 +Calculating the value: 526.2460).
Example F83: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- (1-glycoloylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f44) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=512(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.73(br.s, 1H, -NH), 8.92(s, 1H), 8.82(d, J =7.7, 1H, -NH), 7.47(d, J =11.9, 1H), 6.92(d, J =7.3, 1H), 4.50(t, J =5.3, 1H, -OH), 4.22-4.06(m, 2H and d, J =5.3, 2H), 3.97(s, 3H), 3.94(d, J =6.9, 2H), 3.68(m, 1H), 3.19(m, 1H), 3.02(m, 1H), 2.79(s, 3H), 1.96(m, 2H), 1.54(m, 1H), 1.41(m, 1H), 0.96(m, 1H), 0.38(m, 2H), 0.25(m, 2H).
Example F84: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N-piperidin-4-yl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f44) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=526(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(br.s, 1H,-NH); 8.92(s, 1H); 8.82(d, J=7.7, 1H,-NH); 7.47(d, J=11.9, 1H); 6.92(d, J=7.3, 1H); 4.86(d, J=6.9, 1H,-OH); 4.46(m, 1H); 4.28-4.07(m, 2H); 3.97(s, 3H); 3.94(d, J=6.9, 2H); 3.30(m, 1H); 3.00(m, 1H); 2.79(s, 3H); 1.98(m, 2H); 1.53(m, 1H); 1.41(m, 1H); 1.21(br.s, 3H); 0.96(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example F85: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f45) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=526(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.70(s, 1H, -NH), 8.92(s, 1H), 8.66(d, J =7.7, 1H, -NH), 7.47(d, J =8.2, 1H, -NH and d, J =11.7, 1H), 6.93(d, J =7.3, 1H), 5.40(t, J =5.8, 1H, -OH), 3.97(s, 3H), 3.94(d, J =6.9, 2H), 3.79(m, 1H and d, J =5.8, 2H), 3.69(m, 1H), 2.78(s, 3H), 2.01(m, 2H), 1.82(m, 2H), 1.44(m, 4H), 0.96(m, 1H), 0.38(m, 2H), 0.25(m, 2H).
Example F86: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f45) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=540(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.70(s, 1H, -NH), 8.92(s, 1H), 8.65(d, J =7.7, 1H, -NH), 7.47(d, J =11.9, 1H), 7.42(d, J =8.2, 1H, -NH), 6.92(d, J =7.3, 1H), 5.40(d, J =5.1, 1H, -OH), 3.97(s, 3H), 3.94(d, J =6.9, 2H and m, 1H), 3.80(m, 1H), 3.63(m, 1H), 2.78(s, 3H), 2.00(m, 2H), 1.82(m, 2H), 1.42(m, 4H), 1.21(d, J =6.7, 3H), 0.96(m, 1H), 0.38(m, 2H), 0.25(m, 2H).
Example F87: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f46) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=526(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.70(s, 1H,-NH); 8.97(d, J=7.7, 1H,-NH); 8.95(s, 1H); 7.53(d, J=7.8, 1H,-NH); 7.47(d, J=11.9, 1H); 6.93(d, J=7.3, 1H); 5.33(t, J=5.8, 1H,-OH); 4.06(m, 1H); 3.97(s, 3H); 3.94(d, J=7.1, 2H); 3.82(d, J=5.8, 1H); 3.80(m,1H); 2.79(s, 3H); 1.82-1.59(m, 8H); 0.96(m, 1H); 0.39(m, 2H); 0.25(m, 2H)。
Example F88: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f46) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=540(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.70(s, 1H, -NH), 8.96(s, 1H and d, J =7.3, 1H, -NH), 7.47(d, J =11.9, 1H), 7.46(d, J =7.7, 1H, -NH), 6.93(d, J =7.3, 1H), 5.36(d, J =5.5, 1H, -OH), 4.05(m, 1H), 4.00(m, 1H), 3.97(s, 3H), 3.94(d, J =6.9, 2H), 3.75(m, 1H), 2.79(s, 3H), 1.80-1.58(m, 8H), 1.22(d, J =6.8, 3H), 0.96(m, 1H), 0.39(m, 2H), 0.25(m, 2H).
Example F89: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f47) and commercially available 2-chloro-2-oxoethyl acetate gave the title compound as a colorless solid.
HR-MS(ESI): m/z=528.2267([MH]+, C26H31FN5O6 +Calculating the value: 528.2253).
Example F90: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide and 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3, diastereomer mixtures of 2-d pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Starting from pyrimidine-7-carboxamide hydrochloride (example d.f47) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=542.2406([MH]+, C27H33FN5O6 +Calculating the value: 542.2409).
Example F91: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f48) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=492(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.76(s, 1H,-NH); 8.94(s, 1H); 8.83(d, J=7.7, 1H,-NH); 7.45(d, J=2.2, 1H); 7.36(dd, J=8.4, 2.2, 1H); 7.08(d, J=8.4, 1H); 4.49(br.s, 1H,-OH); 4.24-4.03(m, 2H); 4.13(d, J=4.6, 2H); 3.87(d, J=6.9, 2H); 3.68(m, 1H); 3.22(m, 1H); 3.03(m, 1H); 2.78(s, 3H); 2.64(qu, J=7.5, 2H); 1.97(m, 2H); 1.54(m, 1H); 1.42(m, 1H); 1.18(t, J=7.5, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example F92: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f48) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=505(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.75(s, 1H,-NH); 8.95(s, 1H); 8.83(d, J=7.5, 1H,-NH); 7.45(d, J=2.4, 1H); 7.36(dd, J=8.6, 2.4, 1H); 7.08(d, J=8.6, 1H); 4.86(d, J=6.9, 1H,-OH); 4.47(m, 1H); 4.25-4.11(m, 2H); 3.95(m, 1H); 3.87(d, J=6.9, 2H); 3.27(m, 1H); 3.00(m, 1H); 2.78(s, 3H); 2.64(qu, J=7.6, 2H); 1.98(m, 2H); 1.53(m, 1H); 1.42(m, 1H); 1.21(br.s, 3H); 1.18(t, J=7.6, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example F93: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f49) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=506(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.72(br.s, 1H, -NH), 8.95(s, 1H), 8.66(d, J =7.9, 1H, -NH), 7.48(d, J =8.4, 1H, -NH), 7.45(d, J =2.4, 1H), 7.35(dd, J =8.6, 2.4, 1H), 7.08(d, J =8.6, 1H), 5.40(t, J =5.7, 1H, -OH), 3.87(d, J =6.9, 2H), 3.79(d, J =5.7, 2H and m, 1H), 3.68(m, 1H), 2.77(s, 3H), 2.64(qu, J =7.5, 2H), 2.02(m, 2H), 1.83(m, 2H), 1.44 (t = 4, 1H), 3.94 (t, 3.4, 94H), 1H) 0.36(m, 2H) and 0.22(m, 2H).
Example F94: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f49) and the commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=520(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.72(s, 1H,-NH); 8.95(s, 1H); 8.66(d, J=7.8, 1H,-NH); 7.45(d, J=2.4, 1H); 7.42(d, J=8.4, 1H,-NH); 7.36(dd, J=8.6, 2.4, 1H); 7.08(d, J=8.6, 1H); 5.40(t, J=5.1, 1H,-OH); 3.94(m, 1H); 3.86(d, J=6.9, 2H); 3.82(m, 1H); 3.63(m, 1H); 2.77(s, 3H); 2.64(qu, J=7.5, 2H); 2.00(m, 2H); 1.82(m, 2H); 1.43(m, 4H); 1.21(d, J=6.8, 3H); 1.18(t, J=7.5, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example F95: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f50) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=506(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 8.98(s, 1H); 8.97(d, J=7.5, 1H,-NH); 7.53(d, J=7.8, 1H,-NH); 7.45(d, J=2.3, 1H); 7.36(dd, J=8.6, 2.3, 1H); 7.08(d, J=8.6, 1H); 5.33(br.s, 1H,-OH); 4.06(m, 1H); 3.87(d, J=6.8, 2H); 3.83(s, 2H); 3.80(m, 1H); 2.78(s, 3H); 2.64(qu, J=7.5, 2H); 1.85-1.55(m, 8H); 1.19(t, J=7.6, 53H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example F96: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f50) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=520(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 8.98(s, 1H); 8.96(d, J=7.5, 1H,-NH); 7.48(d, J=7.8, 1H,-NH); 7.45(d, J=2.2, 1H); 7.36(dd, J=8.4, 2.2, 1H); 7.08(d, J=8.4, 1H); 5.37(d, J=5.3, 1H,-OH); 4.06(m, 1H); 3.99(m, 1H); 3.87(d, J=6.8, 2H); 3.75(m, 1H); 2.78(s, 3H); 2.64(qu, J=7.6, 2H); 1.83-1.56(m, 8H); 1.21(t, J=7.6, 3H); 1.17(d, J=7.7, 1H); 0.94(m, 1H); 0.36(m, 2H); 0.23(m, 2H)。
Example F97: 4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (hydroxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From 4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f51) and commercially available 2-chloro-2-oxoethyl acetate gave the title compound as a colorless solid.
MS(ESI): m/z=494(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.80(s, 1H,-NH); 8.92(s, 1H);[8.88(d, J=7.1), 8.84(d, J=6.6), 1H,-NH]; 7.44(d, J=2.4, 1H); 7.36(dd, J=8.4, 2.4, 1H); 7.08(d, J=8.4, 1H);[5.57(d, J=3.8), 5.51(d, J=4.0), 1H,-OH];[4.64(t, J=5.6), 4.60(t, J=5.6), 1H,-OH];[4.38(m), 4.20(m, 1H]; 4.28(m, 1H);[4.06(br.s), 4.04(br.s), 2H]; 3.86(d, J=6.9, 2H); 3.84-3.60(m, 2H); 3.46-3.27(m, 2H); 2.78(s, 3H); 2.63(qu, J=7.5, 2H); 1.18(t, J=7.5, 3H); 0.93(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example F98 diastereomer mixture of 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide and 4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide.
From 4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Starting from pyrimidine-7-carboxamide hydrochloride (example d.f51) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=508.2548([MH]+, C27H34N5O5 +Meter for measuringCalculating the value: 508.2554).
Example F99: 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f52) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=520(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.76(s, 1H, -NH), 8.95(s, 1H), 8.83(d, J =7.1, 1H, -NH), 7.46(d, J =2.4, 1H), 7.39(dd, J =8.6, 2.4, 1H), 7.08(d; J =8.6, 1H), 4.86(d, J =6.9, 1H, -OH), 4.47(m, 1H), 4.27-4.08(m, 2H), 3.95(m, 1H), 3.87(d, J =6.9, 2H), 3.27(m, 1H), 3.09-2.87(m, 1H and sept, J =6.9, 1H), 2.78(s, 3H), 1.98(m, 2H), 1.53(m, 1H), 1.42(m, 1H =6, 1H), 22.42 (d, 6, 1H and br, 3H) 0.94(m, 1H), 0.36(m, 2H) and 0.22(m, 2H).
Example F100: 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f53) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=534(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.73(s, 1H,-NH); 8.96(s, 1H); 8.66(d, J=7.7, 1H,-NH); 7.47(d, J=2.4, 1H); 7.42(d, J=7.9, 1H,-NH); 7.39(dd, J=8.6, 2.4, 1H); 7.08(d; J=8.6, 1H); 5.40(d, J=5.3, 1H,-OH); 3.94(td, J=6.8, 5.3, 1H); 3.87(d, J=6.9, 2H); 3.81(m, 1H); 3.64(m, 1H); 2.94(sept, J=6.9, 1H); 2.77(s, 3H); 2.01(m, 2H); 1.82(m, 2H); 1.43(m, 4H); 1.22(d, J=6.9, 6H); 1.21(d, J=6.8, 3H); 0.94(m, 1H); 0.36(m, 2H); 0.22(m, 2H)。
Example F101: 4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (cis-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f54) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=534(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6) 11.74(s, 1H, -NH), 8.99(s, 1H), 8.96(d, J =7.5, 1H, -NH), 7.48(d, J =7.7, 1H, -NH), 7.47(d, J =2.4, 1H), 7.39(dd, J =8.6, 2.4, 1H), 7.09(d; J =8.6, 1H), 5.37(d, J =5.4, 1H, -OH), 4.05(m, 1H), 3.99(td, J =6.8, 5.4, 1H), 3.87(d, J =6.9, 2H), 3.75(m, 1H), 2.95(sept, J =6.9, 1H), 2.78(s, 3H), 1.81-1.59(m, 8H, -1.6 =6, 1H), 3.81 (d, 6, 3H =6, 94, 3, 1H) 0.36(m, 2H) and 0.23(m, 2H).
Example F102: 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f55) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=506(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.88(s, 1H,-NH); 8.99(s, 1H); 8.82(d, J=7.7, 1H,-NH); 8.21(d, J=2.3, 1H); 8.15(dd, J=8.8, 2.3, 1H); 7.30(d, J=8.8, 1H); 4.51(t, J=5.5, 1H,-OH); 4.24-4.06(m, 4H); 4.01(d, J=7.0, 2H); 3.68(m, 1H); 3.20(m, 1H); 3.03(m, 1H); 2.79(s, 3H); 2.58(s, 3H); 1.97(m, 2H); 1.55(m, 1H); 1.44(m, 1H); 0.99(m, 1H); 0.39(m, 2H); 0.28(m, 2H)。
Example F103: 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f55) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=520(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.88(s, 1H,-NH); 9.00(s, 1H); 8.81(d, J=6.7, 1H,-NH); 8.21(d, J=2.3, 1H); 8.15(dd, J=8.8, 2.3, 1H); 7.30(d, J=8.8, 1H); 4.47(br.s, 1H,-OH); 4.27-4.10(m, 2H); 4.01(d, J=7.1, 2H); 3.95(m, 1H); 3.27(m, 1H); 3.00(m, 1H); 2.79(s, 3H); 2.58(s, 3H); 1.99(m, 2H); 1.55(m, 1H); 1.41(m, 1H); 1.21(br.s, 3H); 0.99(m, 1H); 0.39(m, 2H); 0.28(m, 2H)。
Example F104: 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- (trans-4-aminocyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f56) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=520(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.85(s, 1H,-NH); 9.00(s, 1H); 8.65(d, J=7.7, 1H,-NH); 8.21(d, J=2.3, 1H); 8.15(dd, J=8.8, 2.3, 1H); 7.48(d, J=8.3, 1H,-NH); 7.30(d, J=8.8, 1H); 5.40(t, J=5.8, 1H,-OH); 4.01(d, J=7.0, 2H); 3.82(m, 1H); 3.79(d, J=5.8, 2H); 3.69(m, 1H); 2.79(s, 3H); 2.58(s, 3H); 2.01(m, 2H); 1.83(m, 2H); 1.45(m, 4H); 0.99(m, 1H); 0.39(m, 2H); 0.28(m, 2H)。
Example F105: 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- (trans-4-aminocyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f56) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=534(MH+, 100%)。
1H-NMR(400 MHz, DMSO-d6): 11.85(s, 1H,-NH); 9.00(s, 1H); 8.65(d, J=7.7, 1H,-NH); 8.21(d, J=2.2, 1H); 8.15(dd, J=8.9, 2.2, 1H); 7.42(d, J=8.3, 1H,-NH); 7.30(d, J=8.9, 1H); 5.40(d, J=5.1, 1H,-OH); 4.01(d, J=7.0, 2H); 3.94(td, J=6.8, 5.1, 1H); 3.82(m, 1H); 3.64(m, 1H); 2.78(s, 3H); 2.58(s, 3H); 2.01(m, 2H); 1.84(m, 2H); 1.44(m, 4H); 1.21(d, J=6.8, 3H); 0.99(m, 1H); 0.39(m, 2H); 0.27(m, 2H)。
Example F106: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example D.f57) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=492(MH+ , 100%)
1H-NMR(300 MHz, DMSO-d6): 11.60(s, 1H,-NH); 9.05(d, J=7.5, 1H,-NH); 7.39(d, J=2.0, 1H); 7.31(dd, J=8.6, 2.0, 1H); 7.04(d, J=8.6, 1H); 4.52(t, J=5.3, 1H,-OH); 4.24-4.04(m, 2H); 4.13(m, 2H); 3.85(d, J=6.9, 2H); 3.67(m, 1H); 3.24(m, 1H); 3.12(m, 1H); 2.75(s, 3H); 2.72(s, 3H); 2.32(s, 3H); 1.96(m, 2H); 1.69-1.36(m, 2H); 0.93(m, 1H); 0.35(m, 2H); 0.22(m, 2H)。
Example F107: 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f57) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=506(MH+ , 100%)
1H-NMR(300 MHz, DMSO-d6): 11.58(s, 1H,-NH); 9.05(br.s, 1H,-NH); 7.39(d, J=1.8, 1H); 7.31(dd, J=8.4, 1.8, 1H); 7.04(d, J=8.4, 1H); 4.86(m, 1H,-OH); 4.47(m, 1H); 4.21-3.99(m,2H); 3.99-3.80(m, 1H); 3.84(d, J=6.9, 2H); 3.43-3.24(m, 1H); 3.24-2.98(m, 1H); 2.75(s, 3H); 2.72(s, 3H); 2.33(s, 3H); 2.05-1.89(m, 2H); 1.63-1.36(m, 2H); 1.21(d, J=6.0, 3H); 0.93(m, 1H); 0.35(m, 2H); 0.22(m, 2H)。
Example F108: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f58) and commercially available (2S) -1-chloro-1-oxoprop-2-yl acetate, the title compound was obtained as a colorless solid.
MS(ESI): 540(MH+, 100%)
1H-NMR(300 MHz, DMSO-d6): 11.56(s, 1H,-NH); 9.04(m, 1H,-NH); 7.43(d, J=11.9, 1H); 6.91(d, J=7.3, 1H); 4.91-4.80(m, 1H,-OH); 4.47(m, 1H); 4.21-4.07(m, 2H); 3.96(s, 3H); 3.93(d, J=6.9, 2H); 3.89(m, 1H); 3.44-3.25(m, 1H); 3.38-3.25(m, 1H); 3.25-2.99(m, 1H); 2.76(s, 3H); 2.71(s, 3H); 2.04-1.89(m, 2H); 1.64-1.34(m, 2H); 1.21(d, J=6.2, 3H); 0.95(m, 1H); 0.38(m, 2H); 0.25(m, 2H)。
Example F109: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f59) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=526(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.61(s, 1H,-NH); 9.02(d, J=7.7, 1H,-NH); 7.34(d, J=9.9, 1H); 7.16(d, J=13.3, 1H); 4.50(t, J=5.5, 1H,-OH); 4.21-4.05(m, 2H); 4.13(s, 2H); 3.84(s, 3H); 3.82(d, J=6.8, 2H); 3.66(m, 1H); 3.24(m, 1H); 3.11(m, 1H); 2.75(s, 3H); 2.73(s, 3H); 1.96(m, 2H); 1.64-1.37(m, 2H); 0.92(m, 1H); 0.35(m, 2H); 0.19(m, 2H)。
Example F110: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f59) and commercially available 2-chloro-2-oxoethyl acetate, the title compound was obtained as a colorless solid.
MS(ESI): m/z=540(MH+, 100%)。
1H-NMR(300 MHz, DMSO-d6): 11.61(s, 1H,-NH); 9.03(br.s, 1H,-NH); 7.33(d, J=9.9, 1H); 7.16(d, J=13.5, 1H); 4.86(br.s, 1H,-OH); 4.47(m, 1H); 4.23-4.00(m, 2H); 3.88(m, 1H); 3.84(s, 3H); 3.82(d, J=6.8, 2H); 3.36(m, 1H); 3.10(m, 1H); 2.75(s, 3H); 2.73(s, 3H); 1.97(m, 2H); 1.62-1.37(m, 2H); 1.21(d, J=6.0, 3H); 0.91(m, 1H); 0.35(m, 2H); 0.19(m, 2H)。
Example F111: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
MS(ESI): m/z=498(MH+, 100 %)。
1H-NMR (300 MHz, DMSO-d6): 11.80(s, 1H, _ NH), [ 8.95(s, 1H) ], [8.92(d, J =7.3), 8.90(d, J =7.9), 1H, -NH ]; 7.93(d, J =9.8, 1H), [ 7.18(d, J =13.4, 1H) ], 4.67-4.46(m, 1H), [ 4.56T, J =5.7, 1H, -OH ], [4.06(d, J =5.7), 4.01(d, J =5.7), 1H ]; 3.85(d, J =6.9, 2H and s, 3H) ], 3.81-3.69(m, 1H), [ 3.64-3.46(m, 2H), [ 3.38-3.31(m, 1H); 2.79(s, 2H); 2H, 2H ]; 2.05-2H ]; 2.05(m, 1H ]; 2.05, 1.93(m, 1H), 0.93(m, 1H), 0.36(m, 2H), 0.22(m, 2H).
Example F112: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
MS(ESI): m/z=512(MH+, 100 %)。
1H-NMR (300 MHz, DMSO-d6): 11.80(s, 1H, -NH), [8.95(s), 8.92(s), 1H ]; 8.92(d, J =7.1, 1H, -NH), [ 8.39 (d, J =9.9, 1H), [ 7.18(d, J =13.5, 1H) [4.91(d, J =6.9), [ 4.84(d, J =6.9), [ 1H, -OH ]; [4.58(m), 4.51(m), 1H ]; [4.33(m), 4.26(m), 1H ]; 3.84(d, J =6.6, 2H and s, 3H); 3.87-3.79(m, 1H); 3.87-3.42(m, 2H); 3.39-3.27(m, 1H); 2.79(s, 2H); 3.05 (m, 1H); 2H); 2.05(m, 1H); 15, 1.92(m), 1H ], [1.23(d, J =6.6), 1.20(d, J =6.6), 3H ], (0.93 (m, 1H); 0.36(m, 2H); 0.21(m, 2H).
Example F113: 4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
MS(ESI): m/z=514(MH+, 100 %)。
1H-NMR (300 MHz, DMSO-d6): 11.81(s, 1H, -NH), [8.94(s), 8.93(s), 1H ], [8.86(d, J =7.3), 8.82(d, J =6.6), 1H, -NH ], [ 7.39(d, J =9.9, 1H), [ 7.18(d, J =13.3, 1H ], [5.57(d, J =3.8), 5.50(d, J =4.0), 1H, -OH ], [4.64(t, J =5.7), 4.60(t, J =5.7), 1H, -OH ], [ 4.41-4.17(m, 2H), [4.06(br.s), [ 4.04(br.s), 2H ], [ 3.84(d, J =6.8, 2H, 3.80, 3.79 ], [ 3.80H = 3.79 ], [ 3.46, 3.7, 3H) 0.92(m, 1H), 0.36(m, 2H), 0.20(m, 2H).
Example F114: 4- [2- (Ring)Propylmethoxy) -4-fluoro-5-methoxyphenyl]-N-{(3R*,4R*) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl group]Pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides (mixture of diastereomers)
MS(ESI): m/z=528(MH+, 100 %)。
1H-NMR (300 MHz, DMSO-d6): 11.81(s, 1H, -NH), [8.93(s), 8.91(s), 8.89(s), 8.88(s), 1H ]; 8.87-8.82(m, 1H, -NH ]; 7.39(d, J =9.9, 1H); 7.18(d, J =13.3, 1H); [5.57(d, J =3.7), 5.55(d, J =3.7), 5.50(d, J =2.0), 5.49(d, J =1.8), 1H, -OH ]; 4.64(t, J =5.7), 4.60(t, J =5.7), 1H, -OH ]; 4.41-4.17(m, 2H) [ -4.97 (d, J =6.8), 4.95(d = 4.7), 3.87 (d =3.7), 3.5.5H ]; 4.87(d, J = 4.7), -OH ]; 4.38-4.17(m, 3H); 4.03-3.27(m, 4H); 3.84(d, J =6.9, 2H and s, 3H); 2.79(s, 3H); 1.27-1.21(m, 3H); 0.92(m, 1H); 0.36(m, 2H); 0.20(m, 2H).
Example F115: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
MS(ESI): m/z=498(MH+, 100%)。
Example F116: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
MS(ESI): m/z=512(MH+, 100%)。
Example F117: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
MS(ESI): m/z=514(MH+, 100%)。
Example F118: 4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-{(3R*,4R*) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl group]Pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides (mixture of diastereomers)
MS(ESI): m/z=528(MH+, 100%)。
Example F119: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
MS(ESI): m/z=496(MH+, 100%)。
Example F120: 4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-{(3R*,4R*) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl group]Pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides (mixture of diastereomers)
MS(ESI): m/z=510(MH+, 100%)。
The compounds of the following list are within the class of the compounds of the formula I described in claim 1
A salt thereof, or a stereoisomer of the compound or salt thereof.
The following compounds in the above table were prepared in analogy to the procedure described in example E1 above.
Example P1N- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f60) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=498.2303([MH]+, C26H30F2N5O3 +Calculating the value: 498.2311).
Example P2: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f60) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=512.2453([MH]+, C27H32F2N5O3 +Calculating the value: 512.2468).
Example P3: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- (piperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f60) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=528.2394([MH]+, C27H32F2N5O4 +Calculating the value: 528.2417).
Example P6N- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f61) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=512.2457([MH]+, C27H32F2N5O3 +Calculating the value: 512.2468).
Example P7: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f61) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=526.2621([MH]+, C28H34F2N5O3 +Calculating the value: 526.2624).
Example P8: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- (trans-4-aminocyclohexyl) -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f61) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=542.2571([MH]+, C28H34F2N5O4 +Calculating the value: 542.2573).
Example P24N- [ (3S,5S) -1-acetyl-5-methylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
From 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ]-6-methyl-N- [ (3S)*,5S*) -5-methylpyrrolidin-3-yl]-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f66) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=498.2316([MH]+, C26H30F2N5O3 +Calculating the value: 498.2311).
Example P25: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- [ (3S,5S) -5-methyl-1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
From 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-N- [ (3S)*,5S*) -5-methylpyrrolidin-3-yl]-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f66) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=512.2466([MH]+, C27H32F2N5O3 +Calculating the value: 512.2468).
Example P26: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -N- [ (3S,5S) -1- (methoxyacetyl) -5-methylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
From 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-N- [ (3S)*,5S*) -5-methylpyrrolidin-3-yl]-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f66) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=528.2411([MH]+, C27H31F2N5O4 +Calculating the value: 528.2417).
Example P89: N- [ (1S,3S) -3- (acetylamino) cyclopentyl ] -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- [ (1S,3S) -3-aminocyclopentyl ] -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f64) and commercially available acetyl chloride, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=498.2305([MH]+, C26H30F2N5O3 +Calculating the value: 498.2311).
Example P90: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- [ (1S,3S) -3- (propionylamino) cyclopentyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- [ (1S,3S) -3-aminocyclopentyl ] -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f64) and commercially available propionyl chloride, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=512.2474([MH]+, C27H32F2N5O3 +Calculating the value: 512.2468).
Example P91: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -N- { (1S,3S) -3- [ (methoxyacetyl) amino ] cyclopentyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide
Starting from N- [ (1S,3S) -3-aminocyclopentyl ] -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide hydrochloride (example d.f64) and commercially available methoxy-acetyl chloride, the title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=528.2418([MH]+, C27H32F2N5O4 +Calculating the value: 528.2417).
Example P99: N- [ (1R)*,2R*,4R*) -4- (acetylamino) -2-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1R)*,2R*,4R*) -4-amino-2-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide (example d.f71) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=516.2221([MH]+, C26H29F3N5O3 +Calculating the value: 516.2217).
Example P100: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-[(1R*,2R*,4R*) -2-fluoro-4- (propionylamino) cyclopentyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1R)*,2R*,4R*) -4-amino-2-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide (example d.f71) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=530.2375([MH]+, C27H31F3N5O3 +Calculating the value: 530.2374).
Example P101: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1R*,2R*,4R*) -2-fluoro-4- [ (methoxyacetyl) amino]Cyclopentyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamides
From N- [ (1R)*,2R*,4R*) -4-amino-2-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide (example d.f71) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=546.2324([MH]+, C27H31F3N5O4 +Calculating the value: 546.2323).
Example P139: N- [ (1S)*,2S*,4S*) -4- (acetylamino) -2-methylcyclohexyl radical]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1S)*,2S*,4S*) -4-amino-2-methylcyclohexaneBase of]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f63) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=526.2625([MH]+, C28H34F2N5O3 +Calculating the value: 526.2624).
Example P140: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-N- [ (1S)*,2S*,4S*) -2-methyl-4- (propionylamino) cyclohexyl]-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1S)*,2S*,4S*) -4-amino-2-methylcyclohexyl radical]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f63) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=540.2773([MH]+, C29H36F2N5O3 +Calculating the value: 540.2781).
Example P141: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ]-N-{(1S*,2S*,4S*) -4- [ (methoxyacetyl) amino]-2-methylcyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamides
From N- [ (1S)*,2S*,4S*) -4-amino-2-methylcyclohexyl radical]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f63) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=556.2726([MH]+, C29H36F2N5O4 +Calculating the value: 556.2730).
Example P159: N- [ (1R)*,2R*,4R*) -4- (acetylamino) -2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1R)*,2R*,4R*) -4-amino-2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide (example d.f67) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=530.2386([MH]+, C27H31F3N5O3 +Calculating the value: 530.2374).
Example P160: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-[(1R*,2R*,4R*) -2-fluoro-4- (propionylamino) cyclohexyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1R)*,2R*,4R*) -4-amino-2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d ]Pyrimidine-7-carboxamide (example d.f67) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=544.2539([MH]+, C28H33F3N5O3 +Calculating the value: 544.2530).
Example P161: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1R*,2R*,4R*) -2-fluoro-4- [ (methoxyethyl) ethyl esterAcyl) amino]Cyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamides
From N- [ (1R)*,2R*,4R*) -4-amino-2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide (example d.f67) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=560.2487([MH]+, C28H32F3N5O4 +Calculating the value: 560.2479).
Example P169: N- [ (1S)*,2R*,4S*) -4- (acetylamino) -2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1S)*,2R*,4S*) -4-amino-2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide (example d.f73) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=530.2378([MH]+, C27H31F3N5O3 +Calculating the value: 530.2374).
Example P170: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-[(1S*,2R*,4S*) -2-fluoro-4- (propionylamino) cyclohexyl ]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1S)*,2R*,4S*) -4-amino-2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide (example D.f73) and commercially available propionyl chloride to yieldThe title compound was obtained as a colorless solid.
HR-MS(ESI): m/z=544.2528([MH]+, C28H33F3N5O3 +Calculating the value: 544.2530).
Example P171: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1S*,2R*,4S*) -2-fluoro-4- [ (methoxyacetyl) amino]Cyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamides
From N- [ (1S)*,2R*,4S*) -4-amino-2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide (example d.f73) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=560.2479([MH]+, C28H33F3N5O4 +Calculating the value: 560.2479).
Example P189: N- [ (1S)*,3S*,4S*) -4- (acetylamino) -3-methylcyclohexyl radical]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1S)*,3S*,4S*) -4-amino-3-methylcyclohexyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f65) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=540.2788([MH]+, C29H36F2N5O3 +Calculating the value: 540.2781).
Example P190: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-N- [ (1S)*,3S*,4S*) -3-methyl-4- (propionylamino) cyclohexyl]-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1S)*,3S*,4S*) -4-amino-3-methylcyclohexyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f65) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=526.2615([MH]+, C28H34F2N5O3 +Calculating the value: 526.2624).
Example P191: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1S*,3S*,4S*) -4- [ (methoxyacetyl) amino]-3-methylcyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamides
From N- [ (1S)*,3S*,4S*) -4-amino-3-methylcyclohexyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f65) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=556.2729([MH]+, C29H36F2N5O4 +Calculating the value: 556.2730).
Example P199: N- [ (1S)*,3R*,4S*) -4- (acetylamino) -3-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [, (1S*,3R*,4S*) -4-amino-3-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f72) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=530.2381([MH]+, C27H31F3N5O3 +Calculating the value: 530.2374).
Example P200: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-[(1S*,3R*,4S*) -3-fluoro-4- (propionylamino) cyclohexyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1S)*,3R*,4S*) -4-amino-3-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f72) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=544.2525([MH]+, C28H33F3N5O3 +Calculating the value: 544.2530).
Example P201: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1S*,3R*,4S*) -3-fluoro-4- [ (methoxyacetyl) amino]Cyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamides
From N- [ (1S)*,3R*,4S*) -4-amino-3-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f72) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=560.2478([MH]+, C28H33F3N5O4 +Calculating the value: 560.2479).
Example P209: N- [ (1S)*,3S*,4S*) -4- (acetylamino) -3-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1S)*,3S*,4S*) -4-amino-3-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f62) and commercially available acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=530.2359([MH]+, C27H31F3N5O3 +Calculating the value: 530.2374).
Example P210: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-[(1S*,3S*,4S*) -3-fluoro-4- (propionylamino) cyclohexyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamides
From N- [ (1S)*,3S*,4S*) -4-amino-3-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f62) and commercially available propionyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=544.2536([MH]+, C28H33F3N5O3 +Calculating the value: 544.2530).
Example P211: 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1S*,3S*,4S*) -3-fluoro-4- [ (methoxyacetyl) amino]Cyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamides
From N- [ (1S)*,3S*,4S*) -4-amino-3-fluorocyclohexyl ]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide hydrochloride (example d.f62) and commercially available methoxy-acetyl chloride gave the title compound as a colorless solid.
HR-MS(ESI): m/z=560.2466([MH]+, C28H33F3N5O4 +Calculating the value: 560.2479).
Commercial applicability
The compounds of formula (I), their salts and stereoisomers of the compounds and their salts are hereinafter referred to simply as the compounds which are the subject of the present invention. In particular, the compounds of the subject invention are pharmaceutically acceptable compounds.
The compounds of the subject invention possess valuable pharmaceutical properties which make them commercially available. In particular, as inhibitors of phosphodiesterase type 5 (PDE5), they can affect the physiology of various cells and physiological functions of diseases such as, but not limited to: smooth muscle cells, fibroblasts, myofibroblasts and platelets are involved in a variety of physiological and disease physiological mechanisms. In particular, PDE5 inhibiting compounds, which are the subject of the present invention, may influence the relaxation of the vascular system, thereby increasing blood flow, improving the spatial balance between blood perfusion and oxygen supply in the lungs ("re-matching" effect), thereby reducing the number of so-called low V/Q-regions [ regions of high perfusion (Q) but no or reduced oxygen supply (V) and high V/Q-regions (regions of low perfusion but high oxygen supply) in the lungs ], inducing neurogenesis, inhibiting platelet functions such as aggregation, adhesion and mediator release, and thereby having an anti-inflammatory effect. The compounds of the subject invention are notable for valuable and desirable properties, e.g., high potency, low toxicity, generally superior bioavailability (e.g., good enteral absorption), superior therapeutic window, superior pharmacokinetics (e.g., half-life), absence of significant side effects and other beneficial effects associated with their therapeutic and pharmaceutical suitability.
Accordingly, the present subject matter further relates to compounds of the present subject matter for the treatment or prevention of diseases, in particular diseases which can be alleviated by inhibition of phosphodiesterase type 5. In particular, the present subject matter relates to compounds of the present subject matter for the treatment or prevention of the following diseases:
male and female sexual dysfunction such as, but not limited to: male erectile dysfunction, premature ejaculation, Peyronie's disease;
acute and chronic respiratory diseases such as, but not limited to: COPD (chronic obstructive pulmonary disease), bronchitis, emphysema, pulmonary vascular remodeling, pulmonary arterial hypertension (pulmony hypertension), pulmonary fibrosis, Idiopathic Pulmonary Fibrosis (IPF), asthma, cystic fibrosis, bronchiectasis, bronchiolitis obliterans, connective tissue disease, sarcoidosis, scoliosis, pneumoconiosis, amyotrophic lateral sclerosis, thoracoplasty, exogenous allergic alveolitis;
inflammatory diseases such as, but not limited to: inflammation of the vascular system, acute dyspnea syndrome, nephritis, mesangial glomerulonephritis, chronic inflammatory bowel disease, inflammation in the spreading blood vessels, allergic vasculitis, skin disorders (such as, but not limited to: psoriasis, toxic and allergic contact dermatitis, disseminated neurodermatitis, seborrhoeic eczema, lichen simplex, sunburn, pruritus ani and genital areas, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and epidemic pyoderma, endogenous and exogenous acne, rosacea), disorders of the arthritis type (such as, but not limited to: rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis), disorders of the immune system [ such as, but not limited to: AIDS (AIDS), multiple sclerosis ], graft-versus-host reactions, allograft rejection, shock [ such as but not limited to: septic shock, endotoxic shock, gram-negative septic shock, toxic shock syndrome and ARDS (adult respiratory distress syndrome) ], gastrointestinal inflammation (such as, but not limited to: Crohn's disease and ulcerative colitis); based on allergic and/or chronic conditions, immune pseudo-reactions (such as, but not limited to, allergic rhinitis, allergic sinusitis, chronic rhinitis, chronic sinusitis, allergic conjunctivitis, nasal polyps);
Pain, such as but not limited to: inflammatory pain;
right heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia;
ischemic diseases such as, but not limited to: diabetes, stroke, coronary artery disease, angina (including but not limited to vasospastic angina), myocardial infarction, peripheral artery disease, cerebrovascular occlusion, sleep apnea, macular ischemia, arterial and venous occlusion, congestive heart failure;
diabetic gastroparesis and diseases with gastroparesis symptoms;
diseases or conditions where inhibition of platelet function is desired, such as, but not limited to: after stent implantation (such as but not limited to coronary stent), after shortcut surgery, in pulmonary hypertension (pulmonary hypertension), thrombotic diseases, stenosis after angioplasty, coronary artery disease, infarction (such as but not limited to myocardial infarction), unstable angina, stroke and arterial and venous occlusion diseases (such as but not limited to intermittent claudication);
diseases or disorders with defects or dysfunction of cerebral vascular reactivity and/or neurovascular junctions, such as, but not limited to: arteriosclerotic dementia, multi-infarct dementia, cerebral aging;
Diseases based on neuronal damage or degeneration such as, but not limited to: stroke, spinal cord injury, brain injury, parkinson's disease, amyotrophic lateral sclerosis, alzheimer's disease, amyloidosis, prion disease and neuropathy;
peripheral arterial disease, chronic renal failure, chronic heart failure, sepsis, senile dementia (alzheimer's disease), Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes-related encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, parkinson's disease, multiple sclerosis and preeclampsia;
portal hypertension, cirrhosis, toxic liver injury (such as, but not limited to, alcohol-induced liver injury), hepatitis, portal thrombosis, hepatic vein occlusion syndrome, hepatic vein malformations, hepatic vein constriction (such as, but not limited to, hepatic vein constriction due to tumors), arteriovenous fistulas, diseases associated with splenomegaly, schistosomiasis (Schistosoma disease), sarcoidosis and other granulomatous diseases, Charcot liver cirrhosis, myeloproliferative disorders (such as, but not limited to, chronic myelogenous leukemia, myelofibroma), diseases of the lymphatic system, collagen diseases (such as, but not limited to, systemic lupus erythematosus, scleroderma), telangiectasia (congenital arteriovenous malformations, particularly in the liver), nodular hyperplasia, tricuspid insufficiency, constrictive pericarditis, Venous Occlusive Disease (VOD), nonalcoholic steatohepatitis (NASH), liver fibrosis;
Benign prostatic hyperplasia;
during pregnancy, the blood flow of uterus and placenta is insufficient, and the growth of a fetus is limited;
brain skills are inadequate, such as but not limited to: verbal skills, attention, concentration, deductive thinking, central auditory process, cognitive ability, learning, alertness, comprehension and responsiveness;
overactive bladder; LUTS = lower urinary tract symptoms; raynaud's syndrome/phenomenon.
In this respect, the term "pulmonary arterial hypertension" includes in particular:
pulmonary arterial hypertension (pulmonary arterial hypertension) includes (e.g. episodic or familial arterial hypertension), and pulmonary arterial hypertension (pulmonary arterial hypertension) relates to, for example but not limited to: collagen vascular disease, congenital body-lung shunt, portal hypertension, HIV infection, drugs or toxins (such as, but not limited to: anorexigens), persistent pulmonary hypertension of the newborn (pulmony hypertension);
pulmonary venous hypertension is due to, for example but not limited to, the following reasons: heart disease of the left atrium or ventricle, left valvular heart disease, extramural compression of the central pulmonary vein (e.g., fibrositis mediastinitis, tumor-related adenopathy), pulmonary vein occlusive disease;
Pulmonary arterial hypertension (pulmonary hypertension) associated with respiratory or hypoxic conditions includes, for example but not limited to: chronic Obstructive Pulmonary Disease (COPD), interstitial lung disease, sleep disordered breathing, alveolar hypoventilation disorder, chronic plateau hypoxic exposure, neonatal lung disease, alveolar-capillary dysplasia;
pulmonary hypertension (pulmonary hypertension) caused by chronic thrombosis or thrombotic diseases comprises: the occlusion of thromboembolic proximal and distal pulmonary arteries, such as pulmonary embolism (due to thrombus mass, tumors, eggs, parasites or foreign matter), orthotopic thrombosis and sickle cell disease, especially chronic thromboembolic pulmonary hypertension (CTEPH);
pulmonary arterial hypertension (pulmony hypertension) caused by disorders directly affecting the pulmonary vasculature comprises: inflammatory disorders (such as, but not limited to, schistosomiasis, sarcoidosis) and pulmonary capillary hemangiomas.
Preferably, the subject matter of the invention further relates to compounds of the subject matter of the invention for the treatment or prophylaxis of acute and chronic respiratory diseases, such as pulmonary arterial hypertension (pulmony hypertension), in particular chronic thromboembolic pulmonary hypertension (pulmony hypertension), pulmonary fibrosis, sarcoidosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease, in particular diseases which can be alleviated by inhibition of phosphodiesterase type 5.
In addition to inhibiting phosphodiesterase type 5, some of the compounds of the inventive subject matter are also substantially active in inhibiting phosphodiesterase type 4 and thus have valuable pharmaceutical properties that make them commercially available.
PDE4 inhibitors are believed to be effective for the treatment or prevention of various diseases and disorders. On the one hand, they are considered suitable as bronchial treatments (for the treatment of airway obstruction due to their dilating action and to their respiratory rate or respiratory drive increasing action) and for the elimination of erectile dysfunction (due to their vasodilating action), but on the other hand, in particular for the treatment of disorders of an inflammatory nature, such as, for example, respiratory tract disorders, skin disorders, intestinal tract disorders, eye disorders, CNS and joint disorders, which are mediated by the following mediators: for example, histamine, PAF (platelet activating factor), arachidonic acid derivatives such as leukotrienes and prostaglandins, cytokines, interleukins, chemokines, alpha-, beta-and gamma-interferons, Tumor Necrosis Factor (TNF) or oxygen free radicals and proteases.
Thus, PDE4 inhibitors are believed to be effective in the treatment or prevention of various diseases and disorders, such as
Acute and chronic respiratory diseases such as, but not limited to: bronchitis, allergic bronchitis, asthma, emphysema, COPD (chronic obstructive pulmonary disease), sarcoidosis, pulmonary hypertension (pulmony hypertension) and pulmonary fibrosis;
immune pseudo-reactions in the upper respiratory tract region (pharynx, nose) and adjacent regions (paranasal sinuses, eyes) based on allergic and/or chronic diseases, such as, but not limited to: allergic rhinitis/sinusitis, chronic rhinitis/sinusitis, allergic conjunctivitis, and nasal polyps;
skin diseases, in particular of the proliferative, inflammatory and allergic type, such as, but not limited to: psoriasis (vulgaris type), toxic and allergic contact dermatitis, atopic dermatitis (eczema), seborrheic eczema, lichen simplex, sunburn, pruritus in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and epidemic pyoderma, endogenous and exogenous acne, rosacea and other proliferative, inflammatory and allergic skin disorders;
diseases based on the excessive release of TNF and leukotrienes, for example, diseases of the arthritis type, such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions;
Fibrotic diseases such as, but not limited to: cystic fibrosis, lung fibrosis, liver fibrosis and kidney fibrosis;
viral, alcohol or drug induced acute and fulminant hepatitis, hepatic lipidosis (alcoholic and non-alcoholic fatty (steato) -hepatitis);
diseases of the immune system such as, but not limited to: AIDS, multiple sclerosis, graft-versus-host reaction, allograft rejection;
cachexia, cancer cachexia, AIDS cachexia;
shock types such as, but not limited to: septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome and ARDS (adult respiratory distress syndrome);
diseases of the gastrointestinal region, e.g., Crohn's disease and ulcerative colitis;
cardiac diseases that can be treated with PDE inhibitors, such as cardiac insufficiency;
diseases that can be treated based on the tissue relaxation effect of PDE inhibitors, for example, erectile dysfunction, renal colic associated with kidney stones and ureteral colic or oncolytic effects (treatment of premature delivery); glomerulonephritis and other urinary tract infections;
diabetes insipidus, diabetes mellitus (type I and especially type II); cancer (particularly lymphoid and spinal cord blood cancers); osteoporosis;
Disorders associated with inhibition of cerebral metabolism, such as, but not limited to: cerebral aging, senile dementia (alzheimer's disease), memory impairment associated with parkinson's disease or multi-infarct dementia;
and central nervous system diseases such as, but not limited to: depression, anxiety states, spinal cord injury, schizophrenia or arteriosclerotic dementia;
preferably, the inhibitors of phosphodiesterase type 4 are used for the treatment or prevention of the following diseases
Acute and chronic respiratory diseases, such as bronchitis, allergic bronchitis, asthma, emphysema, COPD, pulmonary hypertension (pulmony hypertension) and pulmonary fibrosis;
allergic rhinitis;
and skin diseases such as psoriasis and atopic dermatitis (eczema);
rheumatoid arthritis;
and inflammation of the gastrointestinal region, such as Crohn's disease and ulcerative colitis.
It is noteworthy that the compounds of the subject invention mentioned herein, which are inhibitors of phosphodiesterase type 5 (PDE5) and phosphodiesterase type 4 (PDE4), as dual inhibitors of phosphodiesterase type 4/5, like inhibitors of phosphodiesterase type 5 and/or phosphodiesterase type 4, are useful for the treatment or prevention of the above mentioned diseases. Dual phosphodiesterase type 4/5 inhibitors have the potential to be more effective in treating different diseases than compounds that inhibit only one of these two enzymes, since inhibition of PDE4 and PDE5 can address various (divers) and different pathophysiology present within one disease (e.g., pulmonary fibrosis). With respect to pulmonary fibrosis, it has been described that inhibitors of phosphodiesterase type 4 can inhibit TGF- β induced lung fibroblast transition to myofibroblasts (Dunkern et al, eur. j. pharmacol, 572 (1): 12-22, 2007), which is a marker for the development of fibrosis. They are further described as inhibiting the production of matrix metalloproteinases by lung fibroblasts (Martin-Chouy CA et al, Life Sci.75 (7): 823-40, 2004) and preventing chemotaxis of these cells (Kohyama T et al, Am. J. respir. Cell mol. biol., 26 (6): 694-701, 2002), an important disease physiological aspect of pulmonary fibrosis. In addition, the selective phosphodiesterase type 4 inhibitor roflumilast also inhibits the development of fibrosis in vivo in a bleomycin-induced pulmonary fibrosis mouse model (Cortijo J et al, Br. J pharmacol, 156 (3): 534-44, 2009).
On the other hand, with respect to pulmonary fibrosis, PDE5 inhibition by the selective PDE5 inhibitor sildenafil has been shown to reduce bleomycin-induced pulmonary fibrosis and pulmonary arterial hypertension (pulmony hypertension) by inhibiting ROS production and RhoA/Rho kinase activation (Hemnes AR, zaimaman a, Champion HC, Am. j. physiol. Lung cell. mol. physiol. 2008. 1 month; 294(1): L24-33. Epub 2007 10 month 26), and in the clinical human open-label experiment (open-label trials) sildenafil has been shown to improve pulmonary hemodynamics (vascular resistance and oxygen supply/perfusion match) and exercise tolerance in patients with pulmonary fibrosis (Ghofrani et al, Lancet 360, 895-900, 2002; collad et al, Chest 131, 897, 2007-2007).
As noted above, the inventive subject matter also includes dual type 4/5 phosphodiesterase inhibitors in addition to type 5 phosphodiesterase inhibitors. In the context of the present application, preferred dual phosphodiesterase type 4/5 inhibitors have a higher-logIC than 6.0 inhibiting PDE450(mol/l), and a higher-logIC than 8.0 inhibiting PDE550(mol/l). More preferred dual phosphodiesterase type 4/5 inhibitors have a higher-logIC than 7.0 inhibiting PDE4 50(mol/l), and a higher-logIC than 8.0 inhibiting PDE550(mol/l)。
Preferably, the subject matter of the invention relates to compounds of the subject matter of the invention for the treatment or prevention of diseases, in particular of diseases which can be alleviated by the inhibition of dual type 4/5 phosphodiesterase
Pulmonary fibrosis, such as idiopathic pulmonary fibrosis, pulmonary hypertension are pulmonary hypertension, COPD, asthma, bronchitis, emphysema, nephritis such as proliferative glomerulonephritis, liver fibrosis, sarcoidosis, fibrotic disorders in general, such as myelofibrosis, retroperitoneal fibrosis, endocardial myocardial fibrosis, fibrosis of mediastinum, nephrogenic systemic fibrosis, hypertrophic scarring and toxic liver injury, respectively.
The subject of the invention is also the use of the compounds of the subject of the invention for the preparation of pharmaceutical compositions capable of inhibiting phosphodiesterase type 5, in particular for the treatment or prevention of diseases which can be alleviated by the inhibition of phosphodiesterase type 5, preferably for the treatment or prevention of the diseases exemplified above.
The subject of the invention is also the use of the compounds of the subject of the invention for the preparation of a pharmaceutical composition capable of inhibiting dual type 4/5 phosphodiesterase, in particular for the treatment or prevention of a disease which can be alleviated by the inhibition of dual type 4/5 phosphodiesterase, preferably for the treatment or prevention of the above-exemplified diseases.
Preferably, the subject of the present invention relates to the use of the compounds of the subject of the present invention for the preparation of a pharmaceutical composition for the treatment or prevention of acute or chronic respiratory diseases, such as, but not limited to: pulmonary hypertension (pulmonary hypertension), pulmonary fibrosis, sarcoidosis, asthma, bronchitis, emphysema, and chronic obstructive pulmonary disease.
Preferably, the subject of the present invention relates to the use of the compounds of the subject of the present invention for the preparation of a pharmaceutical composition for the treatment or prevention of acute or chronic respiratory diseases, such as, but not limited to: pulmonary hypertension, pulmonary arterial hypertension, pulmonary fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, asthma, bronchitis, emphysema, and chronic obstructive pulmonary disease.
In a particularly preferred embodiment of the subject of the present invention, the subject of the present invention relates to the use of the compounds of the above examples for the preparation of a pharmaceutical composition for the treatment or prevention of acute or chronic respiratory diseases, such as, but not limited to: pulmonary hypertension (pulmonary hypertension), pulmonary fibrosis, sarcoidosis, asthma, bronchitis, emphysema, and chronic obstructive pulmonary disease.
In a particularly preferred embodiment of the subject of the present invention, the subject of the present invention relates to the use of the compounds of the above examples for the preparation of a pharmaceutical composition for the treatment or prevention of acute or chronic respiratory diseases, such as, but not limited to: pulmonary hypertension, pulmonary arterial hypertension, pulmonary fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, asthma, bronchitis, emphysema, and chronic obstructive pulmonary disease.
The present subject matter further relates to methods of treating or preventing a disease, comprising: administering to a patient in need thereof a therapeutically effective amount of at least one compound of the inventive subject matter.
In particular, the subject of the invention relates to a method for the treatment or prevention of one of the above-mentioned diseases, which comprises: administering to a patient in need thereof a therapeutically effective amount of at least one compound of the inventive subject matter.
In particular, the present subject matter relates to methods of treating or preventing a disease that can be alleviated by inhibition of phosphodiesterase type 5, comprising: administering to a patient in need thereof a therapeutically effective amount of at least one compound of the inventive subject matter.
The present subject matter further relates to methods of treating or preventing a disease that can be alleviated by inhibition of dual type 4/5 phosphodiesterase comprising: administering to a patient in need thereof a therapeutically effective amount of at least one compound of the inventive subject matter.
Preferably, the inventive subject matter relates to a method of treating or preventing acute or chronic respiratory diseases (such as, but not limited to: pulmonary hypertension, pulmonary fibrosis, sarcoidosis, asthma, bronchitis, emphysema, and chronic obstructive pulmonary disease), the method comprising: administering to a patient in need thereof a therapeutically effective amount of at least one compound of the inventive subject matter.
Preferably, the inventive subject matter relates to a method of treating or preventing acute or chronic respiratory diseases (such as, but not limited to, pulmonary hypertension, pulmonary arterial hypertension, pulmonary fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, asthma, bronchitis, emphysema, and chronic obstructive pulmonary disease), the method comprising: administering to a patient in need thereof a therapeutically effective amount of at least one compound of the inventive subject matter.
In the above method, preferably the patient is a mammal, more preferably a human. Furthermore, in the above-mentioned process, at least one compound of the subject matter of the invention can be used. Preferably, one or two compounds of the subject invention are used, more preferably, one compound of the subject invention is used.
In a particularly preferred embodiment of the subject of the invention, the above-mentioned method of treating or preventing one of the above-mentioned diseases comprises: administering to a patient in need thereof a therapeutically effective amount of a compound according to an embodiment of the inventive subject matter.
Furthermore, the subject matter of the present invention relates to pharmaceutical compositions comprising at least one compound of the subject matter of the present invention and at least one pharmaceutically acceptable auxiliary.
The subject of the invention is furthermore a pharmaceutical composition for the treatment or prophylaxis of acute or chronic respiratory diseases, in particular for the treatment or prophylaxis of pulmonary hypertension, pulmonary fibrosis, sarcoidosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
The subject of the invention furthermore relates to pharmaceutical compositions for the treatment or prophylaxis of acute or chronic respiratory diseases, in particular for the treatment or prophylaxis of pulmonary hypertension (pulmony hypertension), pulmonary hypertension (pulmony arterial hypertension), pulmonary fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
Preferably, the pharmaceutical composition comprises one or two compounds of the inventive subject matter. More preferably, the pharmaceutical composition comprises one compound of the inventive subject matter.
In a particularly preferred embodiment of the subject matter of the present invention, the pharmaceutical composition comprises a compound according to the examples of the subject matter of the present invention and at least one pharmaceutically acceptable auxiliary.
The subject of the invention is furthermore a pharmaceutical composition comprising at least one compound of the subject of the invention, at least one pharmaceutically acceptable auxiliary and at least one therapeutic agent selected from: corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, phosphodiesterase type 4 inhibitors, guanylate cyclase activators/activators, pirfenidone (pirfenidone), antidepressants, antibiotics, anticoagulants, diuretics, and digitosides.
In this regard, therapeutic agents include free compound forms of the corticosteroid, anticholinergic agents, beta-mimetics, pulmonary surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, phosphodiesterase type 4 inhibitors, guanylate cyclase activator/activator, pirfenidone (pirfenidone), antidepressants, antibiotics, anticoagulants, diuretics, and digitosides, pharmaceutically acceptable salts thereof, pharmaceutically acceptable derivatives thereof (such as, but not limited to, ester derivatives), solvates thereof, and stereoisomers of the compounds, salts, derivatives, and solvates.
Co-administration of at least one compound of the inventive subject matter with at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, phosphodiesterase type 4 inhibitors, guanylate cyclase activators/activators, pirfenidone (pirfenidone), antidepressants, antibiotics, anticoagulants, diuretics, and digitosides can be carried out in the form of a fixed composition, a non-fixed composition, or a kit of parts.
"fixed composition" is defined as: the compounds and therapeutic agents of the presently disclosed subject matter are intended to be co-administered in a composition that is presented in one dosage unit or a single unit. An example of a fixed composition is a pharmaceutical composition in which the compound of the inventive subject matter and the therapeutic agent are present in a mixture that is administered simultaneously. Another example of a fixed composition is a pharmaceutical composition in which the compound of the inventive subject matter and the therapeutic compound are present in one dosage unit without mixing.
"non-fixed composition" or "kit of parts" is defined as: the compounds and therapeutic agents of the present subject matter are compositions that are present in more than one dosage unit. The compounds of the subject invention and the therapeutic agents are provided in separate formulations in a kit of parts or non-fixed compositions. They may be packaged and provided together in separate components of a packaged composition for simultaneous, sequential or separate use in combination therapy. Preferably, the compound and therapeutic agent of the presently disclosed subject matter are administered simultaneously or sequentially. Where the compound of the inventive subject matter and the therapeutic agent are administered sequentially or separately, the compound of the inventive subject matter may be administered before or after the therapeutic agent.
Where the compound of the inventive subject matter and the therapeutic agent are administered sequentially or separately, the compound of the inventive subject matter may be administered before or after the therapeutic agent.
Sequential administration includes a short period of time between administration of a compound of the inventive subject matter and a therapeutic agent, or vice versa (e.g., the time required to swallow one tablet followed by the other tablet).
Separate administration includes a longer period of time between administration of the compound of the inventive subject matter and the therapeutic agent. In preferred embodiments of the inventive subject matter, the compounds of the inventive subject matter are administered while the therapeutic agent still has a therapeutic effect on the patient being treated (or vice versa).
The type of formulation of the compound of the subject invention and the therapeutic agent in the non-fixed composition or kit of parts may be the same, i.e., both the compound of the subject invention and the therapeutic agent are formulated, for example, as powders, solutions or suspensions suitable for administration by inhalation, or may be different, i.e., suitable for different forms of administration, e.g., the compound of the subject invention is formulated as a powder, solution or suspension suitable for administration by inhalation, while the therapeutic agent is formulated as an oral tablet or capsule.
Accordingly, the subject matter of the present invention also relates to a pharmaceutical composition provided in the form of a fixed composition, a non-fixed composition or a kit of parts comprising at least one compound of the subject matter of the present invention, at least one therapeutic agent selected from the group consisting of: corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, phosphodiesterase type 4 inhibitors, guanylate cyclase activators/activators, pirfenidone (pirfenidone), antidepressants, antibiotics, anticoagulants, diuretics, and digitosides.
Examples of corticosteroids include, but are not limited to: budesonide, fluticasone such as fluticasone propionate, beclomethasone such as beclomethasone propionate, fluorohydroxydehydrocortisol such as triamcinolone acetonide, mometasone and ciclesonide. Examples of anticholinergics include, but are not limited to: tiotropium, such as tiotropium bromide, and ipratropium, such as ipratropium bromide, aclidinium sucg, such as aclidinium bromide, glycopyrronium, such as glycopyrronium bromide. Examples of β -mimetics include, but are not limited to: indacaterol (indacaterol), formoterol, e.g. formoterol fumarate, and salmeterol, e.g. salmeterol xinafoate, salbutamol, milveterol, carmoterol (carmoterol). Examples of pulmonary surfactants include, but are not limited to: rushulpeptide (lusupultide), porcine lung phospholipid (poractant alfa), sinapultide (sinapultide), beracantan (beractant), bovactant, colfosciri auch, e.g. palmityl choline, surfactant-TA and calfantan (calfantant). Examples of endothelin antagonists include, but are not limited to: bosentan, ambrisentan (ambrisentan), atrasentan (atrasentan), darussan (daruentan), clatansan (clazosentan), avosentan (avosentan) and stasentan (sitaxsentan), for example sodium stasentan (sitaxsentan). Examples of prostacyclanes include, but are not limited to: iloprost (iloprost), such as iloprost (iloprost) tromethamine, epoprostenol, such as epoprostenol sodium, and treprostinil, such as treprostinil sodium. Examples of calcium channel blockers include, but are not limited to: amlodipine, e.g. amlodipine besylate and amlodipine maleate, nifedipine, diltiazem E.g. diltiazem hydrochlorideVerapamil, such as verapamil hydrochloride, and felodipine. Examples of beta-blockers include, but are not limited to: bisoprolol, such as bisoprolol fumarate, nebivolol (nebivolol), metoprolol, such as metoprolol succinate and metoprolol tartrate, carvedilol, atenolol and propranolol. Examples of type 4 phosphodiesterase inhibitors include, but are not limited to: roflumilast, roflumilast N-oxide, cilomilast (cilomilast), tetomilast (tetomilast), apleside (apremilast) and oglemilast. Examples of antidepressants include, but are not limited to: bupropion, such as bupropion hydrochloride. Examples of antibiotics include, but are not limited to: amoxicillin, ampicillin, levofloxacin, clarithromycin and ciprofloxacinSuch as ciprofloxacin hydrochloride, telithromycin (telithromycin) and azithromycin. Examples of anticoagulants include, but are not limited to: clopidogrel, enoxaparin, cilostazol, nadroparin, warfarin and abciximab. Examples of diuretics include, but are not limited to: furosemide, bumetanide and torasemide (torsemide). Examples of digitonin include, but are not limited to: digoxin and digitoxin. Examples of guanylate cyclase activators/activators include, but are not limited to: BAY63-2521(Riociguat) and Ataciguat (Ataciguat).
In another embodiment, the aforementioned kit of parts, fixed composition or non-fixed composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an embodiment of the inventive subject matter or a pharmaceutically acceptable salt thereof), a corticosteroid, and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds and budesonide that are the subject of the present invention,
the compounds of the subject invention and fluticasone,
the compounds of the subject invention and beclomethasone,
the compounds of the subject invention and mometasone,
the compounds which are the subject of the invention and triamcinolone acetonide, or
The compounds and ciclesonide which are the subject of the present invention,
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, the pharmaceutically acceptable derivative of fluticasone is fluticasone-17-propionate. In another embodiment, the pharmaceutically acceptable derivative of beclomethasone is beclomethasone 17, 21-dipropionate. In another embodiment, the pharmaceutically acceptable derivative of mometasone is mometasone furoate.
In another embodiment, the aforementioned kit of parts, fixed composition or non-fixed composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an embodiment of the inventive subject matter or a pharmaceutically acceptable salt thereof), an anticholinergic, and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds which are the subject of the present invention and glycopyrronium bromide,
the compounds which are the subject of the present invention and aclidinium bromide,
the compounds which are the subject of the invention and tiotropium bromide, or
The compounds that are the subject of the present invention and ipratropium bromide,
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, the stereoisomer of glycopyrronium bromide is (R, R) -glycopyrronium bromide. In another embodiment, tiotropium bromide in the form of a monohydrate is used.
In another embodiment, the aforementioned fixed composition, non-fixed composition or kit of parts comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an example of the inventive subject matter or a pharmaceutically acceptable salt thereof), a β -mimetic, and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds which are the subject of the invention and salbutamol,
the compounds of the subject invention and milliterol,
the compounds which are the subject of the invention and indacaterol (indacaterol),
the compounds which are the subject of the invention and carmoterol (carmoterol),
the compounds which are the subject of the present invention and salmeterol,
The compounds which are the subject of the invention and formoterol,
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, the pharmaceutically acceptable salt of salbutamol is salbutamol sulfate. In another embodiment, the pharmaceutically acceptable salt of milveterol is milveterol hydrochloride. In another embodiment, the pharmaceutically acceptable salt of carmoterol (carmoterol) is carmoterol (carmoterol) hydrochloride. In another embodiment, the pharmaceutically acceptable salt of salmeterol is salmeterol xinafoate. In another embodiment, the pharmaceutically acceptable salt of formoterol is formoterol hemifumarate monohydrate. In another embodiment, the stereoisomer of formoterol is R, R-formoterol. In another embodiment, the pharmaceutically acceptable salt of R, R-formoterol is R, R-formoterol L-tartrate.
Preferably, the beta-mimetic is a long-acting beta-mimetic; in this regard, especially those β -mimetics that have a therapeutic effect over a period of 12-24 hours.
In another embodiment, the aforementioned kit of parts, fixed composition or non-fixed composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an example of the inventive subject matter), a pulmonary surfactant and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds and russulide (lusupultide) which are the subject of the present invention,
the compounds of the present subject matter and porcine lung phospholipid (poracan alfa),
the compounds which are the subject of the invention and the sinapultide,
the compounds of the subject invention and beractan (beracant),
the compounds and bovacants of the present subject matter,
the compounds subject of the invention and palm gall bladder phosphorus,
the compounds and surfactants of the subject invention-TA, or
The compounds which are the subject of the invention and calfant (calfanat),
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, the aforementioned fixed composition, non-fixed composition or kit of parts comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an embodiment of the inventive subject matter or a pharmaceutically acceptable salt thereof), an endothelin antagonist, and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds and bosentan, which are the subject of the present invention,
the compounds of the subject invention and ambrisentan (ambrisentan),
the compounds which are the subject of the present invention and atrasentan (atrasentan),
The compounds which are the subject of the present invention and darussentan (darusentan),
the compounds which are the subject of the invention and clavansentan (clavansan), or
The compounds of the subject invention and avosentan (avosentan),
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, bosentan in monohydrate form is used. In another embodiment, the pharmaceutically acceptable salt of clarithrosentan (clazosentan) is the disodium salt of clarithrosentan (clazosentan). In another embodiment, the pharmaceutically acceptable salt of atrasentan (atrasentan) is atrasentan (atrasentan) hydrochloride or atrasentan (atrasentan) sodium salt. In another embodiment, the R-enantiomer of atrasentan (atrasentan) is used. In another embodiment, the S-enantiomer of darussentan (daruentan) is used.
In another embodiment, the aforementioned kit of parts, fixed composition or non-fixed composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an embodiment of the inventive subject matter or a pharmaceutically acceptable salt thereof), a prostacyclin and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds which are the subject of the present invention and iloprost (iloprost),
the compounds which are the subject of the present invention and epoprostenol,
the compounds and triprostinil which are the subject of the invention,
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, the aforementioned kit of parts, fixed composition or non-fixed composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an embodiment of the inventive subject matter or a pharmaceutically acceptable salt thereof), a calcium channel blocker and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds which are the subject of the present invention and amlodipine,
the compounds which are the subject of the present invention and nifedipine,
compounds and diltiazem subject of the invention，
The compounds which are the subject of the invention and verapamil, or
The compounds of the subject invention and felodipine,
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, the aforementioned kit of parts, fixed composition or non-fixed composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an embodiment of the inventive subject matter or a pharmaceutically acceptable salt thereof), a beta-blocker, and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds of the subject of the invention and bisoprolol,
the compounds of the subject invention and nebivolol (nebivolol),
the compounds of the subject invention and metoprolol,
the compounds of the subject invention and carvedilol,
the compounds of the subject invention and atenolol, or
The compounds which are the subject of the invention and nafarel,
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, the aforementioned fixed composition, non-fixed composition or kit of parts comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an embodiment of the inventive subject matter or a pharmaceutically acceptable salt thereof), a phosphodiesterase type 4 inhibitor and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds which are the subject of the invention and roflumilast,
the compounds which are the subject of the invention and roflumilast N-oxide,
the compounds which are the subject of the invention and cilomilast (cilomilast),
the compounds which are the subject of the invention and tetomilast (tetomilast),
the compounds which are the subject of the invention and apremilast, or
The compounds and oglemilast, which are the subject of the present invention,
And at least one pharmaceutically acceptable auxiliary.
In another embodiment, the aforementioned kit of parts, fixed composition or non-fixed composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an example of the inventive subject matter or a pharmaceutically acceptable salt thereof), an antidepressant and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds and bupropion subject of the present invention,
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, the aforementioned kit of parts, fixed composition or non-fixed composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an example of the inventive subject matter or a pharmaceutically acceptable salt thereof), an antibiotic and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds which are the subject of the present invention and amoxicillin,
the compounds which are the subject of the present invention and ampicillin,
the compounds which are the subject of the present invention and levofloxacin,
The compounds that are the subject of the present invention and clarithromycin,
the compounds that are the subject of the present invention and ciprofloxacin,
the compounds which are the subject of the invention and telithromycin (telithromycin), or
The compounds and azithromycin that are the subject of the invention,
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, amoxicillin is used in the form of a trihydrate. In another embodiment, ampicillin is used in the form of a trihydrate. In another embodiment, the pharmaceutically acceptable salt of ampicillin is ampicillin sodium. In another embodiment, levofloxacin is used in the hemihydrate form. In another embodiment, the pharmaceutically acceptable salt of ciprofloxacin is ciprofloxacin hydrochloride monohydrate. In another embodiment, the azithromycin is used in the form of a monohydrate.
In another embodiment, the aforementioned kit of parts, fixed composition or non-fixed composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an embodiment of the inventive subject matter or a pharmaceutically acceptable salt thereof), an anticoagulant, and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds which are the subject of the present invention and clopidogrel,
the compounds of the subject invention and enoxaparin,
the compounds which are the subject of the present invention and cilostazol,
the compounds which are the subject of the invention and nadroparin (nadroparin),
the compounds of the subject invention and warfarin, or
The compounds and abciximab, which are the subject of the present invention,
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, the aforementioned kit of parts, fixed composition or non-fixed composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an embodiment of the inventive subject matter or a pharmaceutically acceptable salt thereof), a diuretic and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds and the furosemide subject of the invention,
the compounds which are the subject of the invention and bumetanide, or
The compounds of the present subject matter and torasemide (torsemide),
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, the aforementioned kit of parts, fixed composition or non-fixed composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an embodiment of the inventive subject matter or a pharmaceutically acceptable salt thereof), digitonin and at least one pharmaceutically acceptable auxiliary. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds which are the subject of the invention and digoxin, or
The compounds and digitoxin of the subject of the invention,
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, the aforementioned kit of parts, fixed composition or non-fixed composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an embodiment of the inventive subject matter or a pharmaceutically acceptable salt thereof), a corticosteroid, a β -mimetic, and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds, budesonide and salbutamol, which are the subject of the present invention,
the compounds of the subject invention, budesonide and milveterol,
the compounds which are the subject of the invention, budesonide and indacaterol (indacaterol),
the compounds which are the subject of the invention, budesonide and carmoterol (carmoterol),
the compounds, budesonide and salmeterol, which are the subject of the present invention,
the compounds, budesonide and formoterol, which are the subject of the present invention,
the compounds, subject of the invention, fluticasone and salbutamol,
the compounds of the subject invention, fluticasone and milliterol,
The compounds which are the subject of the invention, fluticasone and indacaterol (indacaterol),
the compounds which are the subject of the invention, fluticasone and carmoterol (carmoterol),
the compounds, fluticasone and salmeterol, which are the subject of the present invention,
the compounds, fluticasone and formoterol, which are the subject of the present invention,
the compounds, beclomethasone and salbutamol, which are the subject of the present invention,
the compounds of the subject invention, beclomethasone and milveterol,
the compounds which are the subject of the invention, beclomethasone and indacaterol (indacaterol),
the compounds which are the subject of the invention, beclomethasone and carmoterol (carmoterol),
the compounds, beclomethasone and salmeterol, which are the subject of the present invention,
the compounds, beclomethasone and formoterol, which are the subject of the present invention,
the compounds, mometasone and salbutamol, which are the subject of the present invention,
the compounds which are the subject of the invention, mometasone and milveterol,
the compounds which are the subject of the invention, mometasone and indacaterol (indacaterol),
the compounds which are the subject of the invention, mometasone and carmoterol (carmoterol),
the compounds, mometasone and salmeterol, which are the subject of the present invention,
the compounds, mometasone and formoterol, which are the subject of the present invention,
The compounds which are the subject of the invention, triamcinolone acetonide and salbutamol,
the compounds which are the subject of the invention, triamcinolone acetonide and milveteol,
the compounds which are the subject of the invention, triamcinolone acetonide (triamcinolone acetonide) and indacaterol (indacaterol),
the compounds which are the subject of the invention, triamcinolone acetonide (triamcinolone acetonide) and carmoterol (carmoterol),
the compounds which are the subject of the invention, triamcinolone acetonide and salmeterol,
the compounds which are the subject of the invention, triamcinolone acetonide and formoterol,
the compounds, ciclesonide and salbutamol, which are the subject of the present invention,
the compounds of the subject invention, ciclesonide and milveterol,
the compounds which are the subject of the invention, ciclesonide and indacaterol (indacaterol),
the compounds which are the subject of the invention, ciclesonide and carmoterol (carmoterol),
the compounds which are the subject of the invention, ciclesonide and salmeterol, or
The compounds, ciclesonide and formoterol, which are the subject of the present invention,
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, the aforementioned kit of parts, fixed composition or non-fixed composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an embodiment of the inventive subject matter or a pharmaceutically acceptable salt thereof), a β -mimetic, an anticholinergic, and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds, salbutamol and glycopyrrolate, which are the subject of the present invention,
the compounds which are the subject of the invention, salbutamol and aclidinium bromide,
the compounds, salbutamol and tiotropium bromide, which are the subject of the present invention,
the compounds which are the subject of the invention, salbutamol and ipratropium bromide,
the compounds which are the subject of the invention, milveterol and glycopyrronium bromide,
the compounds which are the subject of the invention, milveterol and aclidinium bromide (aclidinium bromide),
the compounds which are the subject of the invention, milveterol and tiotropium bromide,
the compounds which are the subject of the invention, milveterol and ipratropium bromide,
the compounds which are the subject of the invention, salmeterol and glycopyrrolate,
the compounds which are the subject of the invention, salmeterol and aclidinium bromide,
the compounds, salmeterol and tiotropium bromide, which are the subject of the invention,
the compounds which are the subject of the invention, salmeterol and ipratropium bromide,
the compounds which are the subject of the invention, formoterol and glycopyrronium bromide,
the compounds which are the subject of the invention, formoterol and aclidinium bromide,
the compounds, formoterol and tiotropium bromide, which are the subject of the present invention,
the compounds which are the subject of the invention, formoterol and ipratropium bromide,
The compounds which are the subject of the invention, indacaterol (indacaterol) and glycopyrronium bromide,
the compounds which are the subject of the invention, indacaterol (indacaterol) and aclidinium bromide (aclidinium bromide),
the compounds which are the subject of the invention, indacaterol (indacaterol) and tiotropium bromide,
the compounds which are the subject of the invention, indacaterol (indacaterol) and ipratropium bromide,
the compounds which are the subject of the invention, carmoterol (carmoterol) and glycopyrronium bromide,
the compounds which are the subject of the invention, carmoterol (carmoterol) and aclidinium bromide (aclidinium bromide),
the compounds which are the subject of the invention, carmoterol (carmoterol) and tiotropium bromide, or
The compounds which are the subject of the invention, carmoterol (carmoterol) and ipratropium bromide,
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, the aforementioned kit of parts, fixed composition or non-fixed composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an embodiment of the inventive subject matter or a pharmaceutically acceptable salt thereof), a corticosteroid, an anticholinergic, and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds, budesonide and glycopyrrolate which are the subject of the present invention,
the compounds, budesonide and aclidinium bromide, which are the subject of the present invention,
the compounds, budesonide and tiotropium bromide, which are the subject of the present invention,
the compounds, budesonide and ipratropium bromide, which are the subject of the present invention,
the compounds, fluticasone and glycopyrronium bromide subject of the invention,
the compounds which are the subject of the present invention, fluticasone and aclidinium bromide,
the compounds, subject of the present invention, fluticasone and tiotropium bromide,
the compounds, subject of the present invention, fluticasone and ipratropium bromide,
the compounds, beclomethasone and glycopyrronium bromide, which are the subject of the present invention,
the compounds of the subject invention, beclomethasone and aclidinium bromide,
the compounds, beclomethasone and tiotropium bromide, which are the subject of the invention,
the compounds, beclomethasone and ipratropium bromide, which are the subjects of the present invention,
the compounds, mometasone and glycopyrrolate, which are the subject of the present invention,
the compounds which are the subject of the invention, mometasone and aclidinium bromide,
the compounds which are the subject of the present invention, mometasone and tiotropium bromide,
the compounds which are the subject of the present invention, mometasone and ipratropium bromide,
The compounds which are the subject of the present invention, triamcinolone acetonide and glycopyrrolate,
the compounds which are the subject of the present invention, triamcinolone acetonide and aclidinium bromide,
the compounds which are the subject of the present invention, triamcinolone acetonide and tiotropium bromide,
the compounds which are the subject of the present invention, triamcinolone acetonide and ipratropium bromide,
the compounds, ciclesonide and glycopyrrolate, which are the subject of the present invention,
the compounds, ciclesonide and aclidinium bromide (aclidinium bromide) which are the subject of the present invention,
the compounds, ciclesonide and tiotropium bromide which are the subject of the invention, or
The compounds, ciclesonide and ipratropium bromide, which are the subject of the present invention,
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, the aforementioned kit of parts, non-immobilized composition or composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an embodiment of the inventive subject matter or a pharmaceutically acceptable salt thereof), a guanylate cyclase activator/activator, and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds of the subject invention and BAY63-2521(Riociguat),
the compounds which are the subject of the invention and ataxitt (Ataciguat),
and at least one pharmaceutically acceptable auxiliary.
In another embodiment, the aforementioned kit of parts, fixed composition or non-fixed composition comprises a compound of the inventive subject matter (in particular, a compound of the inventive subject matter is an example of the inventive subject matter or a pharmaceutically acceptable salt thereof), pirfenidone (pirfenidone), and at least one pharmaceutically acceptable adjuvant. In a particularly further embodiment, the kit of parts of the above-described fixed composition, non-fixed composition or fixed composition comprises
The compounds of the subject invention and pirfenidone (pirfenidone),
and at least one pharmaceutically acceptable auxiliary.
The compounds of the above-described subject matter of the invention are preferably the compounds according to the examples.
Furthermore, the subject of the present invention is the above-mentioned pharmaceutical composition according to the subject of the present invention, which inhibits phosphodiesterase type 5, in particular for the treatment or prevention of diseases which can be alleviated by the inhibition of phosphodiesterase type 5, in particular for the treatment or prevention of the diseases exemplified above.
Furthermore, the subject of the present invention is also the above-mentioned pharmaceutical composition according to the subject of the present invention, which inhibits the dual type 4/5 phosphodiesterase, in particular for the treatment or prevention of diseases which can be alleviated by the inhibition of the dual type 4/5 phosphodiesterase, in particular for the treatment or prevention of the diseases exemplified above.
The subject of the invention is also the pharmaceutical compositions according to the subject of the invention described above for the treatment or prevention of acute and chronic respiratory diseases such as pulmonary hypertension, pulmonary fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
Preferably, the pharmaceutical compositions according to the inventive subject matter contain the compounds of the inventive subject matter in a total amount of 0.1 to 99.9 wt.%, more preferably 5 to 95 wt.%, in particular 20 to 80 wt.%. In case at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, phosphodiesterase type 4 inhibitors, guanylate cyclase activator/activator, pirfenidone (pirfenidone), antidepressants, antibiotics, anticoagulants, diuretics and digitosides is present in the pharmaceutical composition of the subject matter of the present invention, the total amount of said therapeutic agent in the pharmaceutical composition is preferably in the range of 0.1 to 99.9 wt%, more preferably 5 to 95wt%, especially 20 to 80wt%, with the proviso that: the total amount of the compound and therapeutic agent of the inventive subject matter is less than 100 wt%. Preferably, the at least one compound of the inventive subject matter and the at least one therapeutic agent are present in the pharmaceutical composition in a weight ratio of 1000: 1 to 1: 1000, more preferably 500: 1 to 1: 500.
As pharmaceutically acceptable auxiliary agents, any known auxiliary agents suitable for the preparation of pharmaceutical compositions may be used. Examples include, but are not limited to: solvents, excipients, dispersants, emulsifiers, solubilizers, gel templating agents, ointment bases, antioxidants, preservatives, stabilizers, carriers, fillers, binders, thickeners, complexing agents, disintegrants, buffers, permeation enhancers, polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, colorants, flavors, sweeteners, and dyes. In particular, the type of adjuvant used is adapted to the desired formulation and the desired mode of administration.
For example, the pharmaceutical compositions may be formulated as tablets, dragees (troches), pills, cachets, capsules (caplets), granules, powders, suppositories, solutions (such as, but not limited to, sterile solutions), emulsions, suspensions, ointments, creams, lotions, pastes, oils, gels, sprays, and patches (such as, but not limited to, transdermal therapeutic systems). In addition, pharmaceutical compositions can be prepared as liposome delivery systems, systems in which the compounds of the inventive subject matter are conjugated to monoclonal antibodies, and systems in which the compounds of the inventive subject matter are conjugated to polymers (such as, but not limited to, dissolvable or biodegradable polymers).
Where a pharmaceutical composition comprises at least one compound of the inventive subject matter and at least one therapeutic agent selected from the group consisting of a corticosteroid, an anticholinergic, a beta-mimetic, a pulmonary surfactant, an endothelin antagonist, a prostacyclin, a calcium channel blocker, a beta-blocker, a phosphodiesterase type 4 inhibitor, a guanylate cyclase activator/activator, pirfenidone, an antidepressant, an antibiotic, an anticoagulant, a diuretic, and a digitoside, the compound of the inventive subject matter and the therapeutic agent may be formulated together in the same dosage form (e.g., but not limited to, a tablet), separately in the same dosage form (e.g., but not limited to, a tablet), or in different dosage forms (e.g., but not limited to, the compound of the inventive subject matter may be formulated as a tablet, the therapeutic agent may be formulated as a powder, a tablet, a powder, a, A solution or suspension).
The pharmaceutical compositions may be prepared in a manner known to those skilled in the art, for example, by means of dissolution, mixing, granulation, dragee preparation, grinding, emulsification, sealing, collection or freeze-drying processes.
The choice of formulation depends inter alia on the route of administration of the pharmaceutical composition. The pharmaceutical compositions of the subject invention may be administered by any suitable route, for example, orally, sublingually, buccally, intravenously, by intraarterial injection, intramuscularly, subcutaneously, intradermally, topically, transdermally, intranasally, intraocularly, intraperitoneally, intrasternally, intracoronary, transurethral, rectal or vaginal route, by inhalation or by spray. Oral administration is preferred.
Where a pharmaceutical composition comprises at least one compound of the inventive subject matter and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, phosphodiesterase type 4 inhibitors, guanylate cyclase activators/activators, pirfenidone (pirfenidone), antidepressants, antibiotics, anticoagulants, diuretics, and digitosides, the compounds of the inventive subject matter and the therapeutic agents may be administered by the same route, such as, but not limited to: orally, or by different routes, such as, but not limited to: the compounds of the subject invention may be administered orally, while the therapeutic agent may be administered by inhalation or instillation.
For example, tablets, sugar-coated tablets (dragees), pills, cachets, capsules (caplets), granules, solutions, emulsions and suspensions are suitable for oral administration. In particular, the formulations may be formulated to represent, for example, enteric forms, immediate release forms, delayed release forms, repeated dose release forms, extended release forms or sustained release forms. The form can be obtained using the following method: for example, coated tablets, tablets divided into several parts by layers which disintegrate under different conditions (e.g. pH conditions), or compounds which are the subject of the invention combined with biodegradable polymers.
Preferably, administration is by inhalation or instillation using an aerosol. An aerosol is a liquid-gas dispersion, a solid-gas dispersion or a mixed liquid/solid-gas dispersion.
Aerosols may be formed by means of aerosol generating devices, such as Dry Powder Inhalers (DPIs), Pressurized Metered Dose Inhalers (PMDIs) and nebulizers. Depending on the type of compound and optional therapeutic agent of the subject invention being administered, the aerosol generating device may contain the compound and optional therapeutic agent in the form of a powder, solution or dispersion. The powders may contain, for example, one or more of the following adjuvants, carriers, stabilizers and fillers. In addition to solvents, solutions may contain, for example, one or more of the following adjuvants: propellants, solubilizers (co-solvents), surfactants, stabilizers, buffers, tonicity adjusting agents, preservatives and flavoring agents. In addition to the dispersing agent, the dispersion may contain, for example, one or more of the following auxiliaries, propellants, surfactants, stabilizers, buffers, preservatives and flavorings. Examples of vectors include, but are not limited to: sugars such as lactose and glucose. Examples of propellants include, but are not limited to: fluorinated hydrocarbons such as 1,1,1, 2-tetrafluoroethane and 1,1,1,2,3,3, 3-heptafluoropropane.
The particle size of the aerosol particles (solid, liquid or solid/liquid particles) is preferably less than 100 μm, more preferably in the range from 0.5 to 10 μm, in particular in the range from 2 to 6 μm (value D50, determined by laser diffraction).
Specific aerosol generating devices that may be used for administration by inhalation include, but are not limited to: cyclohaller, Diskhaller, Rotadik, Turbohaller, Autohaler, Turbohaller, Novollyzer, Easyhaler, Aerlizor, Jethhaler, Diskus â, Ultrahaler and Mystic inhaler. The aerosol generating device can be combined with spacers or extenders, for example Aerocalar, Nebulator, Volumatic and Rondo ® granules for improving the inhalation effect.
In the case of topical administration, suitable pharmaceutical preparations are, for example, ointments, creams, lotions, pastes, gels, powders, solutions, emulsions, suspensions, oils, sprays and patches (such as, but not limited to, transdermal therapeutic systems).
For parenteral modes of administration, for example, intravenous, intraarterial, intramuscular, subcutaneous, intradermal, intraperitoneal and intrasternal administration, it is preferred to use solutions (e.g., but not limited to, sterile solutions, isotonic solutions). Preferably, they are administered by injection or infusion techniques.
In the case of intranasal administration, for example, sprays and solutions used in the form of drops are the preferred formulations.
For intraocular administration, solutions, gels and ointments used in the form of drops are exemplary formulations.
In general, pharmaceutical compositions according to the inventive subject matter may be administered with dosages of the inventive subject matter compounds within the usual ranges for phosphodiesterase type 5 inhibitors or dual phosphodiesterase type 4/5 inhibitors. In particular, a dosage in the range of 0.01 to 4000 mg of a compound of the subject invention per day is a preferred dosage. In this connection, it is to be noted that the dosage depends, for example, on the particular compound used, the species treated, the age, body weight, general health, sex and diet of the patient to be treated, the mode and time of administration, the rate of excretion, the severity of the disease to be treated and the drug combination. In the case where the pharmaceutical composition of the inventive subject matter comprises at least one compound of the inventive subject matter and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, phosphodiesterase type 4 inhibitors, guanylate cyclase activators/activators, pirfenidone (pirfenidone), antidepressants, antibiotics, anticoagulants, diuretics, and digitosides, the same dosage ranges apply to the therapeutic agent.
A single dose of a pharmaceutical composition according to the inventive subject matter may be administered per day, or multiple sub-doses may be administered, for example, 2 to 4 doses per day. A single dosage unit of a pharmaceutical composition may contain, for example, from 0.01 mg to 4000 mg of a compound of the subject invention, preferably from 0.1 mg to 2000 mg, more preferably from 0.5 to 1000 mg, most preferably from 1 to 500 mg. In the case where a pharmaceutical composition subject of the present invention comprises at least one compound subject of the present invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, phosphodiesterase type 4 inhibitors, guanylate cyclase activators/activators, pirfenidone, antidepressants, antibiotics, anticoagulants, diuretics, and digitosides, a single dosage unit of the pharmaceutical composition may contain from 0.01 mg to 4000 mg of the therapeutic agent, preferably from 0.1 mg to 2000 mg, more preferably from 0.5 to 1000 mg, most preferably from 1 to 500 mg. Furthermore, the pharmaceutical composition may be suitable for weekly, monthly or even less frequent administration, e.g. using implants, such as subcutaneous or intramuscular implants, using compounds of the subject invention in the form of slightly soluble salts, or using compounds of the subject invention in combination with a polymer. Preferably, the pharmaceutical composition is administered in a single dose per day.
In the case where the pharmaceutical composition of the inventive subject matter comprises at least one compound of the inventive subject matter and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, phosphodiesterase type 4 inhibitors, guanylate cyclase activators/activators, pirfenidone (pirfenidone), antidepressants, antibiotics, anticoagulants, diuretics, and digitosides, the compounds of the inventive subject matter and the therapeutic agent may be administered either simultaneously or sequentially. In the case of sequential administration, the compounds of the subject invention may be administered before or after administration of the therapeutic agent.
Biological investigation
Method for determining inhibition of phosphodiesterase type 5 (PDE5) Activity
For the source of human PDE5, platelets were used. For this purpose, 150 ml of fresh blood (obtained from human donors, treated with citrate [ final concentration 0.3% (w/v) ]]Anticoagulated blood) was centrifuged at 200 g for 10 minutes, and so-called platelet-rich plasma (PRP) was obtained in the form of the supernatant. A volume of 1/10 ACD solution (85 mM Na)3Citrate, 111 mM D-glucose, 71 mM citric acid, pH4.4) to 9/10 volumes of PRP. After centrifugation (1,400 g, 10 min), the cell pellet was resuspended in 3 ml of homogenization buffer (NaCl 140 mM, KCl 3.8 mM, EGTA (ethylene glycol tetraacetic acid) 1mM, MgCl 21mM, Tris-HCl 20 mM, beta-mercaptoethanol 1mM, pH8.2) plus protease inhibitor to obtain the final concentrations of 0.5 mM Pefablock (Roche), 10. mu.M leupeptin, 5. mu.M trypsin inhibitor, 2mM benzamidine and 10. mu.M gastric inhibitory peptide A. The suspension was sonicated and then centrifuged at 10,000 g for 15 minutes. The resulting supernatant (platelet lysate) was used for enzyme assay.
In a modified SPA (scintillation proximity assay) assay provided by Amersham Biosciences (performed in 96-well microtiter plates (MTP's)) (see Process Specification "phosphodiesterase [3H ] assay]cAMP SPA enzyme activity assay, encoding TRKQ 7090 "), utilize compounds of the inventive subject matter to inhibit PDE5a1 activity. The test volume was 100. mu.l and contained 20 mM Tris buffer (pH7.4), 0.1 Mg BSA (bovine serum albumin)/ml, 5 mM Mg2+1 μ M motapizone, 2- (3, 4-dimethoxybenzyl) -7- [ (1R,2R) -2-hydroxy-1- (2-phenylethyl) propyl ] PDE2 inhibitor (10 nM)]-5-methylimidazo [5,1-f][1,2,4]Triazin-4 (3H) -one, 0.5 μ M cGMP (cyclic guanosine monophosphate) (including about 50,000 cpm of [3H ]]cGMP as tracer), 1 μ l of the corresponding compound (diluted in dimethyl sulfoxide (DMSO) and enough platelet lysate containing PDE5 (10,000 × g supernatant, see above) to ensure conversion of 10-20 wt% cGMP under the experimental conditions. In this assay, the final concentration of DMSO (1% v/v) did not substantially affect the activity of the PDE studied. After a preliminary incubation at 37 ℃ for 5 minutes, the reaction was initiated by addition of matrix (cGMP) and the assay was incubated for a further 15 minutes; the reaction was then stopped by the addition of SPA beads (50. mu.l). SPA pellets had been resuspended in water beforehand, but then diluted in water (1:3(v/v)) according to the manufacturer's instructions; the diluted solution also contained 3 mM 8-methoxymethyl-3-isobutyl-1-methylxanthine (IBMX) in order to ensure complete termination of PDE activity. After the pellets have been deposited ( >30 minutes), the MTP's were analyzed using a commercially available fluorescence detection device. Determination of the corresponding IC of a Compound inhibiting PDE Activity from a concentration-Effect Curve by means of non-Linear regression50The value is obtained.
PDE5A1 inhibition values determined for the following compounds [ as-logIC ]50(mol/l) form to determine]Between 8.0 and 9.0. The numbering of the compounds corresponds to the numbering of the examples.
The compound is E28, E31-E33, E36, E39, E45-E54, E80, E154, E156, E158, E162, E177, E192-E194, F17, F19-F23, F27-F33, F97-F98, F119-F120, P3, P24-P26.
PDE5A1 inhibition values determined for the following compounds [ as-logIC ]50(mol/l) form to determine]Higher than 9.0. The numbering of the compounds corresponds to the numbering of the examples.
E1-E27, E29-E30, E34-E35, E37-E38, E40-E44, E55-E79, E81-E153, E155, E157, E159-E161, E163-E176, E178-E191, E-195-E203, F1-F16, F18, F24-F26, F34-F74, F76-F96, F99-F118, P1-P2, P6-P8, P89-P91, P139-P141, P159-P161, P169-P171, P169-P191, P199-P201, P199-P211.
Method for determining inhibition of phosphodiesterase type 4 (PDE4) Activity
PDE4B1(GB No. L20966) is a gift from prof. m. Conti (Stanford University, USA). It was amplified from the original plasmid (pCMV5) by PCR with primers Rb18(5'-CAGACATCCTAAGAGGGGAT-3') and Rb10(5'-AGAGGGGGATTATGTATCCAC-3') and cloned into PCR-Bac vector (Invitrogen, groingen, NL).
In SF9 insect cells, recombinant baculoviruses were prepared using homologous recombination. The expression plasmid was co-transfected with Baculo-Gold DNA (Pharmingen, Hamburg) using standard protocols (Pharmingen, Hamburg). Wt virus-free recombinant virus supernatants were selected using the plaque assay. Then, high titer virus supernatants were prepared by amplification 3 times. Between 1 and 10 of Sf9-S2(PAA, Pasching, Austria) in serum-free medium insect expression, 2X 10 by infection with MOI (multiple infection)6Individual cells/ml, SF21 cells were used to express PDE4B 1. The cells were incubated at 28 ℃ for 48-72 hours, after which they were pelleted at 1000Xg and 4 ℃ for 5-10 minutes.
SF21 insect cells were resuspended in ice cold (4 ℃) homogenization buffer (20 mM Tris, pH8.2, containing the following additions: 140 mM NaCl, 3.8 mM KCl, 1 mM EGTA, 1 mM MgCl210 mM beta-mercaptoethanol, 2 mM benzamidine, 0.4 mM Pefablock, 10. mu.M leupeptin, 10. mu.M pepstatin A, 5. mu.M trypsin inhibitor), at a concentration of about 107Individual cells/ml and disrupted by sonication. Then the product is mixed withThe homogenate was centrifuged at 1000Xg for 10 minutes and the supernatant was stored at-80 ℃ until later use (see below). Protein content was determined using the Bradford method (BioRad, Munich) using BSA as standard.
In a modified SPA (scintillation proximity assay) assay provided by Amersham Biosciences (performed in 96-well microtiter plates (MTP's)) (see Process Specification "phosphodiesterase [3H ] assay]cAMP SPA enzyme activity assay, encoding TRKQ 7090 "), utilize compounds according to the inventive subject matter to inhibit PDE4B1 activity. The test volume was 100. mu.l and contained 20 mM Tris buffer (pH7.4), 0.1 Mg/ml BSA, 5 mM Mg2+0.5 μ M cAMP (including approximately 50,000 cpm of [3H ]]cAMP), 1 μ l of the corresponding substance (diluted in DMSO) and enough recombinant PDE (1000 × g supernatant, see above) to ensure cAMP conversion 10-20% under the experimental conditions. In this assay, the final concentration of DMSO (1% v/v) did not substantially affect the activity of the PDE studied. After a preliminary incubation at 37 ℃ for 5 minutes, the reaction was initiated by addition of substrate (cAMP) and the assay was incubated for a further 15 minutes; the reaction was then stopped by the addition of SPA beads (50. mu.l). SPA pellets had been resuspended in water beforehand, but then diluted in water (1:3(v/v)) according to the manufacturer's instructions; the diluted solution also contained 3 mM IBMX to ensure complete termination of PDE activity. After the pellets have been deposited ( >30 minutes), the MTP's were analyzed using a commercially available fluorescence detection device. Determination of the corresponding IC of a Compound inhibiting PDE4B1 Activity from a concentration-Effect Curve by means of non-Linear regression50The value is obtained.
PDE4B1 inhibition values determined for the following compounds [ as-logIC ]50(mol/l) form to determine]Between 6.0 and 7.0. The numbering of the compounds corresponds to the numbering of the examples.
The compound is E37-E40, E45, E66-E74, E96, E145-E147, E151-E157, E159-E160, E169-E171, E177-E178, F23-F24, F27, F41-F46, F58, F97, F99-F101 and F106.
PDE4B1 inhibition values determined for the following compounds [ as-logIC ]50(mol/l) form to determine]Higher than 7.0. The numbering of the compounds corresponds to the numbering of the examples.
The compound is E41-E44, E81-E95, E97-E98, E148-E150, E176, E-195-E203, F25-F26, F51-F57, F59-F62, F93-F96, P1-P3, P6-P8, P24-P26, P89-P91, P99-P101, P139-P141, P159-P161, P169-P171, P189-P191, P199-201 and P209-P211.
Animal pharmacological test for PDE5 inhibition of Compounds
Nitric oxide regulates smooth muscle elasticity (tone) by activating guanylate cyclase, followed by cyclic GMP-dependent protein kinase, which increases cGMP. In smooth muscle, the magnitude and duration of the cGMP signal is regulated primarily by cGMP-specific cyclic nucleotide phosphodiesterase 5(PDE 5). Thus, inhibition of PDE5 or activation of guanylate cyclase results in altered arterial blood pressure response, which is more pronounced under acute arterial hypertension conditions, which can be readily induced by continuous intravenous (i.v.) Phenylephrine (PE) infusion. The objective of this study was to evaluate the effect of selective PDE5 inhibitors described in the inventive subject matter on the epinephrine-induced acute arterial hypertension and Sodium Nitroprusside (SNP) -induced blood pressure response in anesthetized male Spraque Dawley rats.
Method of producing a composite material
The conscious Spraque Dawley rat test compound (suspended in 4% w/v aqueous methylcellulose, 3 or 10 mg/kg) or placebo (i.e., 4% aqueous methylcellulose) was administered orally 90 minutes prior to SNP administration. After 40 minutes, rats were anesthetized by intramuscular administration of 80 mg/kg ketamine-HCl + 4 mg/kg xylazine-HCl and ventilated with-1.5% isoflurane (in a mixture of ambient air and 40% oxygen). Catheters were inserted for i.v. PE-and SNP-administration and recording of mean arterial blood pressure (MAP). One hour after compound or placebo administration, continuous i.v. (femoral vein) PE-infusion (3 μ g/kg/min, infusion rate 0.06 ml/min) was started and maintained until the end of the experiment. 30 minutes after the start of PE-infusion, NO-donor sodium nitroprusside (SNP, 30 μ g/kg, volume 1.0 m) was administeredl/kg) of i.v. bolus injection (bolus). To evaluate the effect of the test compounds compared to placebo (PDE5 inhibitory activity), MAP responses were analyzed. The area under the MAP curve (corrected for initial MAP (corr. AUC) within 180 seconds after SNP administration and MAP before SNP administration were usedMAP 0-180s) Altered arterial vascular response and the resulting in vivo PDE5 inhibitory activity are described. In this model, the effect achieved (in% change with respect to the control) for examples E1, E94, E102, E131, F24, F65, F69, F84 and F112 was between-11% and-40% effect.
Animal pharmacological test for PDE4 inhibition of Compounds
The PDE4 inhibitory activity of the compounds is well described, leading to anti-inflammatory effects. Thus, the compounds of the present subject matter have been tested for inhibition of lipopolysaccharide-induced tumor necrosis factor alpha (TNF α) release in male Sprague Daley rats.
For examples E84, E86, E87, E89, E93, E94, E95, F12, F53, F55, F56, P7, P8, P89, P90, P140, P141, P160, P161, P170, P171, P189-P191, P199-P201, P210 and P211, the inhibition of LPS-induced TNF α production obtained by the test compound in this model was between 7% and 99%.
Method of producing a composite material
Male Sprague Daley rats (n =6-8 animals for each dosing group) were given different doses of compound. LPS and placebo treated controls were attached (n =6 to 8 animals). One hour prior to LPS stimulation, compound and placebo were administered orally (p.o.) by feeding (administration volume: 10 ml/kg).
LPS was injected intravenously (i.v.) at a dose of 1 mg/kg (administration volume: 10 ml/kg). 1.5 hours after LPS stimulation, animals were sacrificed by i.v. injection of sodium pentobarbital (120 mg/kg). Heparinized blood was obtained by cardiac puncture. The blood was centrifuged (21,000 x g, 4 ℃, 15 min) and the plasma samples were kept frozen at-80 ℃ until TNF α levels were determined by ELISA.

Claims (22)

1. A compound of formula (I)
Wherein
R1 is-CH2-3-4C-cycloalkyl or 2-4C-alkyl,
r2 is hydrogen or 1-4C-alkyl,
r21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-fluoroalkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 4-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -H, -C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R43,
r41 is 1-4C-alkoxy or hydroxy,
r43 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
R6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is hydrogen, 1-4C-alkyl optionally substituted by R71, or 1-4C-alkoxy optionally substituted by R73,
r71 is 1-4C-alkoxy or hydroxy,
r73 is 1-4C-alkoxy or hydroxy,
or a salt thereof.
2. A compound according to claim 1, wherein
R1 is-CH2-3-4C-cycloalkyl or 2-4C-alkyl,
r2 is hydrogen or 1-4C-alkyl,
r21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-4C-alkyl or 1-4C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-fluoroalkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is optionally substituted by R4 and/or by one or two substituents R5, or 3-6C-cycloalkyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is 1-4C-alkoxy, halogen, 1-4C-alkyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from halogen or 1-4C-alkyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
R6 is-NH-C (O) -R7, halogen, hydroxy or NH2，
R61 is halogen, 1-4C-alkyl or hydroxy,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
or a salt thereof.
3. A compound according to claim 1, wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is hydrogen or a methyl group,
r21 is hydrogen or fluorine,
r22 is hydrogen, halogen, 1-4C-alkyl, 1-2C-alkoxy, 1-4C-fluoroalkoxy, -C (O) -1-2C-alkyl or 1-2C-fluoroalkyl,
or R21 and R22 combine to form a group-O-CH2-O-，
R23 is hydrogen, halogen, 1-2C-alkoxy,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is a 5-to 6-membered saturated heterocyclic ring containing one nitrogen atom, which heterocyclic ring is substituted on the nitrogen atom by R4 and on the heterocyclic ring optionally by one or two substituents R5, or cyclohexyl or cyclopentyl substituted by R6 and optionally substituted by R61,
r4 is-C (O) -1-4C-alkyl, wherein 1-4C-alkyl is optionally substituted by R41, or-C (O) -O-1-4C-alkyl,
r41 is 1-4C-alkoxy or hydroxy,
if only one substituent R5 is present, then
R5 is fluoro, methyl or hydroxy,
if two substituents R5 are present, these two substituents are identical and are bonded to the same carbon atom, are selected from fluorine or methyl, or together with the carbon atom to which they are bonded form a spiro-linked cyclopropane ring,
R6 is-NH-C (O) -R7, fluoro, hydroxy or NH2，
R61 is fluoro, methyl or hydroxy,
r7 is 1-4C-alkyl, which is optionally substituted by R71, or 1-4C-alkoxy,
r71 is 1-4C-alkoxy or hydroxy,
or a salt thereof.
4. A compound according to claim 1, wherein
R1 is-CH2-a 3-4C-cycloalkyl group,
r2 is a hydrogen atom or a salt thereof,
r21 is a hydrogen atom or a salt thereof,
r22 is difluoromethyl or trifluoromethyl,
r23 is a hydrogen atom or a salt thereof,
r24 is a hydrogen atom or a salt thereof,
y is- (CH)2)n-，
n is a number of 0, and n is,
r3 is cyclohexyl substituted by R6 and optionally substituted by R61,
r6 is-NH-C (O) -R7,
r61 is fluorine or a methyl group,
r7 is methyl or ethyl optionally substituted with R71,
r71 is a methoxy group or a hydroxy group,
or a salt thereof.
5. A compound according to claim 1 selected from
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester;
N- (trans-4-acetamidocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
ethyl { trans-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
n- (cis-4-acetamidocyclohexyl) -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
Ethyl { cis-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl ]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
N-[(3S*,4S*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3S*,4S*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3S*,4S*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid (1-acetyl-piperidin-4-yl) -amide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid [1- (2-methoxy-acetyl) -piperidin-4-yl ] -amide;
4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
Ethyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
N- (1-acetylpiperidin-4-yl) -4- (2-ethoxy-5-fluorophenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-ethoxy-5-fluorophenyl) -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-ethoxy-5-fluorophenyl) -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl)) Piperidin-4-yl radical]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
Ethyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
N-[(3S*,4S*) -1-acetyl-4-hydroxypiperidin-3-yl ]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyPhenyl radical]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -4-hydroxy-1-propionylpiperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -4-hydroxy-1- (methoxyacetyl) piperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl radical]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl radical]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid ethyl ester;
n- (trans-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (cis-4-acetamidocyclohexyl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
ethyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
N-[(3R*,4R*) -1-acetyl-3-hydroxypiperidin-4-yl]-4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1-propionylpiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (methoxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-N- [ cis-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d ]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ cis-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- { cis-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- (1-acetylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
(3R) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid ethyl ester;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
n- [ (3R) -1-acetylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-N- [ (3R) -1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ (3R) -1- (methoxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
N-[(3R*,4R*) -1-acetyl-4-hydroxypyrrolidin-3-yl]-4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1-propionylpyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (methoxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- (1-glycolylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ trans-4- (ethanolamido) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ cis-4- (ethanolamido) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- [ (3R) -1-ethanoylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- (1-glycolylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- [ (3R) -1- (hydroxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3R*,4R*) -4-hydroxy-1- (hydroxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide and 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl]-N-[(3S*,4S*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid [1- (2-hydroxy-acetyl) -piperidin-4-yl ] -amide;
4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxylic acid [1- ((S) -2-hydroxy-propionyl) -piperidin-4-yl ] -amide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- [ (3R) -1- (hydroxyacetyl) pyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-ethoxy-5-fluorophenyl) -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- (2-ethoxy-5-fluorophenyl) -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- (1-glycoloylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- (1-glycoloylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- (1-glycoloylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac) -3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac) -3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*) -1-glycolyl-4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac) -3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (rac) -3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl radical]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxyacetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- (1-glycoloylpiperidin-4-yl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ trans-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ cis-4- (glycoloylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -3-hydroxy-1- (hydroxy)Acetyl) piperidin-4-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { (3R,4R) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { (3S,4S) -3-hydroxy-1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { cis-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl]-N-[(3R*,4R*) -4-hydroxy-1- (hydroxyacetyl) pyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { (3R,4R) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -N- { (3S,4S) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -N- (cis-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- { trans-4- [ (hydroxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [ 5-acetyl-2- (cyclopropylmethoxy) phenyl ] -N- (trans-4- { [ (2S) -2-hydroxypropionyl ] amino } cyclohexyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [1- (hydroxyacetyl) piperidin-4-yl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1S,2S) -2-hydroxycyclopentyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1S,2R) -2-hydroxycyclopentyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -N- [ (1R,2R) -2-hydroxycyclopentyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl]-N-{(3R*,4R*) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl group]Pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- [ (3R) -1-glycoloylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -N- { (3R) -1- [ (2S) -2-hydroxypropionyl ] pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl]-N-{(3R*,4R*) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl group]Pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-methylAn amide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl]-N-[(3R*,4R*) -1-glycolyl-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ]-N-{(3R*,4R*) -4-hydroxy-1- [ (2S) -2-hydroxypropionyl group]Pyrrolidin-3-yl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
(3R) -3- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester;
(3R*,4R*) -3- [ ({4- [5- (cyclopropylmethoxy) -1, 3-benzodioxol-4-yl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
Tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
(3R) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester;
(3R*,4R*) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester;
(3S*,4S*) -4- [ ({4- [2- (cyclopropylmethoxy) -4-fluorophenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- ({1- [4- (2-cyclopropylmethoxy-5-fluoro-phenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl ] -formyloxy } -amino) -piperidine-1-carboxylic acid tert-butyl ester;
tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
(3R) -3- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester;
(3R*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5-fluorophenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- ({ [4- (2-ethoxy-5-fluorophenyl) -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl ] carbonyl } amino) piperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
(3R) -3- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester;
(3R*,4R*) -3- [ ({4- [2- (cyclopropylmethoxy) -4-methoxyphenyl) ]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
(3R) -3- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester;
(3R*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
Tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
4- [ ({4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
4- [ ({4- [ 2-ethoxy-5- (trifluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
(3R*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
(3S*,4S*) -3- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
(3R*,4R*)-4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methylphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
(3R*,4R*) -4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
tert-butyl { trans-4- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
tert-butyl { cis-4- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamate;
(3R*,4R*) -3- [ ({4- [2- (cyclopropylmethoxy) -5-ethylphenyl)]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidin-7-yl } carbonyl) amino]-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
{ cis-4- [ ({4- [2- (cyclopropylmethoxy) -5- (prop-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
{ trans-4- [ ({4- [2- (cyclopropylmethoxy) -5- (2-methyl-1, 3-dioxolan-2-yl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] cyclohexyl } carbamic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-methylphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -5-fluoro-4-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
4- [ ({4- [2- (cyclopropylmethoxy) -4-fluoro-5-methoxyphenyl ] -2, 6-dimethyl-5H-pyrrolo [3,2-d ] pyrimidin-7-yl } carbonyl) amino ] piperidine-1-carboxylic acid tert-butyl ester;
n- (1-acetylpiperidin-4-yl) -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- (1-propionylpiperidin-4-yl) -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -N- [1- (methoxyacetyl) piperidin-4-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ trans-4- (acetylamino) cyclohexyl ] -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N- [ (3S,5S) -1-acetyl-5-methylpyrrolidin-3-yl ] -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- [ (3S,5S) -5-methyl-1-propionylpyrrolidin-3-yl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -N- [ (3S,5S) -1- (methoxyacetyl) -5-methylpyrrolidin-3-yl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
n- [ (1S,3S) -3- (acetylamino) cyclopentyl ] -4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- [ (1S,3S) -3- (propionylamino) cyclopentyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -N- { (1S,3S) -3- [ (methoxyacetyl) amino ] cyclopentyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide;
N-[(1R*,2R*,4R*) -4- (acetylamino) -2-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ]-N-[(1R*,2R*,4R*) -2-fluoro-4- (propionylamino) cyclopentyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1R*,2R*,4R*) -2-fluoro-4- [ (methoxyacetyl) amino]Cyclopentyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamide;
N-[(1S*,2S*,4S*) -4- (acetylamino) -2-methylcyclohexyl radical]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-N-[(1S*,2S*,4S*) -2-methyl-4- (propionylamino) cyclohexyl]-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1S*,2S*,4S*) -4- [ (methoxyacetyl) amino]-2-methylcyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamide;
N-[(1R*,2R*,4R*) -4- (acetylamino) -2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-[(1R*,2R*,4R*) -2-fluoro-4- (propionylamino) cyclohexyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1R*,2R*,4R*) -2-fluoro-4- [ (methoxyacetyl) amino ]Cyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamide;
N-[(1S*,3S*,4S*) -4- (acetylamino) -3-methylcyclohexyl radical]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-N- [ (1S)*,3S*,4S*) -3-methyl-4- (propionylamino) cyclohexyl]-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1S*,3S*,4S*) -4- [ (methoxyacetyl) amino]-3-methylcyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamide;
N-[(1S*,3S*,4S*) -4- (acetylamino) -3-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-[(1S*,3S*,4S*) -3-fluoro-4- (propionyl)Alkylamino) cyclohexyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1S*,3S*,4S*) -3-fluoro-4- [ (methoxyacetyl) amino]Cyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamide;
N-[(1R*,3S*,4S*) -3- (acetylamino) -4-methylcyclopentyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d ]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-N- [ (1R)*,3S*,4S*) -3-methyl-4- (propionylamino) cyclopentyl]-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1R*,3S*,4S*) -3- [ (methoxyacetyl) amino]-4-methylcyclopentyl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
N-[(1R*,2R*,4S*) -4- (acetylamino) -2-methylcyclopentyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-N- [ (1R)*,2R*,4S*) -2-methyl-4- (propionylamino) cyclopentyl]-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1R*,2R*,4S*) -4- [ (methoxyacetyl) amino]-2-methylcyclopentyl } -6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
N-[(1S*,3S*,4S*) -3- (acetylamino) -4-fluorocyclopentyl group]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-[(1S*,3S*,4S*) -3-fluoro-4- (propionylamino) cyclopentyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidines-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1S*,3S*,4S*) -3-fluoro-4- [ (methoxyacetyl) amino]Cyclopentyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamide;
N-[(1S*,2R*,4S*) -4- (acetylamino) -2-fluorocyclohexyl]-4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-[(1S*,2R*,4S*) -2-fluoro-4- (propionylamino) cyclohexyl]-6-methyl-5H-pyrrolo [3,2-d]Pyrimidine-7-carboxamide;
4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl]-N-{(1S*,2R*,4S*) -2-fluoro-4- [ (methoxyacetyl) amino]Cyclohexyl } -6-methyl-5H-pyrrolo [3, 2-d)]Pyrimidine-7-carboxamide;
and salts thereof.
6. A compound according to claim 1 selected from 4- [2- (cyclopropylmethoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide or a salt thereof.
7. A compound according to claim 1 selected from 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -6-methyl-N- [ trans-4- (propionylamino) cyclohexyl ] -5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide or a salt thereof.
8. A compound according to claim 1 selected from 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -N- { trans-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide or a salt thereof.
9. A compound according to claim 1 selected from 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -N- [ (1R, 2R, 4R) -2-fluoro-4- (propionylamino) cyclohexyl ] -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide or a salt thereof.
10. A compound according to claim 1 selected from 4- [2- (cyclopropylmethoxy) -5- (difluoromethyl) phenyl ] -N- { (1R, 2R, 4R) -2-fluoro-4- [ (methoxyacetyl) amino ] cyclohexyl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide or a salt thereof.
11. A compound according to claim 1 selected from 4- [2- (cyclopropylmethoxy) -4-fluorophenyl ] -N- {1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } -6-methyl-5H-pyrrolo [3,2-d ] pyrimidine-7-carboxamide or a salt thereof.
12. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable auxiliary.
13. The pharmaceutical composition according to claim 12, further comprising at least one therapeutic agent selected from the group consisting of: corticosteroids, anticholinergics, beta-mimetics, pulmonary surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, phosphodiesterase type 4 inhibitors, guanylate cyclase activators/activators, pirfenidone, antidepressants, and antibiotics.
14. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of acute or chronic respiratory diseases.
15. Use according to claim 14, wherein the acute or chronic respiratory disease is selected from pulmonary hypertension, pulmonary fibrosis, sarcoidosis, asthma, bronchitis, emphysema, cystic fibrosis and chronic obstructive pulmonary disease.
16. Use according to claim 15, wherein the acute or chronic respiratory disease is pulmonary hypertension.
17. The use according to claim 16, wherein the pulmonary arterial hypertension is arterial pulmonary arterial hypertension (pulmony arterial hypertension).
18. Use according to claim 15, wherein the acute or chronic respiratory disease is pulmonary fibrosis.
19. Use according to claim 18, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
20. The use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of peripheral arterial disease, diabetes, raynaud's syndrome, overactive bladder, lower urinary tract symptoms, portal hypertension, nephritis, cirrhosis, toxic liver damage or liver fibrosis.
21. Use of a compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hepatitis.
22. The use according to claim 21, wherein the hepatitis is non-alcoholic steatohepatitis.
HK12110218.1A 2009-08-26 2010-08-24 Methylpyrrolopyrimidinecarboxamides HK1169411B (en)

Applications Claiming Priority (3)

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EP09168685.7 2009-08-26
EP09168685 2009-08-26
PCT/EP2010/062329 WO2011023693A1 (en) 2009-08-26 2010-08-24 Methylpyrrolopyrimidinecarboxamides

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HK1169411B true HK1169411B (en) 2016-07-08

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