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HK1224666A - Aminopyrimidine derivatives as lrrk2 modulators - Google Patents

Aminopyrimidine derivatives as lrrk2 modulators Download PDF

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HK1224666A
HK1224666A HK16112879.3A HK16112879A HK1224666A HK 1224666 A HK1224666 A HK 1224666A HK 16112879 A HK16112879 A HK 16112879A HK 1224666 A HK1224666 A HK 1224666A
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methoxy
ylamino
pyrimidin
methylamino
methanone
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HK16112879.3A
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HK1224666A1 (en
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Aminopyrimidine derivatives as LRRK2 modulators
The application is a divisional application of applications of PCT international application date of 2011, 6 and 1, PCT international application numbers of PCT/EP2011/059009, Chinese national application number of 201180027409.7 and invention name of aminopyrimidine derivatives serving as LRRK2 regulators.
Technical Field
The present invention relates to compounds that modulate the function of LRRK2 and are useful for the treatment of LRRK2 mediated diseases and disorders, such as parkinson's disease.
Background
Neurodegenerative diseases such as Parkinson's disease, Lewy body dementia and Huntington's disease affect millions of individuals. Parkinson's disease is a chronic, progressive motor system disorder, with about one suffering per 1000 persons, with hereditary parkinson's disease accounting for 5-10% of all patients. Parkinson's disease is caused by progressive loss of mesencephalic dopamine neurons, giving patients impaired ability to guide and control their actions. The primary parkinson's disease symptoms are trembling, stiffness, bradykinesia, and impaired balance. Many parkinson's disease patients also experience other symptoms such as mood changes, memory loss, orodental problems and sleep disturbances.
Genes encoding leucine-rich repeat kinase 2 protein (LRRK2) have been identified as being associated with hereditary Parkinson's disease (Paisan-Ruiz et al, Neuron, Vol.44(4), 2004, pp 595-600; Zimphrich et al, Neuron, Vol.44(4), 2004, 60)1-607). In vitro studies have shown that parkinson-disease-associated mutations lead to increased LRRK2 kinase activity and a reduced rate of GTP hydrolysis compared to wild-type (Guo et al, Experimental Cell Research, vol.313(16), 2007, pp.3658-3670). anti-LRRK 2 antibodies have been used to label brainstem Lewy bodies associated with Parkinson's disease and cortical antibodies associated with Lewis body dementia, suggesting that LRRK2 may play an important role in Lewis body formation and pathogenesis associated with these diseases (Zhou et al, Molecular Degeneration, 2006, 1: 17 doi: 10.1186/1750-. LRRK2 has also been identified as a group potentially associated with increased susceptibility to Crohn's disease and leprosyTherefore (Zhang et al, New England J.Med.Vol.361(2009) pp.2609-2618).
LRRK2 is also related to: the shift from mild cognitive impairment to alzheimer's disease (WO 2007/149789); l-dopa-induced dyskinesia (Hurley et al, Eur. J. Neurosci., Vol.26, 2007, pp.171-177); CNS disorders associated with neuronal precursor differentiation (Milosevic et al, neuroregen, vol.4, 2009, p.25); cancers such as renal, breast, prostate, blood and lung cancers and acute myeloid leukemia (WO 2011/038572); papillary renal and thyroid cancers (Looyenga et al, www.pnas.org/cgi/doi/10.1073/pnas.1012500108); multiple myeloma (Chapman et al, Nature Vol.471, 2011, pp.467-472); amyotrophic Lateral Sclerosis (Shtilbans et al, Amyotropic Laterial Sclerosis "Early Online 2011, pp.1-7); rheumatoid arthritis (Nakamura et al, DNA Res.Vol.13(4), 2006, pp.169-183); and spinal rigidity (alkylosingspindylitis) (Danoy et al, PLoS Genetics, Vol.6(12), 2010, e1001195, pp.1-5).
Thus, compounds and compositions effective to modulate LRRK2 activity may provide treatment for the following diseases: neurodegenerative diseases such as parkinson's disease and lewis body dementia, CNS disorders such as alzheimer's disease and L-dopa induced dyskinesia, cancer such as renal, breast, prostate, blood, papillary and lung cancer, acute myeloid leukemia and multiple myeloma, and inflammatory diseases such as leprosy, crohn's disease, amyotrophic lateral sclerosis, rheumatoid arthritis and spinal stiffness. In particular, there is a need for compounds with LRRK2 affinity that are selective for LRRK2 over other kinases such as JAK2, and which can provide effective drugs for the treatment of neurodegenerative diseases such as parkinson's disease.
Disclosure of Invention
The present invention provides compounds of formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
m is 0 to 3;
x is: -NRa-; -O-; or-S (O)r-, where R is 0 to 2 and RaIs hydrogen or C1-6An alkyl group;
R1the method comprises the following steps: c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; hydroxy-C2-6An alkenyl group; amino-C1-6An alkyl group; c1-6alkylsulfonyl-C1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
or R1And RaTogether with the atoms to which they are attached may form a three-to six-membered ring, which may optionally include a further heteroatom selected from O, N and S, and which is oxo, halo or C1-6Alkyl substitution;
R2the method comprises the following steps: halogen; c1-6An alkoxy group; a cyano group; c2-6An alkynyl group; c2-6An alkenyl group; halo-C1-6An alkyl group; halo-C1-6An alkoxy group; c3-6Cycloalkyl, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; acetyl; an oxetanyl group; or oxetane-C1-6An alkyl group;
R3the method comprises the following steps: -OR4(ii) a Halogen; a cyano group; c1-6An alkyl group; halo-C1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R4the method comprises the following steps: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; optionally is covered with C1-6Alkyl or halogen substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl or halogen substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R5the method comprises the following steps: hydrogen; or C1-6An alkyl group;
n is 0 or 1;
R6the method comprises the following steps: hydrogen; c1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; hydroxy-C1-6An alkyl group; amino-C1-6An alkyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; a heterocyclic group; or heterocyclyl-C1-6An alkyl group; wherein said C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-6Alkyl, heterocyclyl and heterocyclyl-C1-6Each alkyl group may be optionally substituted with one, two, three or four groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or in these groupsMay form a five or six membered ring together with the atoms to which they are attached;
or R5And R6Together with the nitrogen atom to which they are attached form a three-to seven-membered ring, which optionally includes an additional ring selected from O, N and S (O)nAnd which is optionally substituted with one, two, three or four groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen, nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring; and is
R7The method comprises the following steps: halogen; c1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkyl group; or halo-C1-6An alkoxy group.
Furthermore, the present invention includes all optical isomers of the compounds of formula I, i.e. diastereomers, mixtures of diastereomers, racemic mixtures, all their corresponding enantiomers and/or tautomers, and solvates thereof.
The invention also provides pharmaceutical compositions comprising the compounds, methods of using the compounds, and methods of making the compounds.
Detailed Description
Definition of
Unless otherwise indicated, the following terms used in the present application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.
"acetyl", alone or in combination with other groups, means the group-C ═ O-CH3。
"alkyl", alone or in combination with other groups, means a monovalent straight or branched chain saturated hydrocarbon moiety consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. "lower alkyl" refers to alkyl of one to six carbon atoms, i.e., C1-6An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl and the like.
"alkenyl", alone or in combination with other groups, refers to a straight-chain monovalent hydrocarbon radical of two to six carbon atoms or a branched-chain monovalent hydrocarbon radical of two to six carbon atoms containing at least one double bond, i.e., C2-6Alkenyl groups such as vinyl, propenyl, and the like.
"alkynyl", alone or in combination with other groups, refers to a straight-chain monovalent hydrocarbon radical of two to six carbon atoms or a branched-chain monovalent hydrocarbon radical of two to six carbon atoms containing at least one triple bond, i.e., C2-6Alkynyl groups such as ethynyl, propynyl and the like.
"alkylene", alone or in combination with other groups, means a straight chain saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, such as methylene, ethylene, 2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.
"alkoxy" and "alkyloxy" are used interchangeably, alone OR in combination with other groups, to refer to a moiety of the formula-OR, where R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
"alkoxyalkyl", alone or in combination with other groups, refers to a moiety of the formula Ra-O-Rb-, where Ra and Rb are, respectively, alkyl and alkylene as defined hereinRadicals, e.g. C1-6alkoxy-C1-6An alkyl group. Exemplary alkoxyalkyl groups include, for example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1- (2-methoxyethyl) -3-methoxypropyl, and 1- (2-methoxyethyl) -3-methoxypropyl.
"Alkoxyalkyloxy", alone or in combination with other groups, refers to the formula-O-R-R ', where R and R' are, respectively, alkylene and alkyloxy groups, as defined herein.
"alkylcarbonyl", alone or in combination with other groups, refers to a moiety of the formula-C (o) -R, wherein R is alkyl as defined herein, e.g., C1-6Alkyl-carbonyl groups.
"alkoxycarbonyl", alone or in combination with other groups, refers to a group of formula-C (O) -R, wherein R is alkoxy as defined herein, e.g., C1-6Alkoxy-carbonyl.
"Alkylcarbonylalkyl", alone or in combination with other groups, refers to a group of the formula-R-C (O) -R, wherein R and R' are independently alkylene and alkyl as defined herein, e.g., C1-6alkyl-carbonyl-C1-6An alkyl group.
"Alkoxycarbonylalkyl", alone or in combination with other groups, means a group of the formula-R-C (O) -R, wherein R and R' are independently alkylene and alkoxy as defined herein, e.g., C1-6alkoxy-carbonyl-C1-6An alkyl group.
"Alkoxycarbonylalkoxy", alone or in combination with other groups, refers to a group of the formula-O-R-C (O) -R ', wherein R and R' are each, as defined herein, alkylene and alkoxy, e.g., C1-6alkoxy-carbonyl-C1-6An alkoxy group.
"Hydroxycarbonylalkoxy", alone or in combination with other groups, refers to a group of the formula-O-R-C (O) -OH, wherein R is alkylene as defined herein, e.g. -C1-6alkoxy-carbonyl-OH.
"Alkylaminocarbonylalkoxy", alone or in combination with other groups, refers to a group of the formula-O-R-C (O) -NHR ', wherein R and R' are independently alkylene and alkyl as defined herein.
"Dialkylaminocarbonylalkoxy", alone or in combination with other groups, refers to a group of the formula-O-R-C (O) -NR 'R ", wherein R is alkylene as defined herein and R' and R" are alkyl as defined herein.
"alkylaminoalkoxy", alone or in combination with other groups, refers to a group of the formula-O-R-NHR ', wherein R and R' are, respectively, alkylene and alkyl as defined herein.
"Dialkylaminoalkoxy", alone or in combination with other groups, refers to a group of the formula-O-R-NR ' R ', wherein R is an alkylene group as defined herein and R ' and R "are alkyl groups as defined herein.
"alkylsulfonyl", alone or in combination with other groups, refers to the formula-SO2A moiety of-R, wherein R is alkyl as defined herein, e.g. C1-6An alkyl-sulfonyl group.
"alkyl-heterocyclyl", alone or in combination with other groups, refers to formula C1-6alkyl-R moieties, wherein R is heterocyclyl as defined herein, e.g. C1-6Alkyl-heterocyclyl.
"Alkylsulfonylalkyl", alone or in combination with other groups, refers to a compound of the formula-R' -SO2A moiety of the formula-R ', wherein R ' and R ' are, respectively, alkylene and alkyl as defined herein, e.g. C1-6alkylsulfonyl-C1-6An alkyl group.
"Alkylsulfonylalkoxy", alone or in combination with other groups, refers to a compound of the formula-O-R-SO2-R 'wherein R and R' are alkylene and alkyl, respectively, as defined herein.
"amino", alone or in combination with other groups, refers to a moiety of the formula-NRR ', where R and R' are each independently hydrogen or alkyl as defined herein. "amino" thus includes "alkylamino (where one of R and R 'is alkyl and the other is hydrogen) and" dialkylamino (where R and R' are both alkyl).
"aminocarbonyl", alone or in combination with other groups, refers to a group of formula-C (O) -R, wherein R is amino as defined herein.
"Alkoxyamino", alone OR in combination with other groups, refers to a moiety of the formula-NR-OR ', wherein R is hydrogen OR alkyl and R' is alkyl, wherein alkyl is as defined herein.
"alkylthio", alone or in combination with other groups, refers to a moiety of formula-SR, wherein R is alkyl as defined herein.
"aminoalkyl", alone or in combination with other groups, refers to the group-R-R ', wherein R' and R are, respectively, amino and alkylene as defined herein, e.g., amino-C1-6An alkyl group. "aminoalkyl" includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl and the like. The amino moiety of "aminoalkyl" may be substituted once or twice with alkyl to provide "alkylaminoalkyl" and "dialkylaminoalkyl", respectively. "alkylaminoalkyl" includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl, and the like. "dialkylaminoalkyl" includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, and the like.
"aminoalkoxy", alone OR in combination with other groups, refers to the group-OR-R ', where R' and R are, respectively, amino and alkylene as defined herein.
"Alkylsulfonamide", alone or in combination with other groups, refers to a compound of the formula-NR' SO2A moiety of-R, wherein R is alkyl and R' is hydrogen or alkyl.
"aminocarbonyloxyalkyl" or "carbamoylalkyl", alone or in combination with other groups, refers to a group of the formula-R-O-C (O) -NR 'R ", wherein R is alkylene and R', R" are each independently hydrogen or alkyl as defined herein.
"Alkynylalkoxy", alone or in combination with other groups, refers to a group of the formula-O-R-R ', wherein R and R' are alkylene and alkynyl groups, respectively, as defined herein.
"aryl", alone or in combination with other groups, refers to a monovalent cyclic aromatic moiety composed of a monocyclic, bicyclic, or tricyclic aromatic ring. Aryl groups may be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfide, diphenylsulfonyl, diphenylisopropylidene, benzodiazepineAlkyl, benzofuranyl, benzodioxolyl, benzopyranyl, benzoAzinyl radical, benzoOxazinonyl (benzoxazinonyl), benzopiperidinyl (benzopiperadinyl), benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, which may be optionally substituted as defined herein.
"arylalkyl" and "aralkyl" are used interchangeably, alone or in combination with other groups, to mean the group-RaRbWherein R isaAnd RbAlkylene and aryl, respectively, as defined herein; for example, phenylalkyl such as benzyl, phenethyl, 3- (3-chlorophenyl) -2-methylpentyl and the like are examples of arylalkyl groups.
"arylsulfonyl", alone or in combination with other groups, means of the formula-SO2-R, wherein R is aryl as defined herein.
"aryloxy", alone or in combination with other groups, refers to a group of the formula-O-R, wherein R is aryl as defined herein.
"aralkoxy", alone or in combination with other groups, refers to a group of the formula-O-R-R ', wherein R and R' are, respectively, alkylene and aryl as defined herein.
"carboxy" or "hydroxycarbonyl" are used interchangeably, and refer to groups of the formula-C (O) -OH, alone or in combination with other groups.
"cyanoalkyl", alone or in combination with other groups, refers to a moiety of the formula-R '-R ", wherein R' is alkylene as defined herein and R" is cyano or nitrile.
"cycloalkyl", alone or in combination with other groups, means a monovalent saturated carbocyclic moiety consisting of a monocyclic or bicyclic ring, e.g. C3-6A cycloalkyl group. Particular cycloalkyl groups are unsubstituted or substituted with alkyl groups. Cycloalkyl groups may be optionally substituted as defined herein. Unless otherwise defined, cycloalkyl groups may be optionally substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated (cycloalkenyl) derivatives thereof.
"cycloalkylalkyl", alone or in combination with other groups, refers to a moiety of the formula-R '-R', where R 'and R' are independently alkylene and cycloalkyl as defined herein, e.g., C3-6cycloalkyl-C1-6An alkyl group.
"cycloalkylalkoxy", alone or in combination with other groups, refers to a group of the formula-O-R-R ', wherein R and R' are, respectively, alkylene and cycloalkyl as defined herein.
"Cycloalkylcarbonyl", alone or in combination with other groups, refers to a moiety of formula-C (O) -RWherein R is cycloalkyl as defined herein, e.g. C3-6Cycloalkyl-carbonyl groups.
"heteroaryl", alone or in combination with other groups, means a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic ring containing one, two or three ring heteroatoms selected from N, O or S, the remaining ring atoms being C, wherein it is understood that the point of attachment of the heteroaryl group is on the aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl,azolyl radical, isoAn azole group, a thiazole group, an isothiazole group,oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzofuranyl, benzothiophenyl, thienyl, and the likeAzolyl radical, benzoOxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, aza-azanylRadical, diazaA group, acridine group, etc., each of which may beOptionally substituted as defined herein.
"heteroarylalkyl" or "heteroaralkyl", alone or in combination with other groups, refers to a group of the formula-R-R ', wherein R and R' are, respectively, alkylene and heteroaryl as defined herein.
"Heteroarylsulfonyl", alone or in combination with other groups, means of the formula-SO2-R, wherein R is heteroaryl as defined herein.
"heteroaryloxy", alone or in combination with other groups, refers to a group of the formula-O-R, wherein R is heteroaryl as defined herein.
"Heteroaralkyloxy", alone or in combination with other groups, refers to a group of the formula-O-R-R ", wherein R and R' are, respectively, alkylene and heteroaryl as defined herein.
The terms "halo", "halogen" and "halide" are used interchangeably and refer to the substituents fluorine (F), chlorine (Cl), bromine (Br), or iodine (I), alone or in combination with other groups.
"haloalkyl", alone or in combination with other groups, means an alkyl group as defined herein wherein one or more hydrogens have been replaced with the same or different halogen, e.g. halo-C1-6An alkyl group. In particular fluorine-C1-6An alkyl group. Exemplary haloalkyl groups include-CH2Cl，-CH2CF3，-CH2CCl3Perfluoroalkyl (e.g. -CF)3) And the like.
"haloalkoxy", alone OR in combination with other groups, refers to a moiety of the formula-OR, wherein R is a haloalkyl moiety as defined herein, e.g., halo-C1-6An alkoxy group. An exemplary haloalkoxy group is difluoromethoxy.
"heterocyclic amino", alone or in combination with other groups, refers to a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.
"heterocyclyl", alone or in combination with other groups, refers to a monovalent saturated moiety consisting of one to three rings, incorporating one, two or three or four heteroatoms (selected from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azaA pyrrolidinyl group, an azetidinyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, an oxetanyl group, etc. Such heterocyclyl groups may be optionally substituted as defined herein. In particular morpholinyl, piperidinyl, octahydro-pyrido [1, 2-a ]]Pyrazinyl, azetidinyl, piperazinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, [1, 4]Oxazepanyl, 3-oxa-8-aza-bicyclo [3.2.1]]Octyl, 2-oxa-5-aza-bicyclo [2.2.1]Heptyl, (1S, 4S) -2-oxa-5-azabicyclo [2.2.1]Heptylalkyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 2-oxa-6-aza-spiro [3.3]Heptyl, pyrimidinyl, and oxetan-3-yl. In particular morpholin-4-yl, piperidin-1-yl, octahydro-pyrido [1, 2-a ]]Pyrazin-2-yl, azetidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, piperidin-4-yl, tetrahydropyran-3-yl, [1, 4]]Oxazepan-4-yl, 3-oxa-8-aza-bicyclo [3.2.1]Oct-8-yl, 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl, (1S, 4S) -2-oxa-5-azabicyclo [2.2.1]Heptan-5-yl, 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl, 2-oxa-6-aza-spiro [3.3]Hept-6-yl, pyrimidin-5-yl and oxetan-3-yl.
"Heterocyclylalkyl", alone or in combination with other groups, refers to a moiety of the formula-R-R ', wherein R and R' are independently alkylene and heterocyclyl as defined herein, e.g., heterocyclyl-C1-6An alkyl group.
"Heterocyclyloxy", alone OR in combination with other groups, refers to a moiety of formula-OR, wherein R is heterocyclyl as defined herein.
"Heterocyclylalkoxy", alone OR in combination with other groups, refers to a moiety of the formula-OR-R ', where R and R' are alkylene and heterocyclyl, respectively, as defined herein.
"hydroxy", alone or in combination with other groups, refers to the group-OH.
"Hydroxyalkoxy", alone OR in combination with other groups, refers to a moiety of the formula-OR, where R is hydroxyalkyl as defined herein.
"Hydroxyalkylamino", alone or in combination with other groups, refers to a moiety of the formula-NR-R ', wherein R is hydrogen or alkyl and R' is hydroxyalkyl as defined herein.
"Hydroxyalkylaminoalkyl", alone or in combination with other groups, refers to a moiety of the formula-R-NR '-R ", wherein R is alkylene, R' is hydrogen or alkyl, and R" is hydroxyalkyl as defined herein.
"Hydroxycarbonylalkyl" or "carboxyalkyl", alone or in combination with other groups, refers to a group of the formula-R- (CO) -OH, wherein R is alkylene as defined herein.
"Hydroxycarbonylalkoxy", alone or in combination with other groups, refers to a group of the formula-O-R-C (O) -OH, wherein R is alkylene as defined herein.
"Hydroxyalkyloxycarbonylalkyl" or "hydroxyalkoxycarbonylalkyl", alone or in combination with other groups, refers to a group of the formula-R-C (O) -O-R-OH, wherein each R is alkylene and can be the same or different.
"hydroxyalkyl", alone or in combination with other groups, means an alkyl moiety as defined herein, which is substituted with one or more, e.g. one, two or three, hydroxyl groups, provided that the same carbon atom does not carry more than one hydroxyl group, e.g. hydroxy-C1-6An alkyl group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutylCyclobutyl, 2, 3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl.
"Hydroxycycloalkyl", alone or in combination with other groups, refers to a cycloalkyl moiety as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl group have been replaced by a hydroxyl substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl and the like.
"Alkoxyhydroxyalkyl" and "hydroxyalkoxyalkyl" are used interchangeably, alone or in combination with other groups, and refer to an alkyl group, as defined herein, substituted at least once with a hydroxyl group and at least once with an alkoxy group. Thus "alkoxyhydroxyalkyl" and "hydroxyalkoxyalkyl" encompass, for example, 2-hydroxy-3-methoxy-propan-1-yl and the like.
"Urea" or "ureido", alone or in combination with other groups, refers to a group of the formula-NR '-C (O) -NR "R'", wherein R ', R "and R'" are each independently hydrogen or alkyl.
"carbamate group," alone or in combination with other groups, refers to a group of the formula-O-C (O) -NR 'R "wherein R' and R" are each independently hydrogen or alkyl.
"carboxy", alone or in combination with other groups, refers to a group of the formula-O-C (O) -OH.
"Sulfonamido" (sulfonamide), alone or in combination with other groups, means a compound of the formula-SO2A group of-NR ' R ', wherein R ', R ' and R ' are each independently hydrogen or alkyl.
When combined with an "aryl", phenyl "," heteroaryl "," cycloalkyl "or" heterocyclyl "moiety," optionally substituted "means that such moiety may be unsubstituted (i.e., all open valences are occupied by hydrogen atoms) or substituted with the specified groups as referred to in this specification.
"leaving group" means a group having the meaning conventionally associated therewith in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions. Examples of leaving groups include, but are not limited to, halogen, alkyl-or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, methylthio, phenylsulfonyloxy, toluenesulfonyloxy, and thienyloxy, dihalophosphonooxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.
"modulator" refers to a molecule that interacts with a target. Such interactions include, but are not limited to, agonism, antagonism, and the like, as defined herein.
"nitrile" or "cyano", alone or in combination with other groups, refers to the group-C ≡ N.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
"disease" and "disease state" refer to any disease, condition, symptom, disorder, or sign.
By "inert organic solvent" or "inert solvent" is meant that the solvent is inert under the conditions of the reaction described in connection therewith and includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran, N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, di-N-butanol, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, N-dimethylformamide, NAlkanes, pyridines, and the like. Unless specified to the contrary, the solvent used in the reaction of the present invention is an inert solvent.
By "pharmaceutically acceptable" it is meant that it can be used to prepare pharmaceutical compositions (i.e., compositions) that are generally safe, non-toxic, and not biologically or otherwise undesirable, and include that they are acceptable for veterinary as well as human pharmaceutical use.
By "pharmaceutically acceptable salt" of a compound is meant a pharmaceutically acceptable salt as defined herein and which possesses the desired pharmacological activity of the parent compound.
It is to be understood that all references to pharmaceutically acceptable salts include the solvent addition forms (solvates) or crystalline forms (polymorphs) of the same acid addition salt as defined herein.
Examples of suitable salts with inorganic and organic acids are, but not limited to, acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, succinic acid, sulfuric acid, tartaric acid, trifluoroacetic acid and the like. Preferred are formic acid, trifluoroacetic acid and hydrochloric acid.
The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable auxiliary substance" refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.
The term "pharmaceutical composition" or "composition" encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Preferably, it encompasses products comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
"protecting group" or "protecting group" refers to a group that selectively blocks one reactive site in a polyfunctional compound in the sense conventionally associated therewith in synthetic chemistry so that a chemical reaction can be selectively carried out at another unprotected reactive site. Certain processes of the present invention rely on protecting groups to block reactive nitrogen and/or oxygen atoms present in the reactants. For example, the terms "amino-protecting group" and "nitrogen-protecting group" are used interchangeably herein and refer to those organic groups intended to protect a nitrogen atom from unwanted reactions during synthetic procedures. Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbonylbenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-Butoxycarbonyl (BOC), and the like. The person skilled in the art knows how to select groups that are easy to remove and that have the ability to withstand subsequent reactions.
"solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. The hydrate maintains its molecular state as H by combining one or more water molecules with water therein2One of the species of O, such combination being capable of forming one or more hydrates.
"Parkinson's disease" refers to a degenerative disorder of the central nervous system that impairs motor skills, speech and/or cognitive function. Symptoms of parkinson's disease may include, for example, muscle stiffness, tremor, slowing of body movement (bradykinesia), and loss of body movement (akinesia).
"Lewis body disease" also known as "Lewis body dementia", diffuse Lewy body disease ", cortical Lewis body disease" refers to a neurodegenerative disorder characterized anatomically by the presence of Lewis bodies in the brain.
By "subject" is meant both mammals and non-mammals. Mammal refers to any member of the mammalian class, including but not limited to humans; non-human primates such as chimpanzees and other apes and monkey species; livestock such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; the experimental animals include rodents such as rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds and the like. The term "subject" does not denote a particular age or gender.
The term "half maximal inhibitory concentration" (IC)50) Represents the concentration of a particular compound required to obtain 50% inhibition of a biological process in vitro. IC (integrated circuit)50The values can be converted logarithmically to pIC50Value (-log IC)50) Where higher values indicate greater potency exponentially. IC (integrated circuit)50The values are not absolute values but depend on the experimental conditions, such as the concentrations used. IC (integrated circuit)50Values can be converted to absolute inhibition constants (Ki) using the Cheng-Prusoff equation (biochem. Pharmacol. (1973) 22: 3099). The term "inhibition constant" (Ki) denotes the absolute binding affinity of a particular inhibitor to a receptor. It is measured using a competitive binding assay and is equal to the concentration at which a particular inhibitor would occupy 50% of the receptors if no competing ligand (e.g., radioligand) were present. Ki values can be converted logarithmically to pKi values (-log Ki), with higher values indicating greater potency exponentially.
"therapeutically effective amount" refers to an amount of a compound that, when administered to a subject to treat a disease state, is sufficient to effect such treatment of the disease state. The "therapeutically effective amount" will vary depending on the compound, the disease state being treated, the severity or disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.
When referring to a variable, the terms "as defined herein" and "as described herein" are incorporated by reference into the broad definition of the variable as well as the preferred, more preferred, and most preferred definitions, if any.
The term "tetrahydrofuranyl-C1-6Alkyl ", alone or in combination with other groups, refers to a tetrahydrofuranyl group linked via an alkyl group as defined herein.
The term "tetrahydropyranyl (tetrahydropyranyl) -C1-6Alkyl ", alone or in combination with other groups, refers to a tetrahydropyranyl group linked via an alkyl group as defined herein.
The term "oxetanyl-C1-6Alkyl ", alone or with othersA combination of groups refers to an oxetanyl group attached via an alkyl group as defined herein.
By "therapeutically effective amount" is meant an amount of a compound that, when administered to a subject to treat a disease state, is sufficient to effect such treatment of the disease state. The "therapeutically effective amount" will vary depending on the compound, the disease state being treated, the severity or disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.
When referring to a variable, the terms "those defined above" and "those defined herein" are incorporated by reference to the broad definition of the variable as well as the specific definitions, if any.
"treating" or "treatment" of a disease state includes, inter alia, inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, and/or alleviating the disease state, i.e., temporary or permanent reduction in the disease state or its clinical symptoms.
The terms "treating", "contacting …", and "reacting …" when referring to a chemical reaction refer to adding or mixing two or more reagents under appropriate conditions to produce the specified and/or desired product. It will be appreciated that the reaction that produces the specified and/or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e., there may be one or more intermediates produced in the mixture that ultimately result in the formation of the specified and/or desired product.
Naming and Structure
In general, the nomenclature and chemical names used in this application are based on ChembioloOffice, from Cambridge SoftTM. Unless otherwise indicated, any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. Where a nitrogen-containing heteroaryl ring is shown having an open valency on a nitrogen atom, and variables such as Ra, Rb, or Rc are shown on the heteroaryl ring, such variables may be bound or joined to the open valency nitrogen. In the case where a chiral center is present in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral center are encompassed by the structure. Where a structure shown herein can exist in multiple tautomeric forms, all such tautomers are encompassed by the structure. The atoms represented in the structures herein are intended to encompass all natural isotopes of such atoms. Thus, for example, hydrogen atoms represented herein are meant to include deuterium and tritium, and carbon atoms are meant to include C13 and C14 isotopes.
All patents and publications identified herein are incorporated by reference in their entirety.
Compounds of the invention
The present invention provides compounds of formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
m is 0 to 3;
x is: -NRa-; -O-; or-S (O)r-, where R is 0 to 2 and RaIs hydrogen or C1-6An alkyl group;
R1the method comprises the following steps: c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; hydroxy-C2-6An alkenyl group; amino-C1-6An alkyl group; c1-6alkylsulfonyl-C1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; a tetrahydropyranyl group; tetrahydropyranyl-C1-6Alkyl, oxetaneA group; or oxetane-C1-6An alkyl group;
or R1And RaTogether with the atoms to which they are attached may form a three-to six-membered ring, which may optionally include a further heteroatom selected from O, N and S, and which is oxo, halo or C1-6Alkyl substitution;
R2the method comprises the following steps: halogen; c1-6An alkoxy group; a cyano group; c2-6An alkynyl group; c2-6An alkenyl group; halo-C1-6An alkyl group; halo-C1-6An alkoxy group; c3-6Cycloalkyl, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; acetyl; an oxetanyl group; or oxetane-C1-6An alkyl group;
R3the method comprises the following steps: -OR4(ii) a Halogen; a cyano group; c1-6An alkyl group; halo-C1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R4the method comprises the following steps: hydrogen, C1-6An alkyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; optionally is covered with C1-6Alkyl or halogen substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl or halogen substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R5the method comprises the following steps: hydrogen; or C1-6An alkyl group;
n is 0 or 1;
R6the method comprises the following steps: hydrogen; c1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; hydroxy-C1-6An alkyl group; amino-C1-6An alkyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; a heterocyclic group; or heterocyclyl-C1-6An alkyl group; wherein said C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-6Alkyl, heterocyclyl and heterocyclyl-C1-6Each alkyl group may be optionally substituted with one, two, three or four groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring;
or R5And R6Together with the nitrogen atom to which they are attached form a three-to seven-membered ring, which optionally includes an additional ring selected from O, N and S (O)nAnd which is optionally substituted with one, two, three or four groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen, nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; c1-6Alkyl-heterocyclyl radical, C1-6alkoxy-C1-6An alkyl or heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring; and is
R7The method comprises the following steps: halogen; c1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkyl group; or halo-C1-6An alkoxy group.
The present invention provides compounds of formula I, or pharmaceutically acceptable salts thereof, wherein:
m is a number of 0 or 1,
x is: -NRa-or-O-, wherein RaIs hydrogen;
R1the method comprises the following steps: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; c1-6alkylsulfonyl-C1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical wherein the C3-6The cycloalkyl moiety is optionally substituted with: a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; a tetrahydropyranyl group; tetrahydropyranyl-C1-6An alkyl group;
or R1And RaTogether with the atoms to which they are attached may form a three to six membered ring, which may optionally include additional heteroatoms selected from O and N;
R2the method comprises the following steps: halogen; c1-6An alkoxy group; a cyano group; c1-6An alkynyl group; halo-C1-6An alkyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety optionally substituted with acetyl;
R3the method comprises the following steps: -OR4(ii) a Halogen; c1-6An alkyl group; c3-6A cycloalkyl group;
R4the method comprises the following steps: hydrogen, C1-6An alkyl group; halo-C1-6An alkyl group; optionally is covered with C3-6cycloalkyl-C1-6Alkyl substituted C3-6A cycloalkyl group;
R5the method comprises the following steps: hydrogen or C1-6 alkyl;
n is 0 or 1;
R6the method comprises the following steps: hydrogen; c1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; hydroxy-C1-6An alkyl group; amino-C1-6An alkyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; a heterocyclic group; or heterocyclyl-C1-6An alkyl group; wherein said C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-6Alkyl, heterocyclyl and heterocyclyl-C1-6Each alkyl group may be optionally substituted with one, two, three or four groups independently selected from: c1-6An alkyl group; halogen and nitrile;
or R5And R6Together with the nitrogen atom to which they are attached, form a three-to seven-membered ring, which optionally includes additional heteroatoms selected from O and N, and which is optionally substituted with one, two, three or four groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen, nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6Cycloalkyl-carbonyl; c1-6Alkyl-heterocyclyl radical, C1-6alkoxy-C1-6Alkyl, heterocyclyl; or two of these groups together with the atoms to which they are attached may form a five or six membered ring; and is
R7The method comprises the following steps: halogen or C1-6An alkoxy group.
The present invention provides compounds of formula I, or pharmaceutically acceptable salts thereof, wherein:
m is a number of 0 or 1,
x is-NH-or-O-,
R1is C1-6An alkyl group;
R2is halogen; cyano or halo-G1-6An alkyl group;
R3is-OR4Or halogen;
R4is C1-6An alkyl group;
R5the method comprises the following steps: hydrogen;
n is 0;
R6is C1-6An alkyl group;
or R5And R6Together with the nitrogen atom to which they are attached form a morpholino ring; and is
R7Is halogen or C1-6An alkoxy group.
The present invention provides compounds of formula I, or pharmaceutically acceptable salts thereof, wherein:
m is a number of 0 or 1,
x is-NH-or-O-,
R1is methyl or ethyl;
R2is Cl, CN or trifluoromethyl;
R3is Cl, methoxy, ethoxy or isopropoxy;
R5the method comprises the following steps: hydrogen;
n is 0;
R6is a tert-butyl group;
or R5And R6Together with the nitrogen atom to which they are attached form a morpholino ring; and is
R7Is F or methoxy.
The present invention also provides compounds of formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
m is 0 to 3;
x is: -NRa-; -O-; or-S (O)r-, where R is 0 to 2 and RaIs hydrogen or C1-6An alkyl group;
R1the method comprises the following steps: c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; hydroxy-C2-6An alkenyl group; amino-C1-6An alkyl group; c1-6alkylsulfonyl-C1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
or R1And RaTogether with the atoms to which they are attached may form a three-to six-membered ring, which may optionally include a further heteroatom selected from O, N and S, and which is oxo, halo or C1-6Alkyl substitution;
R2the method comprises the following steps: halogen; c1-6An alkoxy group; a cyano group; c2-6An alkynyl group; c2-6An alkenyl group; halo-C1-6An alkyl group; halo-C1-6An alkoxy group; c3-6Cycloalkyl, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; acetyl; an oxetanyl group; or oxetane-C1-6An alkyl group;
R3the method comprises the following steps: -OR4(ii) a Halogen; a cyano group; c1-6An alkyl group; halo-C1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R4the method comprises the following steps: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; optionally is covered with C1-6Alkyl or halogen substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl or halogen substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R5the method comprises the following steps: hydrogen; or C1-6An alkyl group;
n is 0 or 1;
R6the method comprises the following steps: hydrogen; c1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; hydroxy-C1-6An alkyl group; amino-C1-6An alkyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; a heterocyclic group; or heterocyclyl-C1-6An alkyl group; wherein said C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-6Alkyl, heterocyclyl and heterocyclyl-C1-6Each alkyl group may be optionally substituted with one, two, three or four groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring;
or R5And R6Together with the nitrogen atom to which they are attached form a three-to seven-membered ring, which optionally includes an additional ring selected from O, N and S (O)nAnd which is optionally substituted with one, two, three or four groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen, nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring; and is
R7The method comprises the following steps: halogen; c1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkyl group; or halo-C1-6An alkoxy group.
In certain embodiments of formula I, n is 0.
In certain embodiments of formula I, n is 1.
In certain embodiments of formula I, R1And RaTogether with the atoms to which they are attached may form a three-to six-membered ring, which may optionally include a further heteroatom selected from O, N and S, and which may be oxo, halo or C1-6The alkyl group is optionally substituted.
In certain embodiments of formula I, R1And RaTogether with the atoms to which they are attached form a five or six membered ring.
In certain embodiments of formula I, R1And RaTogether with the atoms to which they are attached form pyrrolidinyl, piperidinyl orAn oxazolidone group.
In the formula IIn certain embodiments, R2Is an acetyl group.
In certain embodiments, the subject compounds are of formula II:
or a pharmaceutically acceptable salt thereof,
wherein X, m, R1，R2，R3，R5And R7As defined in formula I.
In certain embodiments, the subject compounds are of formula II:
or a pharmaceutically acceptable salt thereof,
wherein:
m is 0 to 3;
x is: -NRa-; -O-; or-S (O)r-, where R is 0 to 2 and RaIs hydrogen or C1-6An alkyl group;
R1the method comprises the following steps: c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; hydroxy-C2-6An alkenyl group; amino-C1-6An alkyl group; c1-6alkylsulfonyl-C1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R2the method comprises the following steps: halogen; c1-6An alkoxy group; a cyano group; c2-6An alkynyl group; c2-6An alkenyl group; halo-C1-6An alkyl group; halo-C1-6An alkoxy group; c3-6Cycloalkyl, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R3the method comprises the following steps: -OR4(ii) a Halogen; a cyano group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R4the method comprises the following steps: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R5the method comprises the following steps: hydrogen; or C1-6An alkyl group;
R6the method comprises the following steps: hydrogen; c1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; amino-C1-6An alkyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; a heterocyclic group; or heterocyclyl-C1-6An alkyl group; wherein said C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-6Alkyl, heterocyclyl and heterocyclyl-C1-6Each alkyl group may optionally be substituted by one, two or three independentlySubstituted with a group selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring;
or R5And R6Together with the nitrogen atom to which they are attached form a three-to seven-membered ring, which optionally includes an additional ring selected from O, N and S (O)nAnd which is optionally substituted with one, two or three groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen, nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring; and is
R7The method comprises the following steps: halogen; c1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkyl group; or halo-C1-6An alkoxy group.
In certain embodiments of formula I, when R1Is C3-6Cycloalkyl or C3-6cycloalkyl-C1-6When alkyl, then X is-O-.
In certain embodiments of formula I, when R1Is cyclopropyl, cyclobutyl, cyclopropyl-C1-6Alkyl or cyclobutyl-C1-6When alkyl, then X is-O-.
In certain embodiments of formula I or formula II, m is 0 to 2.
In certain embodiments of formula I or formula II, m is 0 or 1.
In certain embodiments of formula I or formula II, m is 0.
In certain embodiments of formula I or formula II, m is 1.
In certain embodiments of formula I or formula II, r is 0.
In certain embodiments of formula I or formula II, r is 2.
In certain embodiments of formula I or formula II, X is-NRa-or-O-.
In certain embodiments of formula I or formula II, X is-NRa。
In certain embodiments of formula I or formula II, X is — O-.
In certain embodiments of formula I or formula II, X is-S (O)n-。
In certain embodiments of formula I or formula II, X is-NH-or-O-.
In certain embodiments of formula I or formula II, RaIs hydrogen.
In certain embodiments of formula I or formula II, RaIs C1-6An alkyl group.
In certain embodiments of formula I or formula II, R1The method comprises the following steps: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; amino-C1-6An alkyl group; c1-6alkylsulfonyl-C1-6An alkyl group; c3-6A cycloalkyl group; or C3-6cycloalkyl-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R1The method comprises the following steps: c1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; or C3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution.
In certain embodiments of formula I or formula II, R1The method comprises the following steps: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; amino-C1-6An alkyl group; c1-6alkylsulfonyl-C1-6An alkyl group; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R1The method comprises the following steps: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; amino-C1-6An alkyl group; or C1-6alkylsulfonyl-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R1Is C1-6An alkyl group.
In certain embodiments of formula I or formula II, R1Is halo-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R1Is C1-6alkoxy-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R1Is amino-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R1Is optionally covered with C1-6Alkyl substituted C1-6alkylsulfonyl-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R1Is optionally covered with C1-6Alkyl substituted C3-6A cycloalkyl group.
In certain embodiments of formula I or formula II, R1Is C3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution.
In certain embodiments of formula I or formula II, R1Is tetrahydrofuranyl.
In certain embodiments of formula I or formula II, R1Is tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group.
In certain embodiments of formula I or formula II, R1Is or oxetane-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R1The method comprises the following steps: a methyl group; an ethyl group; n-propyl; isopropyl group; an isobutyl group; 3, 3-dimethylpropyl; a cyclopropyl group; a cyclobutyl group; a cyclopentyl group; a cyclohexyl group; a cyclopropyl methyl group; a cyclobutylmethyl group; a cyclopentyl methyl group; a cyclopropyl ethyl group; a methoxyethyl group; an oxetanyl group; or tetrahydrofurylmethyl.
In certain embodiments of formula I or formula II, R1The method comprises the following steps: a methyl group; an ethyl group; n-propyl; isopropyl group; an isobutyl group; 3, 3-dimethylpropyl; a cyclopentyl group; a cyclohexyl group; a cyclopropyl methyl group; a cyclobutylmethyl group; a cyclopentyl methyl group; a cyclopropyl ethyl group; a methoxyethyl group; an oxetanyl group; or tetrahydrofurylmethyl.
In certain embodiments of formula I or formula II, R1The method comprises the following steps: a methyl group; an ethyl group; n-propyl; isopropyl group; an isobutyl group; 3, 3-dimethylpropyl; a cyclopentyl group; a cyclohexyl group; a cyclopentyl methyl group; a methoxyethyl group; an oxetanyl group; or tetrahydrofurylmethyl.
In certain embodiments of formula I or formula II, R1The method comprises the following steps: a methyl group; an ethyl group; n-propyl; isopropyl group; or an isobutyl group.
In certain embodiments of formula I or formula II, R1Is methyl or ethyl.
In certain embodiments of formula I or formula II, R1Is methyl.
In certain embodiments of formula I or formula II, R1Is ethyl.
In certain embodiments of formula I or formula II, R1The method comprises the following steps: a cyclopropyl group; a cyclobutyl group; a cyclopentyl group; a cyclohexyl group; a cyclopropyl methyl group; a cyclobutylmethyl group; a cyclopentyl methyl group; or a cyclopropylethyl group.
In certain embodiments of formula I or formula II, R1The method comprises the following steps: a cyclopentyl group; a cyclohexyl group; or a cyclopentylmethyl group.
In certain embodiments of formula I or formula II, R2The method comprises the following steps: halogen; c1-6An alkoxy group; halo-C1-6An alkyl group; halo-C1-6An alkoxy group; c3-6Cycloalkyl, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R2The method comprises the following steps: halogen; c1-6An alkoxy group; halo-C1-6An alkyl group; a cyano group; c2-6An alkynyl group; c2-6An alkenyl group; c3-6A cycloalkyl group; or C3-6cycloalkyl-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R2The method comprises the following steps: halogen; c1-6An alkoxy group; halo-C1-6An alkyl group; a cyano group; c3-6A cycloalkyl group; or C3-6cycloalkyl-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R2The method comprises the following steps: halogen; c1-6An alkoxy group; halo-C1-6An alkyl group; c3-6A cycloalkyl group; or C3-6cycloalkyl-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R2The method comprises the following steps: halogen; halo-C1-6An alkyl group; or a cyano group.
In certain embodiments of formula I or formula II, R2The method comprises the following steps: halogen; or halo-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R2Is a halogen.
In certain embodiments of formula I or formula II, R2Is C1-6An alkoxy group.
In certain embodiments of formula I or formula II, R2Is halo-C1-6An alkoxy group.
In certain embodiments of formula I or formula II, R2Is halo-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R2Is C3-6A cycloalkyl group.
In certain embodiments of formula I or formula II, R2Is C3-6cycloalkyl-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R2Is tetrahydrofuranyl.
In certain embodiments of formula I or formula II, R2Is tetrahydrofuryl-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R2Is an oxetanyl group.
In certain embodiments of formula I or formula II, R2Is oxetane-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R2Is halogen, trifluoromethyl or cyano.
In certain embodiments of formula I or formula II, R2Is chloro, trifluoromethyl or cyano.
In certain embodiments of formula I or formula II, R2Is fluorine, chlorine or bromine.
In certain embodiments of formula I or formula II, R2Is chlorine.
In certain embodiments of formula I or formula II, R2Is fluorine.
In certain embodiments of formula I or formula II, R2Is bromine.
In certain embodiments of formula I or formula II, R2Is trifluoromethyl.
In certain embodiments of formula I or formula II, R2Is methoxy.
In certain embodiments of formula I or formula II, R2Is cyano.
In certain embodiments of formula I or formula II, R2Is C2-6Alkynyl.
In certain embodiments of formula I or formula II, R2Is C2-6An alkenyl group.
In certain embodiments of formula I or formula II, R3is-OR4。
In certain embodiments of formula I or formula II, R3The method comprises the following steps: c1-6An alkyl group; or halo-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R3The method comprises the following steps: halogen; OR-OR4。
In certain embodiments of formula I or formula II, R3The method comprises the following steps: halogen; c1-6An alkoxy group; halo-C1-6An alkoxy group; c3-6A cycloalkyloxy group; or C3-6cycloalkyl-C1-6An alkyloxy group.
In certain embodiments of formula I or formula II, R3The method comprises the following steps: c1-6An alkoxy group; halo-C1-6An alkoxy group; c3-6A cycloalkyloxy group; or C3-6cycloalkyl-C1-6An alkyloxy group.
In certain of formula I or formula IIIn an embodiment, R3The method comprises the following steps: halogen; c1-6An alkoxy group; a cyano group; or halo-C1-6An alkoxy group.
In certain embodiments of formula I or formula II, R3The method comprises the following steps: halogen; c1-6An alkoxy group; or halo-C1-6An alkoxy group.
In certain embodiments of formula I or formula II, R3The method comprises the following steps: a methoxy group; halogen; a trifluoromethoxy group; a difluoromethoxy group; 2-halo-ethoxy or 2, 2, 2-trihaloethoxy.
In certain embodiments of formula I or formula II, R3The method comprises the following steps: a methoxy group; or a halogen.
In certain embodiments of formula I or formula II, R3The method comprises the following steps: a methoxy group; chlorine; or fluorine.
In certain embodiments of formula I or formula II, R3Is methoxy.
In certain embodiments of formula I or formula II, R3Is chlorine.
In certain embodiments of formula I or formula II, R3Is fluorine.
In certain embodiments of formula I or formula II, R3The method comprises the following steps: c1-6An alkoxy group; a cyano group; or halo-C1-6An alkoxy group.
In certain embodiments of formula I or formula II, R3The method comprises the following steps: c1-6An alkoxy group; or halo-C1-6An alkoxy group.
In certain embodiments of formula I or formula II, R3Is C1-6An alkoxy group.
In certain embodiments of formula I or formula II, R3Is methoxy.
In certain embodiments of formula I or formula II, R3Is cyano.
In certain embodiments of formula I or formula IIIn the formula, R3Is C3-6A cycloalkyl group.
In certain embodiments of formula I or formula II, R3Is C3-6cycloalkyl-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R3Is tetrahydrofuranyl. In certain embodiments of formula I or formula II, R3Is tetrahydrofuryl-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R3Is an oxetanyl group.
In certain embodiments of formula I or formula II, R3Is oxetane-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R4The method comprises the following steps: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; c3-6A cycloalkyl group; or C3-6cycloalkyl-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R4The method comprises the following steps: c1-6An alkyl group; halo-C1-6An alkyl group; or C3-6A cycloalkyl group.
In certain embodiments of formula I or formula II, R4Is C1-6An alkyl group.
In certain embodiments of formula I or formula II, R4Is halo-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R4Is C1-6alkoxy-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R4Is C3-6A cycloalkyl group.
In certain embodiments of formula I or formula II, R4Is C3-6cycloalkyl-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R4Is tetrahydrofuranyl.
In certain embodiments of formula I or formula II, R4Is tetrahydrofuryl-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R4Is an oxetanyl group.
In certain embodiments of formula I or formula II, R4Is or oxetane-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R4The method comprises the following steps: a methyl group; an ethyl group; isopropyl group; a cyclopropyl group; a cyclobutyl group; a cyclopropyl methyl group; a cyclobutylmethyl group; 2-haloethyl; or a2, 2, 2-trihaloethyl group.
In certain embodiments of formula I or formula II, R4Is methyl.
In certain embodiments of formula I or formula II, R5Is hydrogen.
In certain embodiments of formula I or formula II, R5Is C1-6An alkyl group.
In certain embodiments of formula I or formula II, R5Is methyl.
In certain embodiments of formula I or formula II, R5Is ethyl.
In certain embodiments of formula I or formula II, R6Is hydrogen.
In certain embodiments of formula I or formula II, R6Is C1-6An alkyl group.
In certain embodiments of formula I or formula II, R6Is C1-6alkoxy-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R6Is hydroxy-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R6Is amino-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R6Is C optionally substituted by one, two or three groups independently selected from3-6Cycloalkyl groups: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring.
In certain embodiments of formula I or formula II, R6Is C3-6cycloalkyl-C1-6Alkyl radical, wherein C3-6The cycloalkyl moiety is optionally substituted with one, two or three groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring.
In certain embodiments of formula I or formula II, wherein R is6Is a heterocyclic group, such heterocyclic group may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; morpholinyl; a thiomorpholinyl group; 3-oxa-8-aza-bicyclo [3.2.1]Oct-8-yl; 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl; or 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl; each optionally substituted as defined herein.
In certain embodiments of formula I or formula II, wherein R is6Is a heterocyclic group, such heterocyclic group may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; or a morpholinyl group; each as defined herein, is optionally substituted, i.e., such heterocyclyl is optionally substituted with one, two or three groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring.
In certain embodiments of formula I or formula II, R6Is heterocyclyl optionally substituted by one, two or three groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring.
In certain embodiments of formula I or formula II, wherein R is6Is heterocyclyl-C1-6Alkyl, the heterocyclyl portion of which may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; morpholinyl; a thiomorpholinyl group; 3-oxa-8-aza-bicyclo [3.2.1]Oct-8-yl; 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl; or 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl; each as defined herein, is optionally substituted, i.e., such heterocyclyl moiety is optionally substituted with one, two or three groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring.
In certain embodiments of formula I or formula II, wherein R is6Is heterocyclyl-C1-6Alkyl, the heterocyclyl portion of which may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; or a morpholinyl group; each optionally substituted as defined herein.
In certain embodiments of formula I or formula II, R6Is heterocyclyl-C1-6Alkyl, wherein the heterocyclyl portion thereof is optionally substituted with one, two or three groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring.
In certain embodiments of formula I or formula II, R6The method comprises the following steps: hydrogen; a methyl group; an ethyl group; isopropyl group; or a cyclopropyl group.
In certain embodiments of formula I or formula II, R6The method comprises the following steps: hydrogen; a methyl group; an ethyl group; isopropyl group; 2-amino-propyl; oxetan-3-yl; 2-methoxy-ethyl; 2-hydroxy-ethyl; a cyclopropyl group; piperidin-4-yl; 1-methyl-piperidin-4-yl; a tertiary butyl group; 2-hydroxy-2-methyl-propyl; a cyclobutyl group; 1-methyl-cyclobutyl; 2-hydroxy-propyl; 1-cyano-cyclopropyl; 3, 3-difluoro-cyclobutyl; a cyclopropyl methyl group; 3-fluoro-cyclobutyl; or 2, 2-difluoroethyl;
in certain embodiments of formula I or formula II, R6Is hydrogen.
In certain embodiments of formula I or formula II, R6Is methyl.
In certain embodiments of formula I or formula II, R6Is ethyl.
In certain embodiments of formula I or formula II, R6Is isopropyl.
In certain embodiments of formula I or formula II, R6Is 2-amino-propyl.
In certain embodiments of formula I or formula II, R6Is oxetan-3-yl.
In certain embodiments of formula I or formula II, R6Is 2-methoxy-ethyl.
In certain embodiments of formula I or formula II, R6Is 2-hydroxy-ethyl.
In certain embodiments of formula I or formula II, R6Is cyclopropyl.
In certain embodiments of formula I or formula II, R6Is piperidin-4-yl.
In certain embodiments of formula I or formula II, R6Is 1-methyl-piperidin-4-yl.
In certain embodiments of formula I or formula II, R6Is a tert-butyl group.
In certain embodiments of formula I or formula II, R6Is 2-hydroxy-2-methyl-propyl.
In certain embodiments of formula I or formula II, R6Is a cyclobutyl group.
In certain embodiments of formula I or formula II, R6Is 1-methyl-cyclobutyl.
In certain embodiments of formula I or formula IIIn the formula (II) R6Is 2-hydroxy-propyl.
In certain embodiments of formula I or formula II, R6Is 1-cyano-cyclopropyl.
In certain embodiments of formula I or formula II, R6Is 3, 3-difluoro-cyclobutyl.
In certain embodiments of formula I or formula II, R6Is cyclopropylmethyl.
In certain embodiments of formula I or formula II, R6Is 3-fluoro-cyclobutyl.
In certain embodiments of formula I or formula II, R6Is 2, 2-difluoroethyl.
In certain embodiments of formula I or formula II, R5And R6The nitrogen atom to which they are attached forms a three to seven membered ring, which optionally includes an additional heteroatom selected from O, N and s (o) n, and which is optionally substituted with one, two or three groups independently selected from: c1-6Alkyl, halo-C1-6Alkyl radical, C1-6Alkoxy, halo-C1-6Alkoxy, hydroxy-C1-6Alkyl, halogen, nitrile, C1-6Alkyl-carbonyl, C1-6Alkyl-sulfonyl radical, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-6Alkyl radical, C3-6Cycloalkyl-carbonyl, or heterocyclyl, or two of these groups together with the atoms to which they are attached may form a five or six membered ring.
In certain embodiments of formula I or formula II, wherein R is5And R6Form a three-to seven-membered ring with the nitrogen atom to which they are attached, which ring optionally includes an additional ring selected from O, N and S (O)nSuch ring may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; morpholinyl; a thiomorpholinyl group; aza derivativesA group; 3-oxa-8-aza-bicyclics[3.2.1]Oct-8-yl; 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl; or 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl; each optionally substituted as defined herein.
In certain embodiments of formula I or formula II, wherein R is5And R6Together with the nitrogen atom to which they are attached form a three-to seven-membered ring, which optionally includes an additional ring selected from O, N and S (O)nSuch ring may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; or a morpholinyl group; each optionally substituted as defined herein.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a morpholinyl group, which morpholinyl group is optionally substituted once or twice with a group independently selected from: c1-6Alkyl, halo-C1-6Alkyl radical, C1-6Alkoxy, halo-C1-6Alkoxy, hydroxy-C1-6Alkyl, halogen, nitrile, C1-6Alkyl-carbonyl, C1-6Alkyl-sulfonyl radical, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-6Alkyl radical, C3-6Cycloalkyl-carbonyl, amino, or heterocyclyl, or both groups together with the atoms to which they are attached may form a five or six membered ring.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a piperidinyl group, which piperidinyl group is optionally substituted once or twice by groups independently selected from: c1-6Alkyl, halo-C1-6Alkyl radical, C1-6Alkoxy, halo-C1-6Alkoxy, hydroxy-C1-6Alkyl, halogen, nitrile, C1-6Alkyl-carbonyl, C1-6Alkyl-sulfonyl radical, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-6Alkyl radical, C3-6Cycloalkyl-carbonyl, amino, or heterocyclyl, or both groups together with the atoms to which they are attached may form a five or six membered ring.
In certain embodiments of formula I or formula II, R5And R6(ii) forms a piperazinyl group with the nitrogen atom to which they are attached, which group is optionally substituted once or twice with groups independently selected from: c1-6Alkyl, halo-C1-6Alkyl radical, C1-6Alkoxy, halo-C1-6Alkoxy, hydroxy-C1-6Alkyl, halogen, nitrile, C1-6Alkyl-carbonyl, C1-6Alkyl-sulfonyl radical, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-6Alkyl radical, C3-6Cycloalkyl-carbonyl, amino, or heterocyclyl, or both groups together with the atoms to which they are attached may form a five or six membered ring.
In certain embodiments of formula I or formula II, R5And R6Forming a pyrrolidinyl group with the nitrogen atom to which they are attached, the group being optionally substituted one or two times with groups independently selected from: c1-6Alkyl, halo-C1-6Alkyl radical, C1-6Alkoxy, halo-C1-6Alkoxy, hydroxy-C1-6Alkyl, halogen, nitrile, C1-6Alkyl-carbonyl, C1-6Alkyl-sulfonyl radical, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-6Alkyl radical, C3-6Cycloalkyl-carbonyl, amino, or heterocyclyl, or both groups together with the atoms to which they are attached may form a five or six membered ring.
In certain embodiments of formula I or formula II, R5And R6The nitrogen atom to which they are attached forms a group selected from: morpholin-4-yl; 4-hydroxy-piperidin-1-yl; octahydro-pyrido [1, 2-a ]]Pyrazin-2-yl; 2-hydroxy-piperidin-1-yl; 4, 4-dimethyl-piperidin-1-yl; 3, 5-dimethyl-piperidin-1-yl; 1-hydroxy-1-methyl-ethyl) -piperidin-1-yl; 3-hydroxy-pyrrolidin-1-yl; 4-methyl-piperidin-1-yl; piperidin-1-yl; azetidin-1-yl; 4, 4-difluoro-piperidin-1-yl; 3-methyl-piperidin-1-yl; 4-methoxy-piperidin-1-yl; 3, 3-difluoro-piperidin-1-yl; 4-cyano-piperidin-1-yl; 4-fluoro-piperidin-1-yl; 3-methoxy-piperidin-1-yl; 4-Ethyl-piperazin-1-yl(ii) a 4-acetyl-piperazin-1-yl; 3-trifluoromethyl-piperidin-1-yl; 4-tert-butyl-piperidin-1-yl; 2-hydroxy-ethyl) -piperazin-1-yl; 2-methyl-pyrrolidin-1-yl; 4-hydroxymethyl-piperidin-1-yl; 2-methyl-piperidin-1-yl; pyrrolidin-1-yl; 4-methanesulfonyl-piperazin-1-yl; 3-trifluoromethyl-pyrrolidin-1-yl; 4- (2, 2, 2-trifluoro-ethyl) -piperazin-1-yl; 2-methyl-morpholin-4-yl; (2, 6-dimethyl-morpholin-4-yl; 2, 2-diethyl-morpholin-4-yl; 3-hydroxymethyl-morpholin-4-yl; 2-isobutyl-morpholin-4-yl; 2-hydroxymethyl-morpholin-4-yl; 3, 3-dimethyl-morpholin-4-yl; 4-methyl-piperazin-1-yl; 4-isopropyl-piperazin-1-yl; 3-oxa-8-aza-bicyclo [3.2.1]Oct-8-yl; (S) -3-methyl-morpholin-4-yl; 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl; 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl; (R) -3-methyl-morpholin-4-yl; 4-cyclopropanecarbonyl-piperazin-1-yl; 4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-yl; 4-cyclobutyl-piperazin-1-yl; (R) -3-hydroxy-pyrrolidin-1-yl; 4-oxetan-3-yl-piperazin-1-yl; 3-morpholin-4-yl-azetidin-1-yl; 4- (1-methyl-piperidin-4-yl) -piperazin-1-yl; 3, 3-difluoro-azetidin-1-yl; 4-dimethylamino-piperidin-1-yl; 4-piperidin-4-yl-piperazin-1-yl; (4, 4-difluoro-piperidin-1-yl; (3-morpholin-4-yl-azetidin-1-yl; 2-oxa-6-aza-spiro [3.3]]Hept-6-yl; 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl); 4-methoxy-piperidin-1-yl); [1,4]Oxazepan-4-yl; 2R, 6S) -2, 6-dimethyl-morpholin-4-yl; 3-hydroxy-azetidin-1-yl; 3-cyano-pyrrolidin-1-yl; 3, 5-dimethyl-piperazin-1-yl; (3R, 5S) -dimethyl-piperazin-1-yl; 3-fluoro-pyrrolidin-1-yl; (S) -3-fluoro-pyrrolidin-1-yl; piperazin-1-yl; 3, 3-difluoro-pyrrolidin-1-yl; 3, 3-difluoro-azetidin-1-yl; 2, 2, 6, 6-tetrafluoro-morpholin-4-yl; 2-methoxymethyl-pyrrolidin-1-yl; (S) -2-methoxymethyl-pyrrolidin-1-yl; (1S, 4S) -2-oxa-5-azabicyclo [2.2.1]Heptane-5-yl; (3S, 4S) -3, 4-difluoropyrrolidin-1-yl; 3, 4-difluoropyrrolidin-1-yl; and 3-methoxypyrrolidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6The nitrogen atom to which they are attached forms a group selected from: morpholin-4-yl; 4-hydroxy-piperidin-1-yl; octahydro-pyrido [1, 2-a ]]Pyrazin-2-yl; 2-hydroxy-piperidin-1-yl; 4, 4-dimethyl-piperidin-1-yl; 3, 5-dimethyl-piperidin-1-yl; 1-hydroxy-1-methyl-ethyl) -piperidin-1-yl; 3-hydroxy-pyrrolidin-1-yl; 4-methyl-piperidin-1-yl; piperidin-1-yl; azetidin-1-yl; 4, 4-difluoro-piperidin-1-yl; 3-methyl-piperidin-1-yl; 4-methoxy-piperidin-1-yl; 3, 3-difluoro-piperidin-1-yl; 4-cyano-piperidin-1-yl; 4-fluoro-piperidin-1-yl; 3-methoxy-piperidin-1-yl; 4-ethyl-piperazin-1-yl; 4-acetyl-piperazin-1-yl; 3-trifluoromethyl-piperidin-1-yl; 4-tert-butyl-piperidin-1-yl; 2-hydroxy-ethyl) -piperazin-1-yl; 2-methyl-pyrrolidin-1-yl; 4-hydroxymethyl-piperidin-1-yl; 2-methyl-piperidin-1-yl; pyrrolidin-1-yl; 4-methanesulfonyl-piperazin-1-yl; 3-trifluoromethyl-pyrrolidin-1-yl; 4- (2, 2, 2-trifluoro-ethyl) -piperazin-1-yl; 2-methyl-morpholin-4-yl; (2, 6-dimethyl-morpholin-4-yl; 2, 2-diethyl-morpholin-4-yl; 3-hydroxymethyl-morpholin-4-yl; 2-isobutyl-morpholin-4-yl; 2-hydroxymethyl-morpholin-4-yl; 3, 3-dimethyl-morpholin-4-yl; 4-methyl-piperazin-1-yl; 4-isopropyl-piperazin-1-yl; 3-oxa-8-aza-bicyclo [3.2.1]Oct-8-yl; (S) -3-methyl-morpholin-4-yl; 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl; 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl; (R) -3-methyl-morpholin-4-yl; 4-cyclopropanecarbonyl-piperazin-1-yl; 4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-yl; 4-cyclobutyl-piperazin-1-yl; (R) -3-hydroxy-pyrrolidin-1-yl; 4-oxetan-3-yl-piperazin-1-yl; 3-morpholin-4-yl-azetidin-1-yl; 4- (1-methyl-piperidin-4-yl) -piperazin-1-yl; 3, 3-difluoro-azetidin-1-yl; 4-dimethylamino-piperidin-1-yl; and 4-piperidin-4-yl-piperazin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form morpholin-4-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form4-hydroxy-piperidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form octahydro-pyrido [1, 2-a ]]Pyrazin-2-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 2-hydroxy-piperidin-1-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4, 4-dimethyl-piperidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 3, 5-dimethyl-piperidin-1-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 1-hydroxy-1-methyl-ethyl) -piperidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 3-hydroxy-pyrrolidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4-methyl-piperidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form piperidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form azetidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4, 4-difluoro-piperidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 3-methyl-piperidin-1-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4-methoxy-piperidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 3, 3-difluoro-piperidin-1-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4-cyano-piperidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 4-fluoro-piperidin-1-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 3-methoxy-piperidin-1-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4-ethyl-piperazin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 4-acetyl-piperazin-1-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 3-trifluoromethyl-piperidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4-tert-butyl-piperidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 2-hydroxy-ethyl) -piperazin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 2-methyl-pyrrolidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4-hydroxymethyl-piperidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 2-methyl-piperidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form pyrrolidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4-methanesulfonyl-piperazin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 3-trifluoromethyl-pyrrolidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4- (2, 2, 2-trifluoro-ethyl) -piperazin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 2-methyl-morpholin-4-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form (2, 6-dimethyl-morpholin-4-yl).
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a2, 2-diethyl-morpholin-4-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 3-hydroxymethyl-morpholin-4-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 2-isobutyl-morpholin-4-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 2-hydroxymethyl-morpholin-4-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 3, 3-dimethyl-morpholin-4-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4-methyl-piperazin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4-isopropyl-piperazin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form piperazin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 3-oxa-8-aza-bicyclo [3.2.1]Oct-8-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form (S) -3-methyl-morpholin-4-yl.
In the formula IOr in certain embodiments of formula II, R5And R6Together with the nitrogen atom to which they are attached form 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form (R) -3-methyl-morpholin-4-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4-cyclopropanecarbonyl-piperazin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4-cyclobutyl-piperazin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form (R) -3-hydroxy-pyrrolidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4-oxetan-3-yl-piperazin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 3-morpholin-4-yl-azetidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4- (1-methyl-piperidin-4-yl) -piperazin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 3, 3-difluoro-azetidin-1-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4-dimethylamino-piperidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4-piperidin-4-yl-piperazin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form (4, 4-difluoro-piperidin-1-yl).
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form (3-morpholin-4-yl-azetidin-1-yl).
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 2-oxa-6-aza-spiro [3.3]Hept-6-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl). In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 4-methoxy-piperidin-1-yl).
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form [1, 4]]Oxazepan-4-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached, form a 2R, 6S) -2, 6-dimethyl-morpholin-4-yl group.
In certain embodiments of formula I or formula II，R5And R6Together with the nitrogen atom to which they are attached form a 3-hydroxy-azetidin-1-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 3-cyano-pyrrolidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 3, 5-dimethyl-piperazin-1-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form (3R, 5S) -dimethyl-piperazin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 3-fluoro-pyrrolidin-1-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form (S) -3-fluoro-pyrrolidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form piperazin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form 3, 3-difluoro-pyrrolidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form a 3, 3-difluoro-azetidin-1-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached, form a2, 2, 6, 6-tetrafluoro-morpholin-4-yl group.
In certain embodiments of formula I or formula II, R5And R6Together with their connectionThe nitrogen atoms together form 2-methoxymethyl-pyrrolidin-1-yl. In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form (S) -2-methoxymethyl-pyrrolidin-1-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form (1S, 4S) -2-oxa-5-azabicyclo [2.2.1]]Heptane-5-yl.
In certain embodiments of formula I or formula II, R5And R6Together with the nitrogen atom to which they are attached form (3S, 4S) -3, 4-difluoropyrrolidin-1-yl; 3, 4-difluoropyrrolidin-1-yl; and 3-methoxypyrrolidin-1-yl.
In certain embodiments of formula I or formula II, R7Is a halogen.
In certain embodiments of formula I or formula II, R7Is C1-6An alkyl group.
In certain embodiments of formula I or formula II, R7Is C1-6An alkoxy group.
In certain embodiments of formula I or formula II, R7Is halo-C1-6An alkyl group.
In certain embodiments of formula I or formula II, R7Is halo-C1-6An alkoxy group.
In certain embodiments of formula I or formula II, R7Is halogen or methoxy.
In certain embodiments of formula I or formula II, R7Is fluorine, chlorine or methoxy.
In certain embodiments of formula I or formula II, R7Is fluorine or chlorine.
In certain embodiments of formula I or formula II, R7Is methoxy.
In certain embodiments of formula I or formula II, R7Is chlorine.
In certain embodiments of formula I or formula II, R7Is fluorine.
In certain embodiments of formula I or formula II, wherein R is5And R6The nitrogen atoms to which they are attached form a three-to six-membered ring, and the subject compounds may be represented by formula III:
wherein:
p is 0 to 2;
when p is 1 or 2, Y is: -O-; -S (O)r-；-NR10(ii) a or-CR11R12-; and when p is 0, Y is-CR11R12-；
R8And R9Each independently is: hydrogen; c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group;
or R8And R9Together with the atoms to which they are attached form a five or six membered ring;
R10the method comprises the following steps: hydrogen; c1-6An alkyl group; hydroxy-C1-6An alkyl group; halo-C1-6An alkyl group; hydroxy-C1-6An alkyl group; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; a heterocyclic group; or heterocyclyl-C1-6An alkyl group;
or R8And R9Together with R10And the atoms to which they are attached together form a five or six membered ring;
R11the method comprises the following steps: hydrogen; c1-6An alkyl group; or halogen;
R12the method comprises the following steps: hydrogen; c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; a heterocyclic group; or heterocyclyl-C1-6An alkyl group;
or R11And R12Together with the atoms to which they are attached may form a 3 to 6 membered ring, which optionally includes a heteroatom selected from O, N and S;
or R8And R9Together with R10And the atoms to which they are attached together form a five or six membered ring;
or R8And R9Together with R12And the atoms to which they are attached together form a five or six membered ring; and is
m，r，X，R1，R2，R3And R7As defined herein.
In certain embodiments of formula III, p is 0 or 1.
In certain embodiments of formula III, p is 0.
In certain embodiments of formula III, p is 1.
In certain embodiments of formula III, p is 2.
In certain embodiments of formula III, Y is-O-; -NR10(ii) a or-CR11R12-。
In certain embodiments of formula III, Y is — O-.
In certain embodiments of formula III, Y is-NR 10-。
In certain embodiments of formula III, Y is-S (O)r-。
In certain embodiments of formula III, Y is-CR11R12-。
In certain embodiments of formula III, R8Is hydrogen.
In certain embodiments of formula III, R9Is hydrogen.
In certain embodiments of formula III, R8And R9Is hydrogen.
In certain embodiments of formula III, R8And R9Is hydrogen, C1-6Alkyl or halogen.
In certain embodiments of formula III, R8And R9Together with the atoms to which they are attached form a five or six membered ring.
In certain embodiments of formula III, R8And R9Together with R10Together with the atoms to which they are attached form a five or six membered ring.
In certain embodiments of formula III, R8And R9Together with R12Together with the atoms to which they are attached form a five or six membered ring.
In certain embodiments of formula III, R10Is hydrogen.
In certain embodiments of formula III, R10Is C1-6An alkyl group.
In certain embodiments of formula III, R10Is hydroxy-C1-6An alkyl group.
In certain embodiments of formula III, R10Is halo-C1-6Alkyl radical
In certain embodiments of formula III, R10Is hydroxy-C1-6An alkyl group.
In certain embodiments of formula III, R10Is C1-6Alkyl-carbonyl groups.
In certain embodiments of formula III, R10Is C1-6An alkyl-sulfonyl group.
In certain embodiments of formula III, R10Is C3-6Cycloalkyl radicals
In certain embodiments of formula III, R10Is C3-6cycloalkyl-C1-6An alkyl group.
In certain embodiments of formula III, R10Is C3-6Cycloalkyl-carbonyl groups.
In certain embodiments of formula III, R10Is a heterocyclic group.
In certain embodiments of formula III, R10Is heterocyclyl-C1-6An alkyl group.
In certain embodiments of formula III, R11Is hydrogen or C1-6An alkyl group.
In certain embodiments of formula III, R11And R12Is hydrogen.
In certain embodiments of formula III, R11Is hydrogen.
In certain embodiments of formula III, R11Is C1-6An alkyl group.
In certain embodiments of formula III, R11Is a halogen.
In certain embodiments of formula III, R12Is hydrogen.
In certain embodiments of formula III, R12Is C1-6An alkyl group.
In certain embodiments of formula III, R12Is halo-C1-6An alkyl group.
In certain embodiments of formula III, R12Is C1-6An alkoxy group.
In certain embodiments of formula III, R12Is halo-C1-6An alkoxy group.
In certain embodiments of formula III, R12Is a hydroxyl group.
In certain embodiments of formula III, R12Is hydroxy-C1-6An alkyl group.
In certain embodiments of formula III, R12Is a halogen.
In certain embodiments of formula III, R12Is a nitrile.
In certain embodiments of formula III, R12Is C1-6Alkyl-carbonyl groups.
In certain embodiments of formula III, R12Is C1-6An alkyl-sulfonyl group.
In certain embodiments of formula III, R12Is C3-6A cycloalkyl group.
In certain embodiments of formula III, R12Is C3-6cycloalkyl-C1-6An alkyl group.
In certain embodiments of formula III, R12Is C3-6Cycloalkyl-carbonyl groups.
In certain embodiments of formula III, R12Is an amino group.
In certain embodiments of formula III, R12Is dimethylamino.
In certain embodiments of formula III, R12Is a heterocyclic group.
In an embodiment of formula III, wherein R10Is a heterocyclic group, such heterocyclic groups may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; morpholinyl; a thiomorpholinyl group; 3-oxa-8-aza-bicyclo [32.1 ]]Oct-8-yl; 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl; or 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl; each optionally substituted with one, two or three groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring.
In an embodiment of formula III, wherein R10Is a heterocyclic group, such heterocyclic groups may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; or a morpholinyl group; each optionally substituted as defined herein.
In an embodiment of formula III, wherein R10Is heterocyclyl-C1-6Alkyl, the heterocyclyl portion of which may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; morpholinyl; a thiomorpholinyl group; 3-oxa-8-aza-bicyclo [3.2.1]Oct-8-yl; 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl; or 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl; each optionally substituted as defined herein.
In an embodiment of formula III, wherein R10Is heterocyclyl-C1-6Alkyl, the heterocyclyl portion of which may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; or a morpholinyl group; each optionally substituted with one, two or three groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6Alkoxy radicalA group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring.
In an embodiment of formula III, wherein R12Is a heterocyclic group, such heterocyclic groups may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; morpholinyl; a thiomorpholinyl group; 3-oxa-8-aza-bicyclo [3.2.1]Oct-8-yl; 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl; or 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl; each optionally substituted as defined herein.
In an embodiment of formula III, wherein R12Is a heterocyclic group, such heterocyclic groups may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; or a morpholinyl group; each optionally substituted with one, two or three groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring.
In an embodiment of formula III, wherein R12Is heterocyclyl-C1-6Alkyl, the heterocyclyl portion of which may be; an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; morpholinyl; a thiomorpholinyl group; 3-oxa-8-aza-bicyclo [3.2.1]Oct-8-yl; 2-oxa-5-aza-bicyclo [2.2.1]Hept-5-yl; or 8-oxa-3-aza-bicyclo [3.2.1]Oct-3-yl; wherein each of the heterocyclyl moieties is optionally substituted with one, two or three groups independently selected fromGroup substitution: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring.
In an embodiment of formula III, wherein R12Is heterocyclyl-C1-6Alkyl, the heterocyclyl portion of which may be: an azetidinyl group; a pyrrolidinyl group; a piperidinyl group; a piperazinyl group; or a morpholinyl group; each optionally substituted as defined herein.
In certain embodiments of formula III, R11And R12Together with the atoms to which they are attached form a three to six membered ring, which optionally includes a heteroatom selected from O, N and S.
In certain embodiments, the subject compounds may be more particularly represented by formula IV:
wherein m, X, R1，R2，R3，R7，R8And R9As defined herein.
In certain embodiments, the subject compounds may be more particularly represented by formula V:
wherein m, X, R1，R2，R3，R7，R8，R9And R10As defined herein.
In certain embodiments, the subject compounds may be more particularly represented by formula VI:
wherein m, X, R1，R2，R3，R7，R8，R9，R11And R12As defined herein.
In certain embodiments, the subject compounds may be more particularly represented by formula VII:
wherein m, X, R1，R2，R3，R7，R8，R9，R11And R12As defined herein.
In certain embodiments, the subject compounds may be represented more particularly by formula VIII:
wherein m, p, X, Y, R1，R2，R4，R7，R8And R9As defined herein.
In certain embodiments, the subject compounds may be more particularly represented by formula IX:
wherein m, X, R1，R2，R4，R7，R8And R9As defined herein.
In certain embodiments, the subject compounds may be more particularly represented by formula X:
wherein m, X, R1，R2，R4，R7，R8，R9And R10As defined herein.
In certain embodiments, the subject compounds may be represented more particularly by formula XI:
wherein m, X, R1，R2，R4，R7，R8，R9，R11And R12As defined herein.
In certain embodiments, the subject compounds may be represented more particularly by formula XII:
wherein m, X, R1，R2，R4，R7，R8，R9，R11And R12As defined herein.
In some embodiments, the subject compounds may be represented by formula XIII:
wherein p, X, Y, R1，R2，R3，R7，R8And R9As defined herein.
Wherein R is1，R2，R3，R4，R5，R6，R7，R8，R9，R11And R12Either of which is alkyl or contains an alkyl moiety, such alkyl preferably being lower alkyl, i.e. C1-6Alkyl, and in many embodiments may be C1-4An alkyl group.
In certain embodiments, the present invention provides a compound as described herein selected from the group consisting of:
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N- (2-hydroxy-ethyl) -2-methoxy-benzamide,
5-chloro-N-cyclopropyl-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
((2S, 6R) -2, 6-dimethylmorpholino) (2-fluoro-5-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) methanone,
(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl (2-fluoro-3-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) methanone,
(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl (4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -2-fluoro-3-methoxyphenyl) methanone,
(2, 6-dimethyl-morpholin-4-yl) - [ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -methanone,
(2-ethoxy-5-fluoro-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone,
(2-fluoro-3-isopropoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone,
(2-fluoro-3-isopropoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone,
(2-fluoro-5-methoxy-4- (4- (2-methoxyethoxy) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone,
(2-fluoro-5-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (3-methoxypyrrolidin-1-yl) methanone,
(3-methoxy-4- (5-methoxy-4- (methylamino) pyrimidin-2-ylamino) phenyl) (morpholino) methanone,
(4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -2-fluoro-3-methoxyphenyl) (morpholino) methanone,
(4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -2-fluoro-3-isopropoxyphenyl) (morpholino) methanone,
(4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -3- (trifluoromethoxy) phenyl) (morpholino) methanone,
(4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -3- (trifluoromethoxy) phenyl) (morpholino) methanone,
(4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-yl-amino) -3-isopropoxyphenyl) (morpholino) methanone,
(4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -3-isopropoxyphenyl) (morpholino) methanone,
(4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -5-fluoro-2-methoxyphenyl) (morpholino) methanone,
(4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -3- (trifluoromethoxy) phenyl) (morpholino) methanone,
(4- (5-bromo-4-methoxypyrimidin-2-ylamino) -3-methoxyphenyl) (3- (trifluoromethyl) pyrrolidin-1-yl) methanone,
(4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3-methylphenyl) (morpholino) methanone,
(4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3-methylphenyl) (4-hydroxypiperidin-1-yl) methanone,
(4- (5-chloro-4- (piperidin-1-yl) pyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone,
(4- (5-chloro-4- (pyrrolidin-1-yl) pyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone,
(4- (5-chloro-4-methoxypyrimidin-2-ylamino) -3-methoxyphenyl) (pyrrolidin-1-yl) methanone,
(4- (5-cyclopropyl-4-methoxypyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone,
(4- { 5-chloro-4- [ (tetrahydro-furan-2-ylmethyl) -amino ] -pyrimidin-2-ylamino } -3-methoxy-phenyl) -morpholin-4-yl-methanone,
(4- { 5-chloro-4- [ (tetrahydro-furan-3-ylmethyl) -amino ] -pyrimidin-2-ylamino } -3-methoxy-phenyl) -morpholin-4-yl-methanone,
(4-dimethylamino-piperidin-1-yl) - [ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -methanone,
(4-tert-butyl-piperidin-1-yl) - [4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -methanone,
(5-chloro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (deuteromorpholino) methanone,
(5-chloro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (3-methoxypyrrolidin-1-yl) methanone,
(5-chloro-4- (methylamino) pyrimidin-2-ylamino) -2-methoxyphenyl) (morpholino) methanone,
(5-fluoro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone,
[ 2-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[ 2-chloro-5-methoxy-4- (4-methoxy-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 2-chloro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 2-fluoro-3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 2-fluoro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 2-fluoro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] - ((S) -2-methoxymethyl-pyrrolidin-1-yl) -methanone,
[3- (2-fluoro-ethoxy) -4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-bromo-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-bromo-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-chloro-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-chloro-4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-cyclobutoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-cyclobutylmethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-cyclopropyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-cyclopropylmethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-ethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-isopropoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-methoxy-4- (4-methoxy-5-prop-1-ynyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-methoxy-4- (4-methoxy-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-methoxy-4- (4-methylamino-5-prop-1-ynyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] - (8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -methanone,
[ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] - (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -methanone,
[ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -pyrrolidin-1-yl-methanone,
[ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] - [4- (2, 2, 2-trifluoro-ethyl) -piperazin-1-yl ] -methanone,
[ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] - (4-methoxy-piperidin-1-yl) -methanone,
[ 3-methoxy-4- (4-pyrrolidin-1-yl-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl ] - ((S) -2-methoxymethyl-pyrrolidin-1-yl) -methanone,
[4- (5-bromo-4-ethoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-isopropoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -2-chloro-5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-cyclobutoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-cyclopropoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-ethoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-isopropoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - ((R) -2, 2-di-deuterium-3-methyl-morpholin-4-yl) -methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - ((S) -2, 2-di-deuterium-3-methyl-morpholin-4-yl) -methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-morpholin-4-yl-azetidin-1-yl) -methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4, 4-difluoro-piperidin-1-yl) -methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-ethyl-piperazin-1-yl) -methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - [4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-yl ] -methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - [4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-yl ] -methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-trifluoromethyl-pyrrolidin-1-yl) -methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-cyclobutyl-piperazin-1-yl) -methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - [4- (2, 2, 2-trifluoro-ethyl) -piperazin-1-yl ] -methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-methoxy-piperidin-1-yl) -methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - ((R) -3-hydroxy-pyrrolidin-1-yl) -methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-oxetan-3-yl-piperazin-1-yl) -methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -5-chloro-2-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-cyclobutylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-cyclohexylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-cyclopentylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-ethoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-ethylamino-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-ethylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-isobutylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-isopropoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-isopropylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3- (2, 2, 2-trifluoro-ethoxy) -phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3- (oxetan-3-yloxy) -phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclobutoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclopentyloxy-phenyl ] - (2-oxa-6-aza-spiro [3.3] hept-6-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclopentyloxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclopropoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclopropyl-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-difluoromethoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-difluoromethoxy-phenyl ] - (4-hydroxy-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-ethoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-hydroxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-isopropoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-hydroxy-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (octahydro-pyrido [1, 2-a ] pyrazin-2-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-hydroxy-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4, 4-dimethyl-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3, 5-dimethyl-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - [4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-yl ] -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-hydroxy-pyrrolidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-methyl-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -piperidin-1-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4, 4-difluoro-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-methyl-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-methoxy-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3, 3-difluoro-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-fluoro-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-methoxy-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-ethyl-piperazin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-trifluoromethyl-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-methyl-pyrrolidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-hydroxymethyl-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-methyl-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -pyrrolidin-1-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-methanesulfonyl-piperazin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-trifluoromethyl-pyrrolidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - [4- (2, 2, 2-trifluoro-ethyl) -piperazin-1-yl ] -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-methyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2, 6-dimethyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2, 2-diethyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-hydroxymethyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-isobutyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-hydroxymethyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3, 3-dimethyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-methyl-piperazin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-isopropyl-piperazin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -piperazin-1-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - ((S) -3-methyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - ((R) -3-methyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-cyclopropanecarbonyl-piperazin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-morpholin-4-yl-azetidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - [4- (1-methyl-piperidin-4-yl) -piperazin-1-yl ] -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3, 3-difluoro-azetidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-dimethylamino-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-piperidin-4-yl-piperazin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-oxa-6-aza-spiro [3.3] hept-6-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-trifluoromethoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-propoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-propylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-cyclobutyl-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-cyclobutyl-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-cyclopropyl-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-cyclopropyl-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-fluoro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-fluoro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-hydroxy-piperidin-1-yl) -methanone,
[4- (5-iodo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-iodo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- [ 5-chloro-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino ] -3- (2, 2, 2-trifluoro-ethoxy) -phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-2-ethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -piperazin-1-yl-methanone,
[ 5-chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] - (2, 6-dimethyl-morpholin-4-yl) -methanone,
[ 5-chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-methoxy-phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-4- (5-chloro-4-ethylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -2-methoxy-phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - (4, 4-difluoro-piperidin-1-yl) -methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] -piperazin-1-yl-methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - (4-dimethylamino-piperidin-1-yl) -methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - (3-hydroxy-pyrrolidin-1-yl) -methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] -pyrrolidin-1-yl-methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - (4-hydroxy-piperidin-1-yl) -methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - (2-hydroxymethyl-morpholin-4-yl) -methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - [1, 4] oxazepan-4-yl-methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - ((2R, 6S) -2, 6-dimethyl-morpholin-4-yl) -methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - (3-hydroxy-azetidin-1-yl) -methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - ((3R, 5S) -dimethyl-piperazin-1-yl) -methanone,
[ 5-ethoxy-2-fluoro-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 5-ethoxy-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-phenyl ] -morpholin-4-yl-methanone,
{4- [ 5-bromo-4- (2-methoxy-ethoxy) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-bromo-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino ] -2-fluoro-5-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-bromo-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino ] -3-ethoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-bromo-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino ] -3-isopropoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-bromo-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (1-methyl-cyclobutylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2, 2, 2-trifluoro-ethylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2, 2-difluoro-ethylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl) -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2-cyclopropyl-ethylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2-methanesulfonyl-ethylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2-methoxy-ethoxy) -pyrimidin-2-ylamino ] -3-cyclobutoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2-methoxy-ethoxy) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino ] -3-cyclobutoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2-methoxy-propylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (cyclobutylmethyl-amino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (cyclopentylmethyl-amino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (cyclopropylmethyl-amino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (tetrahydro-furan-3-ylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (tetrahydro-pyran-3-ylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (tetrahydro-pyran-4-yloxy) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
1- (4- (5-bromo-4-methoxypyrimidin-2-ylamino) -3-methoxybenzoyl) piperidine-4-carbonitrile,
1- [ 2-fluoro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzoyl ] -pyrrolidine-3-carbonitrile,
1- [ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzoyl ] -piperidine-4-carbonitrile,
1- [4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzoyl ] -piperidine-4-carbonitrile,
1- [4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzoyl ] -piperidine-4-carbonitrile,
1- [ 5-chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzoyl ] -pyrrolidine-3-carbonitrile,
1- [ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-benzoyl ] -piperidine-4-carbonitrile,
1- [ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-benzoyl ] -pyrrolidine-3-carbonitrile,
1- {2- [ 2-methoxy-4- (morpholine-4-carbonyl) -phenylamino ] -4-methylamino-pyrimidin-5-yl } -ethanone,
1- {4- [4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzoyl ] -piperazin-1-yl } -ethanone,
2- (2-methoxy-4- (2, 2, 6, 6-tetrafluoromorpholine-4-carbonyl) phenylamino) -4- (methylamino) pyrimidine-5-carbonitrile,
2- (2-methoxy-4- (morpholine-4-carbonyl) phenylamino) -4- (methylamino) pyrimidine-5-carbonitrile,
2- (4- ((3S, 4S) -3, 4-difluoropyrrolidine-1-carbonyl) -2-methoxyphenylamino) -4- (methylamino) pyrimidine-5-carbonitrile,
2- (4- (4, 4-difluoropiperidine-1-carbonyl) -2-methoxyphenylamino) -4- (methylamino) pyrimidine-5-carbonitrile,
2- [2, 5-dimethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -1-morpholin-4-yl-ethanone,
2- [ 2-methoxy-4- (morpholine-4-carbonyl) -phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [ 2-methoxy-4- (piperidine-1-carbonyl) -phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [ 2-methoxy-4- (pyrrolidine-1-carbonyl) -phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -1-morpholin-4-yl-ethanone,
2- [4- ((2R, 6S) -2, 6-dimethyl-morpholine-4-carbonyl) -5-fluoro-2-methoxy-phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [4- ((2R, 6S) -2, 6-dimethyl-morpholine-4-carbonyl) -5-fluoro-2-methoxy-phenylamino ] -4-ethylamino-pyrimidine-5-carbonitrile,
2- [4- ((R) -3-fluoro-pyrrolidine-1-carbonyl) -2-methoxy-phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [4- ((S) -3-fluoro-pyrrolidine-1-carbonyl) -2-methoxy-phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [4- (3, 3-difluoro-azetidine-1-carbonyl) -2-methoxy-phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [4- (3, 3-difluoro-pyrrolidine-1-carbonyl) -2-methoxy-phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [4- (3-fluoro-azetidine-1-carbonyl) -2-methoxy-phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -1-morpholin-4-yl-ethanone,
2- [4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -2, 5-dimethoxy-phenyl ] -1-morpholin-4-yl-ethanone,
2- [4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -2, 5-dimethoxy-phenyl ] -1-morpholin-4-yl-ethanone,
2- [4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -1-morpholin-4-yl-ethanone,
2- [4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2, 5-dimethoxy-phenyl ] -1-morpholin-4-yl-ethanone,
2- [4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -1-morpholin-4-yl-ethanone,
2- [4- (azetidine-1-carbonyl) -2-methoxy-phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [ 5-fluoro-2-methoxy-4- (morpholine-4-carbonyl) -phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2-fluoro-5-methoxy-N- (2-methoxy-ethyl) -N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
2-fluoro-5-methoxy-N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
2-fluoro-N- (2-hydroxy-2-methylpropyl) -5-methoxy-N-methyl-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzamide,
3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -N-oxetan-3-yl-benzamide,
3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -N- (1-methyl-piperidin-4-yl) -benzamide,
3-methoxy-N- (2-methoxy-ethyl) -4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
3-methoxy-N- (2-methoxy-ethyl) -N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-N- (2-methoxy-ethyl) -N-methyl-benzamide,
4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -3-methoxy-N- (2-methoxy-ethyl) -N-methyl-benzamide,
4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -N, N, 3-trimethylbenzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N- (tetrahydro-pyran-3-yl) -benzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N, N-dimethyl-benzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N-methyl-benzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N-oxetan-3-yl-benzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N-cyclopropyl-3-methoxy-benzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N-ethyl-3-methoxy-benzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N-isopropyl-3-methoxy-benzamide,
4- (5-cyano-4-ethylamino-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-N, N-dimethyl-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-N, N-dimethyl-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N, N-dimethyl-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N-methyl-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N- (2, 2-difluoro-ethyl) -3-methoxy-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N- (3, 3-difluoro-cyclobutyl) -3-methoxy-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N, N-diethyl-3-methoxy-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N-cyclopropylmethyl-3-methoxy-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N-ethyl-3-methoxy-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N-ethyl-3-methoxy-N-methyl-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N-ethyl-N-isopropyl-3-methoxy-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N-isopropyl-3-methoxy-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N-isopropyl-3-methoxy-N-methyl-benzamide,
4-ethylamino-2- [ 5-fluoro-2-methoxy-4- (morpholine-4-carbonyl) -phenylamino ] -pyrimidine-5-carbonitrile,
4-methoxy-2- [ 2-methoxy-4- (morpholine-4-carbonyl) -phenylamino ] -pyrimidine-5-carbonitrile,
5-chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -N- (1-methyl-piperidin-4-yl) -benzamide,
5-chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -N-oxetan-3-yl-benzamide,
5-chloro-2-methoxy-N, N-dimethyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
5-chloro-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-methoxy-N- (2-methoxy-ethyl) -benzamide,
5-chloro-4- (5-chloro-4-methoxypyrimidin-2-ylamino) -2-methoxy-N-methylbenzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N, N-dimethyl-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N- (2-methoxy-ethyl) -benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N-methyl-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N-oxetan-3-yl-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N- (1-methyl-piperidin-4-yl) -benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N- (2-methoxy-ethyl) -N-methyl-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N- (1-methyl-cyclobutyl) -benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N- (1-cyano-cyclopropyl) -2-methoxy-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N- (2-hydroxy-2-methyl-propyl) -2-methoxy-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N- (2-hydroxy-ethyl) -2-methoxy-N-methyl-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N- (2-hydroxy-propyl) -2-methoxy-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N-cyclopropyl-2-methoxy-benzamide,
5-chloro-N- (1-cyano-cyclopropyl) -2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
5-chloro-N- (1-cyano-cyclopropyl) -2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
5-chloro-N- (2-hydroxy-2-methyl-propyl) -2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
5-chloro-N- (2-hydroxy-2-methyl-propyl) -2-methoxy-N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
5-chloro-N-cyclopropyl-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-methoxy-benzamide,
azetidin-1-yl- [4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -methanone,
n- (3, 3-difluoro-cyclobutyl) -3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
n- (3-aminopropyl) -4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3-methoxybenzamide,
n- (3-amino-propyl) -4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzamide,
n- (3-amino-propyl) -5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-benzamide,
n- (4, 4-difluoro-cyclohexyl) -3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
n, N-diethyl-3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
N-ethyl-2-fluoro-5-methoxy-N- (2-methoxy-ethyl) -4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
N-ethyl-3-methoxy-N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
n-ethyl-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-N- (2-methoxy-ethyl) -benzamide,
n-tert-butyl-4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzamide, and
n-tert-butyl-5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-benzamide, or a pharmaceutically acceptable salt thereof.
In certain embodiments, the present invention provides a compound as described herein selected from the group consisting of:
[ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
(5-chloro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (deuteromorpholino) methanone,
(5-fluoro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone,
[ 2-fluoro-3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-isopropoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-methoxy-phenyl ] -morpholin-4-yl-methanone,
[ 5-ethoxy-2-fluoro-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
2- (2-methoxy-4- (morpholine-4-carbonyl) phenylamino) -4- (methylamino) pyrimidine-5-carbonitrile, and
n-tert-butyl-4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzamide,
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the present invention provides a composition comprising:
(a) a pharmaceutically acceptable carrier; and
(b) the compound of claim 1.
In certain embodiments, the present invention provides a compound as described herein for use as a therapeutically active substance.
In certain embodiments, the present invention provides a method for treating: parkinson's disease, huntington's disease, lewis body dementia, alzheimer's disease, L-dopa-induced dyskinesia, cancer or proliferative disorders, such as renal, breast, prostate, blood, papillary or lung cancer, acute myeloid leukemia, or multiple myeloma, or inflammatory diseases such as leprosy, crohn's disease, amyotrophic lateral sclerosis, rheumatoid arthritis, and ankylosing spondylitis, comprising administering to a subject in need thereof an effective amount of a compound as described herein.
In certain embodiments, the invention relates to the use of a compound as described herein for the preparation of a medicament for the therapeutic and/or prophylactic treatment of parkinson's disease, huntington's disease, Lewie body dementia, alzheimer's disease, L-dopa-induced dyskinesia, cancer or proliferative disorders, such as renal, breast, prostate, blood, papillary or lung cancer, acute myeloid leukemia, or multiple myeloma, or inflammatory diseases such as leprosy, crohn's disease, amyotrophic lateral sclerosis, rheumatoid arthritis, and ankylosing spondylitis.
In certain embodiments, the present invention provides compounds as described herein for use as therapeutically active substances for the therapeutic and/or prophylactic treatment of parkinson's disease, huntington's disease, Lewie body dementia, alzheimer's disease, L-dopa-induced dyskinesia, cancer or proliferative disorders, such as kidney, breast, prostate, blood, papillary or lung cancer, acute myeloid leukemia, or multiple myeloma, or inflammatory diseases such as leprosy, crohn's disease, amyotrophic lateral sclerosis, rheumatoid arthritis, and ankylosing spondylitis.
In certain embodiments, the present invention provides a method for treating parkinson's disease, huntington's disease, lewis body dementia, alzheimer's disease or L-dopa-induced dyskinesia, said method comprising administering to a subject in need thereof an effective amount of a compound as described herein.
In certain embodiments, the present invention relates to the use of a compound as described herein for the preparation of a medicament for the therapeutic and/or prophylactic treatment of parkinson's disease, huntington's disease, lewis body dementia, alzheimer's disease or L-dopa-induced dyskinesia.
In certain embodiments, the present invention provides compounds as described herein for use as therapeutically active substances for the therapeutic and/or prophylactic treatment of parkinson's disease, huntington's disease, lewis body dementia, alzheimer's disease or L-dopa-induced dyskinesia.
In certain embodiments, the present invention provides a method for treating parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound as described herein.
In certain embodiments, the present invention relates to the use of a compound as described herein for the manufacture of a medicament for the therapeutic or prophylactic treatment of parkinson's disease.
In certain embodiments, the present invention provides a compound as described herein for use as therapeutically active substance for the therapeutic and/or prophylactic treatment of parkinson's disease.
The present invention also provides a method for the treatment of a disease or condition mediated by the LRRK2 receptor or otherwise associated therewith, which method comprises administering to a subject in need thereof an effective amount of a compound of the present invention.
The disease may be a neurodegenerative disease such as Parkinson's disease, Huntington's disease or Lewis body dementia.
The disease may be a CNS disorder such as alzheimer's disease and L-dopa induced dyskinesia.
The disease may be cancer or a proliferative disorder such as renal, breast, prostate, blood, papillary or lung cancer, acute myeloid leukemia or multiple myeloma.
The disease may be an inflammatory disease such as leprosy, crohn's disease, amyotrophic lateral sclerosis, rheumatoid arthritis, and ankylosing spondylitis.
The present invention also provides a method for enhancing cognitive memory, comprising administering to a subject in need thereof an effective amount of a compound of the present invention.
Representative compounds of the process according to the invention are shown in the following experimental examples.
Synthesis of
The compounds of the present invention may be prepared by various methods depicted in the exemplary synthetic reaction schemes shown and described below.
The starting materials and Reagents used in preparing these compounds are generally available from commercial suppliers such as aldrich chemical co, or prepared by methods known to those skilled in the art according to procedures set forth in the references, such as Fieser and Fieser's Reagents for Organic Synthesis; wiley & Sons: new York, 1991, Volumes 1-15; rodd's Chemistry of Carbon compounds, Elsevier science publishers, 1989, Volumes 1-5and supplements; and Organic Reactions, Wiley & Sons: new York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely illustrative of the methods by which the compounds of the present invention may be synthesized and various modifications may be made to these synthetic reaction schemes and will be suggested to one skilled in the art having referred to the disclosure contained in this application.
If desired, the starting materials and intermediates of the synthetic reaction schemes can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Unless otherwise specified, the reactions described herein may be carried out under an inert atmosphere at atmospheric pressure at a temperature in the range of from about-78 ℃ to about 150 ℃, for example from about 0 ℃ to about 125 ℃, or conveniently at about room (ambient) temperature, for example about 20 ℃.
Scheme A below illustrates one synthetic procedure that may be used to prepare a particular compound of formula I or formula II, wherein X, m, R1，R2，R3，R5，R6And R7As defined herein.
Scheme 1
In step 1 of scheme a, dichloropyrimidine compound a is reacted with reagent b to provide pyrimidine compound c. The reaction of step 1 may occur under polar solvent conditions. In embodiments of the invention where X is-O- (-reagent b is an alcohol), the reaction of step 1 may be carried out in the presence of a base.
In step 2, the pyrimidine compound c is subjected to a reaction with an aminobenzoic acid compound d to provide an aminopyridine compound e. The reaction of step 2 may take place in a polar protic solvent and in the presence of an acid such as HCl.
The amide coupling reaction is carried out in step 3, wherein compound e is reacted with an amine f to give a compound of formula I or formula II according to the invention. The amide coupling reaction of step 3 may be carried out using various well-known amide coupling reagents such as carbodiimides (e.g., DCC, DIC, EDC, etc.), ammonium salts (e.g., HATU, HBTU, TBTU, etc.) or phosphorusSalts (e.g., BOP, PyBOP, etc.) in the presence or absence of benzotriazole derivatives such as HOBt, HOAt, DhbtOH, etc. In other embodiments, amide formation may be achieved using acid chloride or anhydride intermediates (not shown).
Many variations to the procedure of scheme a are possible and will suggest themselves to those skilled in the art. Specific details for the preparation of the compounds of the present invention are described in the following examples.
Administration and pharmaceutical compositions
The present invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, or a racemic or non-racemic mixture of isomers, or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.
Typically, the compounds of the invention are administered in a therapeutically effective amount by any of the accepted modes of administration for agents used for similar purposes. Suitable dosage ranges are generally from 1 to 500 mg/day, for example from 1 to 100 mg/day, and most preferably from 1 to 30 mg/day, depending on a number of factors such as the severity of the disease being treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication involved in the administration, and the preference and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases, without undue experimentation and relying on personal knowledge and the disclosure of this application, will be able to determine a therapeutically effective amount of a compound of the present invention for a given disease.
The term "pharmaceutically acceptable excipient" means any ingredient that is not therapeutically active and is non-toxic, such as disintegrants, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products.
As long as a chiral carbon is present in a chemical structure, it means that all stereoisomers associated with that chiral carbon are encompassed by the structure.
The invention also provides pharmaceutical compositions, methods of use, and methods of making the foregoing compounds.
All individual embodiments may be combined.
The compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathoracic, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. One particular mode of administration is usually oral, using a convenient daily dosage regimen which may be adjusted according to the degree of affliction.
A compound or compounds of the invention, together with one or more conventional adjuvants, carriers or diluents, may be placed in the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms can be comprised of conventional ingredients in conventional proportions (with or without additional active compounds or ingredients), and the unit dosage forms can contain any suitable effective amount of the active ingredient commensurate with the desired daily dosage range to be employed. The pharmaceutical compositions may be employed as solids such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquid emulsion solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient per tablet, or more broadly from about 0.01 to about one hundred (100) milligrams, are accordingly suitable representative unit dosage forms.
The compounds of the present invention may be formulated into a wide variety of oral dosage forms. Pharmaceutical compositions and dosage forms may comprise a compound or compounds of the invention or a pharmaceutically acceptable salt thereof as the active ingredient. The pharmaceutically acceptable carrier may be a solid or a liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is usually a finely divided solid, which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is usually mixed with a carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Powders and tablets may contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. The term "formulation" is intended to include the formulation of the active compound with encapsulating material as a carrier, providing a capsule in which the active ingredient (with or without a carrier) is surrounded by a carrier with which it is associated. Similarly, cachets and lozenges are included. Tablets, powders, capsules, alkyl, cachets, and lozenges can be as solid forms suitable for oral administration.
Other forms suitable for oral administration include liquid form preparations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted into liquid form preparations immediately prior to use. Emulsions may be prepared in solution, for example in aqueous propylene glycol, or may contain emulsifying agents, for example lecithin, sorbitan monooleate or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, fragrances, stabilizers and thickeners. Aqueous suspensions may be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methyl fibers, sodium carboxymethyl cellulose, and other well-known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The compounds of the invention may be formulated for parenteral administration (e.g., by injection, e.g., bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, pre-filled syringes, small volume infusions or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example, solutions in aqueous polyethylene glycol solutions. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preservatives, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by sterile isolation of a sterile solid, or by lyophilization from a solution thereof which is reconstituted with a suitable vehicle, e.g., sterile pyrogen-free water, prior to use.
The compounds of the invention may be formulated for topical administration to the epidermis as an ointment, cream or lotion, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and arabinose or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
The compounds of the present invention may be formulated for administration as suppositories. A mixture of low melting waxes such as fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously, for example by stirring. The molten homogeneous mixture is then poured into a conveniently sized mold, allowed to cool and solidify.
The compounds of the invention may be formulated for vaginal administration. Pessaries, plugs, creams, gels, pastes, foams or sprays containing such carriers in addition to the active ingredient are known in the art to be suitable.
The subject compounds may be formulated for nasal administration. The solution or suspension is applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or nebulizer. The formulations may be provided in single or multiple dosage forms. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined amount of solution or suspension. In the case of a nebulizer, this can be achieved, for example, by means of a metered nebulization spray pump.
The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract, and include intranasal administration. The compounds typically have a small particle size, for example on the order of five (5) microns or less. Such particle sizes may be obtained by means known in the art, for example by micronisation. The active ingredient is provided in a compressed package with a suitable propellant such as a chlorofluorocarbon (CFC), for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dosage of the drug may be controlled by a metering valve. Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). The powder carrier forms a gel in the nasal cavity. Powder compositions may be presented in unit dosage form, for example in capsules or cartridges, for example in gelatin or film packs, from which the powder may be administered by the inhaler.
When desired, the formulations may be prepared with an enteric coating suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention may be formulated in a transdermal or subcutaneous drug delivery device. These delivery systems are advantageous when sustained release of the compound is desired and patient compliance with a treatment regimen is critical. The compounds in transdermal delivery systems are often attached to a skin-adherent solid carrier. The compound of interest may also be combined with a penetration enhancer, such as azone (1-dodecylazacycloheptan-2-one). The sustained release delivery system is inserted subcutaneously into the subcutaneous layer by surgery or injection. The subcutaneous implants encapsulate the compound in a lipid-soluble membrane, such as silicone rubber, or a biodegradable polymer, such as polylactic acid.
The pharmaceutical preparation may be in unit dosage form. In such form, the preparation can be subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, a package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Moreover, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Other suitable pharmaceutical carriers and their formulations are described in Remington: the Science and practice of Pharmacy 1995, edited by E.W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Representative pharmaceutical formulations containing the compounds of the present invention are described below.
Utility of
The compounds of the invention are useful for treating LRRK2 mediated diseases or conditions, including neurodegenerative diseases such as parkinson's disease, Lewy body dementia, and huntington's disease, and for enhancing cognitive memory in a subject in general need thereof.
Examples
The following preparations and examples are given to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being exemplary and representative thereof.
All temperatures, including melting points (i.e., MP) are in degrees celsius (° c), unless otherwise indicated. It will be appreciated that the reaction which produces the specified and/or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e. there may be one or more intermediates produced in the mixture which ultimately results in the formation of the specified and/or desired product. The following abbreviations may be used in the preparations and examples.
List of abbreviations
AcOH acetic acid
AIBN 2, 2' -azobis (2-methylpropanenitrile)
Atm. atmospheric pressure
(BOC) 2O-Di-tert-butyl dicarbonate
DCM dichloromethane/methylene dichloride
DIAD diisopropyl azodicarboxylate
DIPEA diisopropylethylamine
DMAP 4-dimethylaminopyridine
DME 1, 2-dimethoxyethane
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
DPPF 1, 1' -bis (diphenylphosphino) ferrocene
Et2O diethyl ether
EtOH ethanol/Ethyl alcohol
EtOAc ethyl acetate
HATU 2- (1H-7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethylureaAmmonium methyl hexafluorophosphate
HBTU O-benzotriazole-1-yl-N, N, N ', N' -tetramethylureaHexafluorophosphates
HOBT 1-hydroxybenzotriazole
HPLC high pressure liquid chromatography
RP HPLC reversed-phase high-pressure liquid chromatography
i-PrOH Isopropanol/Isopropanol
LCMS liquid chromatography/Mass Spectrometry
MeOH methanol/methyl alcohol
MW microwave
NBS N-bromosuccinimide
NMP 1-methyl-2-pyrrolidone
PSI PSI
RT Room temperature
TBDMS tert-butyldimethylsilyl group
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
Preparation 1: 2-chloro-5-fluoro-N-methylpyrimidin-4-amine
To a 250mL round bottom flask equipped with a stir bar was added 9.0g of 5-fluoro-2, 4-dichloro-pyrimidine, 40mL of methanol and 15mL of 8M methylamine in ethanol. The reaction was exothermic (slightly exothermic) and allowed to stir at room temperature for-30 minutes. Examination by TLC (1: 1 EtOAc: heptane) and LCMS showed complete reaction. The reaction was concentrated to give 9.77g of crude material, which was purified on a silica column with a gradient of 1% to 10% MeOH flowing in DCM for 35 minutes to give 6.77g of pure 2-chloro-5-fluoro-N-methylpyrimidin-4-amine.
The same procedure was used to prepare the compounds shown in table 1 below, using the appropriate commercially available substituted 2, 4-dichloro-pyrimidines and amines.
TABLE 1
Preparation 2: 2, 5-dichloro-4-methoxypyrimidine
To a 250mL round bottom flask equipped with a stir bar was added 1g of 5-chloro-2, 4-dichloro-pyrimidine and 15mL of diethyl ether. The mixture was cooled to 0 ℃ in an ice bath, then 1 equivalent of sodium methoxide in methanol (prepared from 120mg of sodium reacted with 4ml of methanol at room temperature) was slowly added. The reaction was stirred at room temperature overnight and checked by LCMS. The white precipitate was filtered and the solid was washed with cold methanol. After drying, 0.98g of pure 2, 5-dichloro-4-methoxypyrimidine was obtained and the material was used without further purification.
The same procedure was used to prepare the compounds shown in table 2 below, using the appropriate commercially available alcohol and the appropriately substituted 2, 4-dichloro-pyrimidine.
TABLE 2
Preparation 3: 4- (5-fluoro-4- (methylamino) pyrimidin-2-ylamino) -3-methoxybenzoic acid
50mg of 2-chloro-5-fluoro-N-methylpyrimidin-4-amine, 57mg of 4-amino-3-methoxybenzoic acid, 0.1mL of 4N Cl was placed in a solution of 1, 4-bisThe mixture of alkane and 1mL of n-butanol was placed in a 10mL snap-top microwave bottle (CEMCorp.) and heated to 120 ℃ for 40 min. The reaction was monitored by LC/MS. The precipitated solid was filtered to obtain 80mg of 4- (5-fluoro-4- (methylamino) pyrimidin-2-ylamino) -3-methoxybenzoic acid.
The same procedure was used to prepare the compounds shown in table 3 below, using the appropriate amine and the appropriately substituted 2-chloropyrimidine.
TABLE 3
Preparation 4: 4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3- (difluoromethoxy) benzoic acid
To a solution of 1g of methyl 3-hydroxy-4-nitrobenzoate, 3.31g of cesium carbonate in 20mL of DMF, 1.5 equivalents of difluoromethane iodide were carefully added. The reaction was allowed to warm to room temperature, followed by TLC. After completion of the reaction, the mixture was concentrated and purified by silica gel chromatography to give 1.2g of methyl 3- (difluoromethoxy) -4-nitrobenzoate.
Methyl 3- (difluoromethoxy) -4-nitrobenzoate (0.9g) was placed in a 250mL round bottom flask and dissolved in 30mL ethanol. Pd/C (0.15g, 10% Pd) was added carefully and a hydrogen balloon was attached to the flask. The reaction was stirred vigorously overnight. After checking by TLC, the reaction was filtered through a pad of celite and concentrated to give 0.6g of methyl 4-amino-3- (difluoromethoxy) benzoate, which was used without further purification.
Methyl 4-amino-3- (difluoromethoxy) benzoate (70mg), 2, 5-dichloro-N-methylpyrimidin-4-amine, 0.1mL of 4N HCl/bisAlkane and 1mL of n-butanol were placed in a microwave bottle. The reaction was heated at 150 ℃ for 30 min and monitored by LCMS. The mixture was concentrated and purified by silica gel chromatography to give 100mg of pure methyl 4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3- (difluoromethoxy) benzoate.
Methyl 4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3- (difluoromethoxy) benzoate (500mg) was dissolved in 5mL of THF and 5mL of water. After dissolution, 234mg of lithium hydroxide was added and the reaction was stirred at room temperature overnight. The mixture was checked by LCMS, then carefully acidified with 1N HCl and partitioned with ethyl acetate. The organic layer was concentrated and purified by silica gel chromatography to give 250mg of 4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3- (difluoromethoxy) benzoic acid.
Similarly prepared were:
example 1(4- (5-fluoro-4- (methylamino) pyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino)Ketone
A mixture of 100mg of 4- (5-fluoro-4- (methylamino) pyrimidin-2-ylamino) -3-methoxybenzoic acid, 47. mu.L of morpholine, 205mg of HATU, 188mL of diisopropylethylamine in 1mL of dimethylformamide was stirred at room temperatureStirring overnight. The reaction was checked by LCMS and found to be complete. The reaction was diluted with EtOAc and the organic layer was washed with saturated NaHCO3And a brine wash. The organic layer was concentrated and purified by preparative reverse phase HPLC to give 12mg of (4- (5-fluoro-4- (methylamino) pyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone.
Proton NMR and LRRK2Ki (micromolar) data for the compounds prepared using the above procedure, as well as for selected compounds determined from the assays described below, are shown in table 4 below.
(Ex. in the Table, represents examples)
TABLE 4
Example 2[4- (5-cyclopropyl-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl]-morpholine-4- Alkyl-ketones
To a microwave tube were added (4- (5-bromo-4- (methylamino) pyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone (56mg, 0.13mmol), potassium cyclopropyltrifluoroborate (39mg, 0.27mmol), cesium carbonate (0.13g, 0.40mmol), toluene (1.8mL), and water (0.2 mL). The mixture was degassed by bubbling nitrogen for 15 minutes. XPhos (2-dicyclohexylphosphine-2 ', 4 ', 6 ' -triisopropylbiphenyl) (6.4mg, 0.013mmol) and palladium acetate (2mg, 0.01mmol) were then added. The reaction was heated in a Biotage microwave at 140 ℃ for 20 minutes. The reaction mixture was filtered and concentrated. The crude product was purified by RP-HPLC to give the desired product (12.6mg, 25%).
Additional compounds prepared using the above procedure are shown in table 4 above.
Example 3(4- (5-cyclobutyl-4- (methylamino) pyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) Ketone
To a microwave tube were added (4- (5-bromo-4- (methylamino) pyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone (100mg, 0.24mmol), potassium cyclobutyl trifluoroborate (177mg, 1.1mmol), cesium carbonate (0.23g, 0.71mmol), toluene (2.9mL), and water (0.3 mL). The mixture was degassed by bubbling nitrogen for 15 minutes. Then bis- (1-adamantyl) -n-butylphosphine (19mg, 0.053mmol) and palladium acetate (2.6mg, 0.026mmol) were added. The reaction was sealed and heated at 11 ℃ for 2 hours. The reaction mixture was filtered and concentrated. The crude product was purified by RP-HPLC to give the desired product (8.1mg, 8.6%)
Additional compounds prepared using the above procedure are shown in table 4 above.
Example 4: 1- {2- [ 2-methoxy-4- (morpholine-4-carbonyl) -phenylamino]-4-methylamino-pyrimidine-5- Alkyl-ethanone
A mixture of (4- (5-bromo-4- (methylamino) pyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone (100mg, 0.24mmol), Pd (PPh3)4(36mg, 0.03mmol), and tributylethoxyvinyltin (0.16mL, 0.47mmol) in toluene was stirred in a sealed tube at 110 ℃ for 1 hour. The reaction mixture was filtered and concentrated. The reaction mixture was filtered through a pad of silica gel (eluting with 0-100% EtOAc in heptane) to give the crude product. Purification of the crude product was achieved by reverse phase HPLC (9mg, 10%). Additional compounds prepared using the above procedure are shown in table 4 above.
Example 5: [ 3-methoxy-4- (4-methylamino-5-prop-1-ynyl-)Pyrimidin-2-ylamino) -phenyl]-is Lin-4-yl-methanones
A mixture of (4- (5-bromo-4- (methylamino) pyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone (140mg, 0.233mmol), Pd (PPh3)4(50mg, 0.04mmol), and tributyl (prop-1-ynyl) stannane (0.20mL, 0.66mmol) in toluene (5mL) was stirred in a sealed tube at 110 ℃ for 1 hour. The reaction mixture was filtered and concentrated. Purification of the crude product was achieved by reverse phase HPLC (9mg, 10%). Additional compounds prepared using the above procedure are shown in table 4 above.
Example 6: [4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclopropyl-phenyl ] -amide]-morpholin-4-yl- Ketone
A mixture of [ 3-bromo-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone (0.0500g, 0.117mmol), potassium acetate (0.0172g, 0.176mmol), sodium carbonate (0.0186g, 0.176mmol), and 1, 1' -bis (diphenylphosphino) ferrocenyl palladium (II) chloride (0.00478g, 0.00585mmol) was weighed into a microwave bottle equipped with a stir bar. Acetonitrile (0.94mL, 18mmol) and degassed water (0.3mL, 20mmol) were then added and the reaction mixture was degassed with nitrogen for 4min and then heated to 140 ℃ for 80min under microwave irradiation. The mixture was then filtered through celite, eluting with ethyl acetate and concentrated in vacuo. Purification of the crude product was achieved by reverse phase HPLC.
Example 7: 5-chloro-2-methoxy-4-N, N-dimethyl- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) Phenyl) -benzoylAmines as pesticides
4-amino-5-chloro-2-methoxy-N, N-dimethylbenzamide (110mg, 0.48mmol), 2-chloro-4- (methylamino) -5-trifluoromethylpyrimidine (50mg, 0.23mmol), tris (dibenzylideneacetone) dipalladium (11mg, 0.012mmol), xanthphos (4, 5-bis diphenylphosphino-9, 9-dimethylxanthene) (14mg, 0.024 mmol), and cesium carbonate (235mg, 0.72mmol) in 1, 4-bisThe mixture in the alkane was degassed with nitrogen for 5 minutes and then heated to 1000C for 2 hours. The cooled mixture was diluted with DCM (10ml), washed with water, dried (MgSO4) and concentrated under vacuum. The residue was triturated in diethyl ether to give the title compound as a pale yellow solid, 45mg, 47%.
Additional compounds prepared using the above procedure are shown in table 5 below.
TABLE 5
Example 8: 5-chloro-N- (2-hydroxy-2-methyl-propyl) -2-methoxy-4- (4-methylamino-5-trifluoromethyl) Yl-pyrimidin-2-ylamino) -benzamides
4-amino-5-chloro-2-methoxy-N- (2-methyl-propan-2-ol) -benzamide (95mg, 0.35mmol), 2-chloro-4- (methylamino) -5-trifluoromethylpyrimidine (50mg, 0.23mmol) and p-toluenesulfonic acid monohydrate (49mg, 0.26mmol) in 1, 4-bisThe mixture in alkane (5ml) was stirred at 1000C for 18 h. The solvent was removed by evaporation in vacuo and the residue was partitioned between DCM and aqueous K2CO 3. The organic phase was separated, concentrated to dryness in vacuo and the crude material was purified by RP-HPLC to give the title compound as a cream solid, 57mg, 55%.
Additional compounds prepared using the above procedure are shown in table 6 below.
Example 9(3- (2-Fluoroethoxy) -4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzene Yl) (morpholino) methanone
A mixture of 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (0.10g, 0.47mmol), (4-amino-3- (2-fluoroethoxy) phenyl) (morpholino) methanone (0.13g, 0.47mmol), trifluoroacetic acid (0.07mL, 0.9mmol) in 2-methoxyethanol (2.5mL) was stirred at 95 ℃ for 6 hours. The reaction was concentrated. The crude product was purified by reverse phase HPLC to give the title compound (61mg, 29%). Additional compounds prepared using the above procedure are shown in table 6 below.
Example 10 (2-fluoro-3-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzene Yl) (morpholino) methanone
To a suspension of 2-fluoro-3-methoxy-4-nitrobenzoic acid (180mg, 0.97mmol) in DCM (8mL) was added morpholine (0.17mL, 1.9mmol), DIEA (0.25mL) and HBTU (0.4g, 1.05 mmol). The solution was stirred at room temperature for 18 hours. The reaction was then diluted with water and extracted with DCM (3 ×). The combined extracts were washed with water, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography to give (2-fluoro-3-methoxy-4-nitrophenyl) (morpholino) methanone (0.20g, 83%).
A suspension of (2-fluoro-3-methoxy-4-nitrophenyl) (morpholino) methanone (0.20g) and palladium on carbon (0.1g, 10 wt%) in ethanol was stirred under hydrogen for 18 hours. The reaction was then filtered through celite and concentrated to give (4-amino-2-fluoro-3-methoxyphenyl) (morpholino) methanone.
A mixture of (4-amino-2-fluoro-3-methoxyphenyl) (morpholino) methanone (0.18g, 0.72mmol) and 2-chloro-N-methyl-5- (trifluoromethyl) pyrimidin-4-amine (0.10g, 0.47mmol) in a solution of 2-methoxyethanol (2mL) and TFA (0.055mL) was stirred at 95 ℃ for 2 hours. The reaction was concentrated and purified by reverse phase HPLC to give the title compound. Additional compounds prepared using the above procedure are shown in table 6 below.
TABLE 6
Example 11: 2- [ 2-methoxy-4- (morpholine-4-carbonyl) -phenylamino]-4-methylamino-pyrimidine-5-carbonitrile
To a mixture of (4- (5-bromo-4- (methylamino) pyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone (80mg, 0.19mmol), zinc cyanide (50mg, 0.42mmol), tris (dibenzylideneacetone) dipalladium (9mg, 0.09mmol), DPPF (11mg, 0.02mmol) in DMF (3mL) was stirred at 105 ℃ for 18 hours in a pressure tube. The reaction mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC to give the title compound (70mg, 82%). Additional compounds prepared using the above procedure are shown in table 7 below.
TABLE 7
The corresponding pharmaceutically acceptable salts with acids can be obtained by standard methods known to those skilled in the art, for example by dissolving a compound of formula I in a suitable solvent such as diAlkane or THF and the appropriate amount of the corresponding acid was added. The product can usually be isolated by filtration or by chromatography. The conversion of a compound of formula I into a pharmaceutically acceptable salt with a base can be achieved by treating such a compound with such a base. One possible way of forming such salts is, for example, by reacting 1/n equivalent of a basic salt such as M (OH)nWhere M ═ metal or ammonium cations and n ═ hydroxide anions, are added to a solution of the compound in a suitable solvent (e.g. ethanol, ethanol-water mixtures, tetrahydrofuran-water mixtures) and the solvent is removed by evaporation or lyophilization. Particular salts are the hydrochloride, formate and trifluoroacetate salts. In particularIs a hydrochloride salt.
In the case that their preparation is not described in the examples, the compounds of formula I as well as all intermediates may be prepared according to analogous methods or according to the methods set forth herein. The starting materials are commercially available, known in the art, or can be prepared by methods known in the art or similar methods.
It will be appreciated that the compounds of formula I in the present invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.
Pharmacological testing
The compounds of formula I and their pharmaceutically acceptable salts have valuable pharmacological properties. It has been found that the compounds of the invention are associated with modulation of LRRK2 activity. These compounds were investigated in accordance with the tests given below.
Example 12 in vitro LRRK2LabChip (Lab on chip) assay
This assay was used to determine the efficacy of a compound in inhibiting the activity of LRRK2 by determining Kiapp, IC50, or percent inhibition values. In polypropylene plates, LRRK2, fluorescently labeled peptide substrate, ATP, and test compound were incubated together. Using LabChip 3000(Caliper Life Sciences), after the reaction, the substrate was separated into two populations by capillary electrophoresis: phosphorylated and unphosphorylated. The relative amounts of each are quantified by fluorescence intensity. LRRK2Ki is determined according to the following equation:
Y＝V0*(1-((x+Ki*(1+S/Km)+Et)/(2*Et)-(((x+Ki*(1+S/Km)+Et)^2-(4*Et*x))^0.5)/(2*Et)))。
ki values in table 4 and elsewhere herein are shown in μ M.
The assay conditions and materials used were as follows:
final assay conditions:
materials:
solid carrier: black 50 μ L volume polypropylene 384 well plate (Matrical cat # MP101-1-PP)
Kinase enzymes: LRRK2G2019S (Invitrogen cat # PV 4882).
LRRK2 wild type (Invitrogen cat # PV 4874).
Substrate: 5FAM-GAGRLGRDKYKTLRQIRQ-CONH2
A non-bonded plate: a384 well clear V-bottom polypropylene plate (Greiner cat # 781280).
ATP：10mM ATP(Cell Signaling cat#9804)。
Triton X-100：Triton X-100。
Brij-35：Brij-35(Pierce cat#20150)。
Coating reagent # 3: coating reagent #3 (Caliper).
DMSO：DMSO(Sigma cat#34869-100ML)。
Complete reaction buffer: H2O/25mM Tris, pH 8.0/5mM MgCl2/2mM DTT/0.01% Triton X-100.
Stopping liquid: H2O/100mM HEPES, pH 7.2/0.015% Brij-35/0.2% coating reagent #3/20mM EDTA.
Separating buffer solution: H2O/100mM HEPES, pH 7.2/0.015% Brij-35/0.1% coating reagent # 3/1: 200 coating reagent #8/10mM EDTA/5% DMSO.
Compound plate preparation:
for serial dilutions, 34.6. mu.l DMSO was added to columns 3-24. For assay controls, 37.5. mu.l DMSO was added to columns 1 and 2 of rows A and P, and 50. mu.l 25. mu. M G-028831(Staurosporine) was added to columns 1 and 2 of row B. For the samples: starting at 100. mu.M, 37.5. mu.l DMSO was added to columns 1 and 2, followed by 12.5. mu.l of 10mM compound; starting at 10. mu.M, 78. mu.l DMSO was added to columns 1 and 2, followed by 2. mu.l 10mM compound, and starting at 1. mu.M, 25. mu.M compound (2. mu.l 10mM compound + 798. mu.l DMSO) was added to empty columns 1 and 2. A1: 3.16 dilution series ("PLK _ BM _ serial _ halflog") was performed using precision instrumentation.
ATP preparation：
ATP was diluted to 282.1. mu.M (final concentration of 130. mu.M) in complete kinase buffer.
Bulk and blank preparation：
In complete reaction buffer, the substrate was diluted to 4 μ M. Equal volumes of complete reaction buffer and 4 μ M substrate were combined to obtain a blank. Equal volumes of complete reaction buffer and 4 μ M substrate were combined and 2X final LRRK2 concentration was added to the combined solution.
Measurement procedure：
To a 50. mu.l polypropylene plate, 5. mu.l/well buffer/substrate was added by hand to the blank well. The kinase reaction ("PLK SAR 23 ATP") was initiated using Biomek FX. The following were added to the appropriate wells:
2 μ l compound +23 μ l ATP;
5 μ l/well compound/ATP in assay plate;
5 μ l/well kinase/substrate in assay plate;
the plates were incubated for 2 hours in the dark. Biomek FX was used to terminate kinase reaction kinase ("PLK Stop") and 10. mu.l/well of Stop solution was added to the assay plate. The results were read on a LabChip 3000.
LabChip 3000 protocol：
The LabChip 3000 was run using the work "LRRK 2IC 50" with the following work settings:
pressure: -1.4psi
Downstream voltage: -500V
Upstream voltage: -2350V
Post sample buffer sipping time: 75 seconds
Post dye buffer sipping time: 75 seconds
Final delay time: 200 seconds
Example 13 in vitro LRRK2Lanthascreen binding assay
This assay was used to determine the efficacy of a compound in inhibiting the activity of LRRK2 by determining Kiapp, IC50, or percent inhibition values. In 384 well proxiplates F black plates, shallow well plates LRRK2, Eu-anti-GST-antibody, AlexaThe kinase tracer 236 is incubated with the test compound.
AlexaBinding of the "tracer" to the kinase was detected by the addition of a Eu-labeled anti-GST antibody. Binding of the tracer and antibody to the kinase results in a high degree of FRET, whereas replacement of the tracer with the kinase inhibitor results in loss of FRET.
The assay conditions and materials used were as follows:
final assay conditions：
Materials:
reaction buffer: H2O/50mM Tris, pH 7.4/10mM MgCl2/1mM EGTA/0.01% Brij 35.
Preparation of Compound plate：
Compounds (10mM stock) were serially diluted 1: 3.16(20ul +43.2ul) in 100% DMSO. 12 point curve. Each concentration was diluted 1: 33.3(3ul +97ul) in reaction buffer. Add 5ul to assay plate. The final highest assay concentration was 100 uM.
Bulk and blank preparation：
In the reaction buffer, 5ul of DMSO (3%) was added to the bulk and blank wells and 5ul of Eu-labeled anti-GST antibody (6nM) was added to the blank wells.
Measurement procedure：
5ul of LRRK2(30 nM)/Eu-labeled anti-GST antibody (6nM) mix was added to the compounds and total wells. 5ul of kinase tracer (25.5nM) was added to all wells. The plates were incubated at room temperature on a plate shaker (gentle shaking). Read on a Perkin Elmer EnVision reader HTRF protocol.
Data processing:
calculating the ratio: (665/620)*10000. The average background value was subtracted from all data points. The% of control was calculated for each test value. The% of control is plotted against compound concentration. Ki values were calculated (xlfit curve fitting-Morrison equation).
The results are expressed as Ki (. mu.M). Equation for Ki: Y-V0 (1- ((x + Ki (1+ S/Km) + Et)/(2 Et) - ((x + Ki (1+ S/Km) + Et) ^2- (4 Et x)) > 0.5)/(2 Et)))
Wherein Et is 4nM
kd (tracer) ═ 8.5nM
Tracer concentration (S) 8.5nM.
Example 14 animal models of Parkinson's disease
Parkinson's disease can replicate in mice and primates by administering 1-methyl-4-phenyltetrahydropyridine (MPTP), a selective nigrostriatal dopaminergic neurotoxin that produces a loss of striatal Dopamine (DA) nerve terminal markers. The efficacy of the compounds of the invention in the treatment of Parkinson's disease can be evaluated using MPTP-induced neurodegeneration, generally in accordance with the protocol described by Saponito et al, J.Pharmacology (1999) Vol.288, pp.421-427.
Briefly, MPTP was dissolved in PBS at a concentration of 2-4mg/ml and mice (male C57, 20-25g in weight) were injected subcutaneously with 20-40 mg/kg. The compounds of the invention were solubilized with polyethylene glycol hydroxystearate and dissolved in PBS. Mice were given a 10ml/kg solution of the compound by subcutaneous injection 4 to 6h prior to MPTP administration, and then daily for 7 days. On the day of the last injection, mice were sacrificed and the midbrain was blocked and postfixed (postfix) in paraformaldehyde. Striatum was cut, weighed and stored at-70 ℃.
The striatum thus collected was evaluated for its content of dopamine and its metabolites dihydroxyphenylacetic acid and homovanillic acid by HPLC with electrochemical detection as described by Sonsalla et al, J.Pharmacol.Exp.Ther. (1987) Vol.242, pp.850-857. Striatum may also be assessed by measuring the evolution of 14CO2 associated with the tyrosine hydroxylase-mediated conversion of labeled tyrosine to L-dopa using the tyrosine hydroxylase assay of Okunu et al, Anal Biochem (1987) Vol.129, pp.405-411. The striatum may also be assessed using monoamine oxidase-B as described by White et al, Life Sci, (1984), Vol.35, pp.827-833, and by detecting dopamine uptake as described by Saponito et al, (1992) Vol.260, pp.1400-1409.
While the invention has been described with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the appended claims.
Pharmaceutical composition
The compounds of formula I and pharmaceutically acceptable salts can be used as therapeutically active substances, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, administration can also be effected rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.
The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, paraffins, fats, semi-solid and liquid polyols and the like. However, depending on the nature of the active substance, no carriers are generally required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, paraffins, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical preparations may contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.
The invention also provides medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, as well as processes for their preparation, which comprise bringing one or more compounds of formula I and/or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
The dosage can vary within wide limits and must of course be adjusted in each particular case to suit the individual needs. In the case of oral administration, the dose for an adult may be about 0.01mg to about 1000mg per day of a compound of formula I or a corresponding amount of a pharmaceutically acceptable salt thereof. The daily dose may be administered as a single dose or in divided doses and, in addition, the upper limit thereof may also be exceeded when found necessary.
The following examples illustrate the invention without limiting it, but serve only as representative thereof. The pharmaceutical preparation conveniently contains from about 1 to 500mg, preferably from 1 to 100mg, of a compound of formula I. Examples of compositions according to the invention are the following:
example A
Tablets of the following composition were manufactured in a conventional manner:
table 8: possible tablet compositions
Manufacturing process
1. Ingredients 1, 2, 3 and 4 were mixed and granulated with purified water.
2. The granules were dried at 50 ℃.
3. The particles are passed through a suitable milling apparatus.
4. Add ingredient 5and mix for 3 minutes; pressing on a suitable press.
Example B-1
Capsules of the following composition were made:
table 9: possible capsule ingredient composition
Manufacturing process
1. Ingredients 1, 2 and 3 were mixed in a suitable mixer for 30 minutes.
2. Add ingredients 4 and 5and mix for 3 minutes.
3. Encapsulating into suitable capsule.
The compound of formula I, lactose and corn starch are first mixed in a mixer and then mixed in a mill. The mixture was returned to the mixer, talc was added thereto and mixed well. The mixture is filled by machine into suitable capsules, for example hard gelatin capsules.
Example B-2
Soft gelatin capsules of the following composition were made:
composition (I) mg/capsule
A compound of formula I 5
Yellow wax 8
Hydrogenated soybean oil 8
Partially hydrogenated vegetable oils 34
Soybean oil 110
Total of 165
Table 10: possible soft gelatin capsule ingredient compositions
Composition (I) mg/capsule
Gelatin 75
Glycerin 85% 32
Karion 83 8 (Dry matter)
Titanium dioxide 0.4
Iron oxide yellow 1.1
Total of 116.5
Table 11: possible soft gelatin capsule compositions
Manufacturing process
The compound of formula I is dissolved in a warm melt of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are processed according to conventional procedures.
Example C
Suppositories of the following composition were made:
composition (I) mg/suppository
A compound of formula I 15
Suppository bolus 1285
Total of 1300
Table 12: possible suppository composition
Manufacturing process
The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45 ℃. Thereafter, the finely powdered compound of formula I is added thereto and stirred until it is completely dispersed. Pouring the mixture into a suppository mold with a proper size, and keeping the mixture stand for cooling; the suppositories are then removed from the moulds and individually packaged in waxed paper or metal foil.
Example D
An injection of the following composition was made:
composition (I) mg/injection
A compound of formula I 3
Polyethylene glycol 400 150
Acetic acid Adding into pH 5.0
Water for injection Adding to 1.0ml
Table 13: possible injection compositions
Manufacturing process
The compound of formula I is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH was adjusted to 5.0 with acetic acid. The volume was adjusted to 1.0ml by adding the remaining amount of water. The solution was filtered, filled into vials with the appropriate excess and sterilized.
Example E
Sachets of the following composition were made:
composition (I) mg/sachet
A compound of formula I 50
Lactose, fine powder 1015
Microcrystalline cellulose (AVICEL PH 102) 1400
Sodium carboxymethylcellulose 14
Polyvinylpyrrolidone K30 10
Magnesium stearate 10
Flavoring additive 1
Total of 2500
Table 14: possible sachet composition
Manufacturing process
The compound of formula I is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules were mixed with magnesium stearate and flavouring additives and filled into sachets.

Claims (27)

1. A compound of formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
m is 0 to 3;
x is: -NRa-; -O-; or-S (O)r-, where R is 0 to 2 and RaIs hydrogen or C1-6An alkyl group;
R1the method comprises the following steps: c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; hydroxy-C2-6An alkenyl group; amino-C1-6An alkyl group; c1-6alkylsulfonyl-C1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; a tetrahydropyranyl group; tetrahydropyranyl-C1-6Alkyl, oxetanyl; or oxetane-C1-6An alkyl group;
or R1And RaTogether with the atoms to which they are attached may form a three-to six-membered ring, which may optionally include a further heteroatom selected from O, N and S, and which is oxo, halo or C1-6Alkyl substitution;
R2the method comprises the following steps: halogen; c1-6An alkoxy group; a cyano group; c2-6An alkynyl group; c2-6An alkenyl group; halo-C1-6An alkyl group; halo-C1-6An alkoxy group; c3-6Cycloalkyl, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; acetyl; an oxetanyl group; or oxetane-C1-6An alkyl group;
R3the method comprises the following steps: -OR4(ii) a Halogen; a cyano group; c1-6An alkyl group; halo-C1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R4the method comprises the following steps: hydrogen, C1-6An alkyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; optionally is covered with C1-6Alkyl or halogen substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl or halogen substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R5the method comprises the following steps: hydrogen; or C1-6An alkyl group;
n is 0 or 1;
R6the method comprises the following steps: hydrogen; c1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; hydroxy-C1-6An alkyl group; amino-C1-6An alkyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; a heterocyclic group; or heterocyclyl-C1-6An alkyl group; wherein said C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-6Alkyl, heterocyclyl and heterocyclyl-C1-6Each alkyl group may be optionally substituted with one, two, three or four groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring;
or R5And R6Together with the nitrogen atom to which they are attached form a three-to seven-membered ring, which optionally includes an additional ring selected from O, N and S (O)nAnd which is optionally substituted with one, two, three or four groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen, nitrile; c1-6Alkyl-carbonyl; c1-6Alkyl radical-a sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; c1-6Alkyl-heterocyclyl radical, C1-6alkoxy-C1-6An alkyl or heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring; and is
R7The method comprises the following steps: halogen; c1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkyl group; or halo-C1-6An alkoxy group.
2. A compound of formula I according to claim 2:
or a pharmaceutically acceptable salt thereof,
wherein:
m is 0 to 3;
x is: -NRa-; -O-; or-S (O)n-, where n is 0 to 2 and RaIs hydrogen or C1-6An alkyl group;
R1the method comprises the following steps: c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; hydroxy-C2-6An alkenyl group; amino-C1-6An alkyl group; c1-6alkylsulfonyl-C1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
or R1And RaTogether with the atoms to which they are attached may form a three-to six-membered ring, which may optionally include a further heteroatom selected from O, N and S, and which is oxo, halo or C1-6Alkyl substitution;
R2the method comprises the following steps: halogen; c1-6An alkoxy group; a cyano group; c2-6An alkynyl group; c2-6An alkenyl group; halo-C1-6An alkyl group; halo-C1-6An alkoxy group; c3-6Cycloalkyl, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; acetyl; an oxetanyl group; or oxetane-C1-6An alkyl group;
R3the method comprises the following steps: -OR4(ii) a Halogen; a cyano group; c1-6An alkyl group; halo-C1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R4the method comprises the following steps: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; optionally is covered with C1-6Alkyl or halogen substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl or halogen substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R5the method comprises the following steps: hydrogen; or C1-6An alkyl group;
n is 0 or 1;
R6is that; hydrogen; c1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; hydroxy-C1-6An alkyl group; amino-C1-6An alkyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; a heterocyclic group; or heterocyclyl-C1-6An alkyl group; wherein said C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-6Alkyl, heterocyclyl and heterocyclyl-C1-6Each alkyl group may be optionally substituted with one, two, three or four groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring;
or R5And R6Together with the nitrogen atom to which they are attached form a three-to seven-membered ring, which optionally includes an additional ring selected from O, N and S (O)nAnd which is optionally substituted with one, two, three or four groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen, nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring; and is
R7The method comprises the following steps: halogen; c1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkyl group; or halo-C1-6An alkoxy group.
3. The compound according to any one of claims 1-2, wherein the compound is of formula II:
or a pharmaceutically acceptable salt thereof,
wherein:
m is 0 to 3;
x is: -NRa-; -O-; or-S (O)n-, where n is 0 to 2 and RaIs hydrogen or C1-6An alkyl group;
R1the method comprises the following steps: c1-6An alkyl group; c2-6An alkenyl group; c2-6An alkynyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; hydroxy-C2-6An alkenyl group; amino-C1-6An alkyl group; c1-6alkylsulfonyl-C1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R2the method comprises the following steps: halogen; c1-6An alkoxy group; a cyano group; c2-6An alkynyl group; c2-6An alkenyl group; halo-C1-6An alkyl group; halo-C1-6An alkoxy group; c3-6Cycloalkyl, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R3the method comprises the following steps: -OR4(ii) a Halogen; a cyano group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R4the method comprises the following steps: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; optionally is covered with C1-6Alkyl substituted C3-6A cycloalkyl group; c3-6cycloalkyl-C1-6Alkyl radical, wherein the C3-6Cycloalkyl moiety being optionally substituted by C1-6Alkyl substitution; a tetrahydrofuranyl group; tetrahydrofuryl-C1-6An alkyl group; an oxetanyl group; or oxetane-C1-6An alkyl group;
R5the method comprises the following steps: hydrogen; or C1-6An alkyl group;
R6the method comprises the following steps: hydrogen; c1-6An alkyl group; c1-6alkoxy-C1-6An alkyl group; amino-C1-6An alkyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; a heterocyclic group; or heterocyclyl-C1-6An alkyl group; wherein said C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-6Alkyl, heterocyclyl and heterocyclyl-C1-6Each alkyl group may be optionally substituted with one, two or three groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring;
or R5And R6Together with the nitrogen atom to which they are attached form a three-to seven-membered ring, which optionally includes an additional ring selected from O, N and S (O)nAnd which is optionally substituted with one, two, or three groups independently selected from: c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen, nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group; or two of these groups together with the atoms to which they are attached may form a five or six membered ring; and is
R7The method comprises the following steps: halogen element；C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkyl group; or halo-C1-6An alkoxy group.
4. A compound according to claim 3, wherein m is 0 or 1.
5. A compound according to claim 3, wherein X is-NRa-or-O-.
6. A compound according to claim 3, wherein X is-NRa。
7. A compound according to claim 3, wherein R1Is C1-6An alkyl group.
8. A compound according to claim 3, wherein R2The method comprises the following steps: halogen; halo-C1-6An alkyl group; or a cyano group.
9. A compound according to claim 3, wherein R2The method comprises the following steps: chloro, trifluoromethyl or cyano.
10. A compound according to claim 3, wherein R3The method comprises the following steps: halogen; OR-OR 4.
11. A compound according to claim 3, wherein R3The method comprises the following steps: halogen; c1-6An alkoxy group; or halo-C1-6An alkoxy group.
12. A compound according to claim 3, wherein R3The method comprises the following steps: a methoxy group; chlorine; or fluorine.
13. A compound according to claim 3, wherein m is 1 and R7Is halogen or methoxy.
14. A compound according to claim 3, wherein R5And R6Together with the nitrogen atom to which they are attached form a three to six membered ring, which optionally includes a further heteroatom selected from O, N and S, and which is optionally substituted with one, two or three groups independently selected from: c1-6Alkyl, halo-C1-6Alkyl radical, C1-6Alkoxy, halo-C1-6Alkoxy, hydroxy-C1-6Alkyl, halogen, nitrile, C1-6Alkyl-carbonyl, C1-6Alkyl-sulfonyl radical, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-6Alkyl radical, C3-6Cycloalkyl-carbonyl, amino, or heterocyclyl groups, or two of these groups together with the atoms to which they are attached may form a five or six membered ring.
15. A compound according to claim 3, wherein R5And R6Together with the nitrogen atom to which they are attached form a morpholinyl group, which morpholinyl group is optionally substituted once or twice with a group independently selected from: c1-6Alkyl, halo-C1-6Alkyl radical, C1-6Alkoxy, halo-C1-6Alkoxy, hydroxy-C1-6Alkyl, halogen, nitrile, C1-6Alkyl-carbonyl, C1-6Alkyl-sulfonyl radical, C3-6Cycloalkyl radical, C3-6cycloalkyl-C1-6Alkyl radical, C3-6Cycloalkyl-carbonyl, amino, or heterocyclyl, or both groups together with the atoms to which they are attached may form a five or six membered ring.
16. A compound according to claim 3, wherein the compound is of formula III
Wherein:
p is 0 to 2;
when p is 1 or 2, Y is: -O-; -S (O)n-；-NR10(ii) a or-CR11R12-; and Y is-CR when p is 011R12-；
R8And R9Each independently is: hydrogen; c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; or a heterocyclic group;
or R8And R9Together with the atoms to which they are attached form a five or six membered ring;
R10the method comprises the following steps: hydrogen; c1-6An alkyl group; hydroxy-C1-6An alkyl group; halo-C1-6An alkyl group; hydroxy-C1-6An alkyl group; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; a heterocyclic group; or heterocyclyl-C1-6An alkyl group;
or R8And R9Together with R10And the atoms to which they are attached together form a five or six membered ring;
R11the method comprises the following steps: hydrogen; c1-6An alkyl group; or halogen;
R12the method comprises the following steps: hydrogen; c1-6An alkyl group; halo-C1-6An alkyl group; c1-6An alkoxy group; halo-C1-6An alkoxy group; a hydroxyl group; hydroxy-C1-6An alkyl group; halogen; a nitrile; c1-6Alkyl-carbonyl; c1-6An alkyl-sulfonyl group; c3-6A cycloalkyl group; c3-6cycloalkyl-C1-6An alkyl group; c3-6Cycloalkyl-carbonyl; an amino group; a heterocyclic group; or heterocyclyl-C1-6An alkyl group;
or R11And R12Together with the atoms to which they are attached may form a 3 to 6 membered ring, optionally including a heteroatom selected from O, N and S；
Or R8And R9Together with R10And the atoms to which they are attached together form a five or six membered ring;
or R8And R9Together with R12And the atoms to which they are attached together form a five or six membered ring; and is
m，n，X，R1，R2，R3And R7As defined herein.
17. A compound according to claim 3, wherein p is 1.
18. A compound according to claim 3, wherein Y is-O-; -NR10(ii) a or-CR11R12-。
19. A compound according to claim 3, wherein Y is-O-.
20. A compound according to any one of claims 1 to 19, selected from:
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N- (2-hydroxy-ethyl) -2-methoxy-benzamide,
5-chloro-N-cyclopropyl-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
((2S, 6R) -2, 6-dimethylmorpholino) (2-fluoro-5-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) methanone,
(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl (2-fluoro-3-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) methanone,
(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl (4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -2-fluoro-3-methoxyphenyl) methanone,
(2, 6-dimethyl-morpholin-4-yl) - [ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -methanone,
(2-ethoxy-5-fluoro-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone,
(2-fluoro-3-isopropoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone,
(2-fluoro-3-isopropoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone,
(2-fluoro-5-methoxy-4- (4- (2-methoxyethoxy) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone,
(2-fluoro-5-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (3-methoxypyrrolidin-1-yl) methanone,
(3-methoxy-4- (5-methoxy-4- (methylamino) pyrimidin-2-ylamino) phenyl) (morpholino) methanone,
(4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -2-fluoro-3-methoxyphenyl) (morpholino) methanone,
(4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -2-fluoro-3-isopropoxyphenyl) (morpholino) methanone,
(4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -3- (trifluoromethoxy) phenyl) (morpholino) methanone,
(4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -3- (trifluoromethoxy) phenyl) (morpholino) methanone,
(4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-yl-amino) -3-isopropoxyphenyl) (morpholino) methanone,
(4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -3-isopropoxyphenyl) (morpholino) methanone,
(4- (4- (ethylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -5-fluoro-2-methoxyphenyl) (morpholino) methanone,
(4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) -3- (trifluoromethoxy) phenyl) (morpholino) methanone,
(4- (5-bromo-4-methoxypyrimidin-2-ylamino) -3-methoxyphenyl) (3- (trifluoromethyl) pyrrolidin-1-yl) methanone,
(4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3-methylphenyl) (morpholino) methanone,
(4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3-methylphenyl) (4-hydroxypiperidin-1-yl) methanone,
(4- (5-chloro-4- (piperidin-1-yl) pyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone,
(4- (5-chloro-4- (pyrrolidin-1-yl) pyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone,
(4- (5-chloro-4-methoxypyrimidin-2-ylamino) -3-methoxyphenyl) (pyrrolidin-1-yl) methanone,
(4- (5-cyclopropyl-4-methoxypyrimidin-2-ylamino) -3-methoxyphenyl) (morpholino) methanone,
(4- { 5-chloro-4- [ (tetrahydro-furan-2-ylmethyl) -amino ] -pyrimidin-2-ylamino } -3-methoxy-phenyl) -morpholin-4-yl-methanone,
(4- { 5-chloro-4- [ (tetrahydro-furan-3-ylmethyl) -amino ] -pyrimidin-2-ylamino } -3-methoxy-phenyl) -morpholin-4-yl-methanone,
(4-dimethylamino-piperidin-1-yl) - [ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -methanone,
(4-tert-butyl-piperidin-1-yl) - [4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -methanone,
(5-chloro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (deuteromorpholino) methanone,
(5-chloro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (3-methoxypyrrolidin-1-yl) methanone,
(5-chloro-4- (methylamino) pyrimidin-2-ylamino) -2-methoxyphenyl) (morpholino) methanone,
(5-fluoro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone,
[ 2-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[ 2-chloro-5-methoxy-4- (4-methoxy-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 2-chloro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 2-fluoro-3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 2-fluoro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 2-fluoro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] - ((S) -2-methoxymethyl-pyrrolidin-1-yl) -methanone,
[3- (2-fluoro-ethoxy) -4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-bromo-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-bromo-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-chloro-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-chloro-4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-cyclobutoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-cyclobutylmethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-cyclopropyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-cyclopropylmethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-ethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-isopropoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-methoxy-4- (4-methoxy-5-prop-1-ynyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-methoxy-4- (4-methoxy-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-methoxy-4- (4-methylamino-5-prop-1-ynyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] - (8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -methanone,
[ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] - (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -methanone,
[ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -pyrrolidin-1-yl-methanone,
[ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] - [4- (2, 2, 2-trifluoro-ethyl) -piperazin-1-yl ] -methanone,
[ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] - (4-methoxy-piperidin-1-yl) -methanone,
[ 3-methoxy-4- (4-pyrrolidin-1-yl-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl ] - ((S) -2-methoxymethyl-pyrrolidin-1-yl) -methanone,
[4- (5-bromo-4-ethoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-isopropoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -2-chloro-5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-cyclobutoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-cyclopropoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-ethoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-isopropoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - ((R) -2, 2-di-deuterium-3-methyl-morpholin-4-yl) -methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - ((S) -2, 2-di-deuterium-3-methyl-morpholin-4-yl) -methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-morpholin-4-yl-azetidin-1-yl) -methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4, 4-difluoro-piperidin-1-yl) -methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-ethyl-piperazin-1-yl) -methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - [4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-yl ] -methanone,
[4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - [4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-yl ] -methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-trifluoromethyl-pyrrolidin-1-yl) -methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-cyclobutyl-piperazin-1-yl) -methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - [4- (2, 2, 2-trifluoro-ethyl) -piperazin-1-yl ] -methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-methoxy-piperidin-1-yl) -methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - ((R) -3-hydroxy-pyrrolidin-1-yl) -methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-oxetan-3-yl-piperazin-1-yl) -methanone,
[4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -5-chloro-2-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-cyclobutylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-cyclohexylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-cyclopentylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-ethoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-ethylamino-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-ethylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-isobutylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-isopropoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-isopropylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3- (2, 2, 2-trifluoro-ethoxy) -phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3- (oxetan-3-yloxy) -phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclobutoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclopentyloxy-phenyl ] - (2-oxa-6-aza-spiro [3.3] hept-6-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclopentyloxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclopropoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-cyclopropyl-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-difluoromethoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-difluoromethoxy-phenyl ] - (4-hydroxy-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-ethoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-hydroxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-isopropoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-hydroxy-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (octahydro-pyrido [1, 2-a ] pyrazin-2-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-hydroxy-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4, 4-dimethyl-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3, 5-dimethyl-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - [4- (1-hydroxy-1-methyl-ethyl) -piperidin-1-yl ] -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-hydroxy-pyrrolidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-methyl-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -piperidin-1-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4, 4-difluoro-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-methyl-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-methoxy-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3, 3-difluoro-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-fluoro-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-methoxy-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-ethyl-piperazin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-trifluoromethyl-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-methyl-pyrrolidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-hydroxymethyl-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-methyl-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -pyrrolidin-1-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-methanesulfonyl-piperazin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-trifluoromethyl-pyrrolidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - [4- (2, 2, 2-trifluoro-ethyl) -piperazin-1-yl ] -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-methyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2, 6-dimethyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2, 2-diethyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-hydroxymethyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-isobutyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-hydroxymethyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3, 3-dimethyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-methyl-piperazin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-isopropyl-piperazin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -piperazin-1-yl-methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - ((S) -3-methyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - ((R) -3-methyl-morpholin-4-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-cyclopropanecarbonyl-piperazin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3-morpholin-4-yl-azetidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - [4- (1-methyl-piperidin-4-yl) -piperazin-1-yl ] -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (3, 3-difluoro-azetidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-dimethylamino-piperidin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-piperidin-4-yl-piperazin-1-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (2-oxa-6-aza-spiro [3.3] hept-6-yl) -methanone,
[4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-trifluoromethoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-propoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-propylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-cyclobutyl-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-cyclobutyl-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-cyclopropyl-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-cyclopropyl-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-fluoro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-fluoro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] - (4-hydroxy-piperidin-1-yl) -methanone,
[4- (5-iodo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-iodo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- [ 5-chloro-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino ] -3- (2, 2, 2-trifluoro-ethoxy) -phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-2-ethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -piperazin-1-yl-methanone,
[ 5-chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] - (2, 6-dimethyl-morpholin-4-yl) -methanone,
[ 5-chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-methoxy-phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-4- (5-chloro-4-ethylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -2-methoxy-phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - (4, 4-difluoro-piperidin-1-yl) -methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] -piperazin-1-yl-methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - (4-dimethylamino-piperidin-1-yl) -methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - (3-hydroxy-pyrrolidin-1-yl) -methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] -pyrrolidin-1-yl-methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - (4-hydroxy-piperidin-1-yl) -methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - (2-hydroxymethyl-morpholin-4-yl) -methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - [1, 4] oxazepan-4-yl-methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - ((2R, 6S) -2, 6-dimethyl-morpholin-4-yl) -methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - (3-hydroxy-azetidin-1-yl) -methanone,
[ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-phenyl ] - ((3R, 5S) -dimethyl-piperazin-1-yl) -methanone,
[ 5-ethoxy-2-fluoro-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 5-ethoxy-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-phenyl ] -morpholin-4-yl-methanone,
{4- [ 5-bromo-4- (2-methoxy-ethoxy) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-bromo-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino ] -2-fluoro-5-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-bromo-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino ] -3-ethoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-bromo-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino ] -3-isopropoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-bromo-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (1-methyl-cyclobutylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2, 2, 2-trifluoro-ethylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2, 2-difluoro-ethylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2-cyclopropyl-ethylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2-methanesulfonyl-ethylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2-methoxy-ethoxy) -pyrimidin-2-ylamino ] -3-cyclobutoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2-methoxy-ethoxy) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino ] -3-cyclobutoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2-methoxy-ethylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (2-methoxy-propylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (cyclobutylmethyl-amino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (cyclopentylmethyl-amino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (cyclopropylmethyl-amino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (tetrahydro-furan-3-ylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (tetrahydro-pyran-3-ylamino) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
{4- [ 5-chloro-4- (tetrahydro-pyran-4-yloxy) -pyrimidin-2-ylamino ] -3-methoxy-phenyl } -morpholin-4-yl-methanone,
1- (4- (5-bromo-4-methoxypyrimidin-2-ylamino) -3-methoxybenzoyl) piperidine-4-carbonitrile,
1- [ 2-fluoro-5-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzoyl ] -pyrrolidine-3-carbonitrile,
1- [ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzoyl ] -piperidine-4-carbonitrile,
1- [4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzoyl ] -piperidine-4-carbonitrile,
1- [4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzoyl ] -piperidine-4-carbonitrile,
1- [ 5-chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzoyl ] -pyrrolidine-3-carbonitrile,
1- [ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-benzoyl ] -piperidine 4-carbonitrile,
1- [ 5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-benzoyl ] -pyrrolidine-3-carbonitrile,
1- {2- [ 2-methoxy-4- (morpholine-4-carbonyl) -phenylamino ] -4-methylamino-pyrimidin-5-yl } -ethanone,
1- {4- [4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzoyl ] -piperazin-1-yl } -ethanone,
2- (2-methoxy-4- (2, 2, 6, 6-tetrafluoromorpholine-4-carbonyl) phenylamino) -4- (methylamino) pyrimidine-5-carbonitrile,
2- (2-methoxy-4- (morpholine-4-carbonyl) phenylamino) -4- (methylamino) pyrimidine-5-carbonitrile,
2- (4- ((3S, 4S) -3, 4-difluoropyrrolidine-1-carbonyl) -2-methoxyphenylamino) -4- (methylamino) pyrimidine-5-carbonitrile,
2- (4- (4, 4-difluoropiperidine-1-carbonyl) -2-methoxyphenylamino) -4- (methylamino) pyrimidine-5-carbonitrile,
2- [2, 5-dimethoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -1-morpholin-4-yl-ethanone,
2- [ 2-methoxy-4- (morpholine-4-carbonyl) -phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [ 2-methoxy-4- (piperidine-1-carbonyl) -phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [ 2-methoxy-4- (pyrrolidine-1-carbonyl) -phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -1-morpholin-4-yl-ethanone,
2- [4- ((2R, 6S) -2, 6-dimethyl-morpholine-4-carbonyl) -5-fluoro-2-methoxy-phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [4- ((2R, 6S) -2, 6-dimethyl-morpholine-4-carbonyl) -5-fluoro-2-methoxy-phenylamino ] -4-ethylamino-pyrimidine-5-carbonitrile,
2- [4- ((R) -3-fluoro-pyrrolidine-1-carbonyl) -2-methoxy-phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [4- ((S) -3-fluoro-pyrrolidine-1-carbonyl) -2-methoxy-phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [4- (3, 3-difluoro-azetidine-1-carbonyl) -2-methoxy-phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [4- (3, 3-difluoro-pyrrolidine-1-carbonyl) -2-methoxy-phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [4- (3-fluoro-azetidine-1-carbonyl) -2-methoxy-phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [4- (5-bromo-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -1-morpholin-4-yl-ethanone,
2- [4- (5-bromo-4-methylamino-pyrimidin-2-ylamino) -2, 5-dimethoxy-phenyl ] -1-morpholin-4-yl-ethanone,
2- [4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -2, 5-dimethoxy-phenyl ] -1-morpholin-4-yl-ethanone,
2- [4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -1-morpholin-4-yl-ethanone,
2- [4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2, 5-dimethoxy-phenyl ] -1-morpholin-4-yl-ethanone,
2- [4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -1-morpholin-4-yl-ethanone,
2- [4- (azetidine-1-carbonyl) -2-methoxy-phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2- [ 5-fluoro-2-methoxy-4- (morpholine-4-carbonyl) -phenylamino ] -4-methylamino-pyrimidine-5-carbonitrile,
2-fluoro-5-methoxy-N- (2-methoxy-ethyl) -N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
2-fluoro-5-methoxy-N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
2-fluoro-N- (2-hydroxy-2-methylpropyl) -5-methoxy-N-methyl-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) benzamide,
3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -N-oxetan-3-yl-benzamide,
3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -N- (1-methyl-piperidin-4-yl) -benzamide,
3-methoxy-N- (2-methoxy-ethyl) -4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
3-methoxy-N- (2-methoxy-ethyl) -N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-N- (2-methoxy-ethyl) -N-methyl-benzamide,
4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -3-methoxy-N- (2-methoxy-ethyl) -N-methyl-benzamide,
4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -N, N, 3-trimethylbenzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N- (tetrahydro-pyran-3-yl) -benzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N, N-dimethyl-benzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N-methyl-benzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N-oxetan-3-yl-benzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N-cyclopropyl-3-methoxy-benzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N-ethyl-3-methoxy-benzamide,
4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N-isopropyl-3-methoxy-benzamide,
4- (5-cyano-4-ethylamino-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-N, N-dimethyl-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-N, N-dimethyl-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N, N-dimethyl-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-N-methyl-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N- (2, 2-difluoro-ethyl) -3-methoxy-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N- (3, 3-difluoro-cyclobutyl) -3-methoxy-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N, N-diethyl-3-methoxy-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N-cyclopropylmethyl-3-methoxy-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N-ethyl-3-methoxy-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N-ethyl-3-methoxy-N-methyl-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N-ethyl-N-isopropyl-3-methoxy-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N-isopropyl-3-methoxy-benzamide,
4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -N-isopropyl-3-methoxy-N-methyl-benzamide,
4-ethylamino-2- [ 5-fluoro-2-methoxy-4- (morpholine-4-carbonyl) -phenylamino ] -pyrimidine-5-carbonitrile,
4-methoxy-2- [ 2-methoxy-4- (morpholine-4-carbonyl) -phenylamino ] -pyrimidine-5-carbonitrile,
5-chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -N- (1-methyl-piperidin-4-yl) -benzamide,
5-chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -N-oxetan-3-yl-benzamide,
5-chloro-2-methoxy-N, N-dimethyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
5-chloro-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-methoxy-N- (2-methoxy-ethyl) -benzamide,
5-chloro-4- (5-chloro-4-methoxypyrimidin-2-ylamino) -2-methoxy-N-methylbenzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N, N-dimethyl-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N- (2-methoxy-ethyl) -benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N-methyl-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N-oxetan-3-yl-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N- (1-methyl-piperidin-4-yl) -benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N- (2-methoxy-ethyl) -N-methyl-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-N- (1-methyl-cyclobutyl) -benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N- (1-cyano-cyclopropyl) -2-methoxy-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N- (2-hydroxy-2-methyl-propyl) -2-methoxy-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N- (2-hydroxy-ethyl) -2-methoxy-N-methyl-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N- (2-hydroxy-propyl) -2-methoxy-benzamide,
5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -N-cyclopropyl-2-methoxy-benzamide,
5-chloro-N- (1-cyano-cyclopropyl) -2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
5-chloro-N- (1-cyano-cyclopropyl) -2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
5-chloro-N- (2-hydroxy-2-methyl-propyl) -2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
5-chloro-N- (2-hydroxy-2-methyl-propyl) -2-methoxy-N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
5-chloro-N-cyclopropyl-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-methoxy-benzamide,
azetidin-1-yl- [4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -methanone,
n- (3, 3-difluoro-cyclobutyl) -3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
n- (3-aminopropyl) -4- (5-chloro-4- (methylamino) pyrimidin-2-ylamino) -3-methoxybenzamide,
n- (3-amino-propyl) -4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzamide,
n- (3-amino-propyl) -5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-benzamide,
n- (4, 4-difluoro-cyclohexyl) -3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
n, N-diethyl-3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
N-ethyl-2-fluoro-5-methoxy-N- (2-methoxy-ethyl) -4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
N-ethyl-3-methoxy-N-methyl-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -benzamide,
n-ethyl-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-N- (2-methoxy-ethyl) -benzamide,
n-tert-butyl-4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzamide, and
n-tert-butyl-5-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -2-methoxy-benzamide, or a pharmaceutically acceptable salt thereof.
21. A compound according to any one of claims 1 to 20, selected from:
[ 3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
(5-chloro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (deuteromorpholino) methanone,
(5-fluoro-2-methoxy-4- (4- (methylamino) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (morpholino) methanone,
[ 2-fluoro-3-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-chloro-4- (5-chloro-4-methylamino-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 3-isopropoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-fluoro-5-methoxy-phenyl ] -morpholin-4-yl-methanone,
[4- (5-chloro-4-methoxy-pyrimidin-2-ylamino) -3-methoxy-phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-2-methoxy-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
[ 5-chloro-4- (4-ethylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -2-methoxy-phenyl ] -morpholin-4-yl-methanone,
[ 5-ethoxy-2-fluoro-4- (4-methylamino-5-trifluoromethyl-pyrimidin-2-ylamino) -phenyl ] -morpholin-4-yl-methanone,
2- (2-methoxy-4- (morpholine-4-carbonyl) phenylamino) -4- (methylamino) pyrimidine-5-carbonitrile, and
n-tert-butyl-4- (5-cyano-4-methylamino-pyrimidin-2-ylamino) -3-methoxy-benzamide,
or a pharmaceutically acceptable salt thereof.
22. A composition, comprising:
(a) a pharmaceutically acceptable carrier; and
(b) the compound of claim 1.
23. Compounds of formula I according to any one of claims 1 to 21 for use as therapeutically active substances.
24. A method for treating parkinson's disease, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1.
25. Use of a compound of formula I according to any one of claims 1-21 for the preparation of a medicament for the therapeutic and/or prophylactic treatment of parkinson's disease.
26. A compound of formula I according to any one of claims 1-21 for use as therapeutically active substance for the therapeutic and/or prophylactic treatment of parkinson's disease.
27. The invention as described above.
HK16112879.3A 2010-06-04 2016-11-09 Aminopyrimidine derivatives as lrrk2 modulators HK1224666A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US61/351,530 2010-06-04
US61/482,455 2011-05-04

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HK1224666A true HK1224666A (en) 2017-08-25

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