US 2014/0275085 A1Published application

2-aminopyrimidin-6-ones and analogs exhibiting anti-cancer and anti-proliferative activities

AssigneeDeciphera Pharmaceuticals, LLC

InventorsMichael D. Kaufman, Daniel L. Flynn, YuMi Ahn, Lakshminarayana Vogeti, Timothy Malcolm Caldwell

Life of this patent

Estimating the term…

Abstract

Described are compounds of Formula I which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-1R), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c-FMS, c-KIT, or PDGFR kinases.

Claims33

Dependent claims

A compound of Formula I,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof,
wherein
A is taken from the group consisting of —N(R2)R3 and G;
G is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the pyrimidine ring;
each G moiety may be further substituted with one, two, or three R4 moieties;
W is C5-C6heteroaryl, phenyl, —NHC(O)R6, —NHC(O)R7, —NHC(O)N(R8)R9 or —C(O)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties;
X1 and X2 are individually and independently hydrogen or C1-C6 alkyl;
R1 is hydrogen, C1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl;
R2 is hydrogen, C1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, C3-C8 cycloalkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, —(CH2)m—OR8, or a 3-8 membered heterocyclic ring, wherein each alkylene is optionally substituted with C1-C4 alkyl;
R3 is hydrogen, C1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, C3-C8 cycloalkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated or a 3-8 membered heterocyclic ring;
each R4 is individually and independently hydrogen, halogen, C1-C6 alkyl, fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, —(CH2)m—OR8, —(CH2)m—NR8(R9), —(CH2)m—R7, or cyano, wherein each alkylene is optionally substituted with C1-C4 alkyl;
each R5 is individually and independently hydrogen, C1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, halogen, cyano, fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, —(CH2)m—C(O)NR8(R9), —(CH2)m—C(O)R7, —(CH2)m—OR8, —(CH2)m—NR8(R9), or —(CH2)m—R7, wherein each alkylene is optionally substituted with C1-C4 alkyl;
Each R6 is individually and independently hydrogen, C1-C6 alkyl, branched C3-C8 alkyl, C3-C8 cycloalkyl, —(CH2)m—CN, —(CH2)m—OR8, —(CH2)m—NR8(R9), or —(CH2)m—R7, wherein each alkylene is optionally substituted with C1-C4 alkyl;
each R7 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective W, R5 or R6 moieties containing a R7 moiety;
each R7 is optionally substituted with —(R10)p;
each R8 and R9 is individually and independently hydrogen, C1-C6 alkyl, fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, or branched C3-C8 alkyl;
each R10 is individually and independently C1-C6 alkyl, —(CH2)m—CN, —(CH2)m—OR3, —(CH2)m—NR8(R9), or —(CH2)m—C(O)—R6, wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl;
wherein each alkylene is optionally substituted with C1-C4 alkyl
each m is individually and independently 0, 1, 2, or 3;
and
each p is 0, 1, 2, or 3.

20 more elements

A compound selected from the group consisting of 2-(ethylamino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, 2-(dimethylamino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, 2-(isopropylamino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, 2-(ethylamino)-5-(6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, 2-(ethylamino)-5-(6-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, 2-((2-methoxyethyl)amino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, 5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(methylamino)pyrimidin-4(3H)-one, 2-(ethylamino)-5-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, 5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(pyrrolidin-1-yl)pyrimidin-4(3H)-one, 2-(isopropylamino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, 4-((6-(2-(isopropylamino)-6-oxo-1,6-dihydropyrimidin-5-yl)pyridin-3-yl)oxy)-N-methylpicolinamide, 5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-morpholinopyrimidin-4(3H)-one, 5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(piperidin-1-yl)pyrimidin-4(3H)-one, 2-(cyclopropylamino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, 2-(cyclopentylamino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, 3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(pyrrolidin-1-yl)pyrimidin-4(3H)-one, 2-(cyclopropylamino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, 2-(isopropylamino)-5-(4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, N-(4-((6-(2-(isopropylamino)-6-oxo-1,6-dihydropyrimidin-5-yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)acetamide, 5-(4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(pyrrolidin-1-yl)pyrimidin-4(3H)-one, 5-(5-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-(isopropylamino)pyrimidin-4(3H)-one, (R)-2-((1-methoxypropan-2-yl)amino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, (R)-2-(2-(methoxymethyl)pyrrolidin-1-yl)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, (S)-2-(3-(dimethylamino)pyrrolidin-1-yl)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, 2-(ethylamino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, 2-((2-methoxyethyl)amino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, 5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4(3H)-one, 2-(tert-butylamino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one, 5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(neopentylamino)pyrimidin-4(3H)-one, and 2-(3,3-difluoropyrrolidin-1-yl)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one.

Dependencies are inferred from the claim text.

Facts

Application: 14/214,171Filed 14 Mar 2014
Priority: 15 Mar 2013
Published: 18 Sep 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents

Family

Application61/792,812Us provisional application · filed 15 Mar 2013
US 9,181,223 B2Related patent
US 2014/0275085 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula I,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof,
wherein
A is taken from the group consisting of —N(R2)R3 and G;
G is selected from the group consisting of
and wherein the symbol (**) is the point of attachment to the pyrimidine ring;
each G moiety may be further substituted with one, two, or three R4 moieties;
W is C5-C6heteroaryl, phenyl, —NHC(O)R6, —NHC(O)R7, —NHC(O)N(R8)R9 or —C(O)N(R8)R9, and wherein each C5-C6heteroaryl or phenyl is optionally substituted by one, two, or three R5 moieties;
X1 and X2 are individually and independently hydrogen or C1-C6 alkyl;
R1 is hydrogen, C1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain is partially or completely deuterated, or branched C3-C8 alkyl;
R2 is hydrogen, C1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, C3-C8 cycloalkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, —(CH2)m—OR8, or a 3-8 membered heterocyclic ring, wherein each alkylene is optionally substituted with C1-C4 alkyl;
R3 is hydrogen, C1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, C3-C8 cycloalkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated or a 3-8 membered heterocyclic ring;
each R4 is individually and independently hydrogen, halogen, C1-C6 alkyl, fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, —(CH2)m—OR8, —(CH2)m—NR8(R9), —(CH2)m—R7, or cyano, wherein each alkylene is optionally substituted with C1-C4 alkyl;
each R5 is individually and independently hydrogen, C1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8 alkyl, halogen, cyano, fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, —(CH2)m—C(O)NR8(R9), —(CH2)m—C(O)R7, —(CH2)m—OR8, —(CH2)m—NR8(R9), or —(CH2)m—R7, wherein each alkylene is optionally substituted with C1-C4 alkyl;
Each R6 is individually and independently hydrogen, C1-C6 alkyl, branched C3-C8 alkyl, C3-C8 cycloalkyl, —(CH2)m—CN, —(CH2)m—OR8, —(CH2)m—NR8(R9), or —(CH2)m—R7, wherein each alkylene is optionally substituted with C1-C4 alkyl;
each R7 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment to respective W, R5 or R6 moieties containing a R7 moiety;
each R7 is optionally substituted with —(R10)p;
each R8 and R9 is individually and independently hydrogen, C1-C6 alkyl, fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, or branched C3-C8 alkyl;
each R10 is individually and independently C1-C6 alkyl, —(CH2)m—CN, —(CH2)m—OR3, —(CH2)m—NR8(R9), or —(CH2)m—C(O)—R6, wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl;
wherein each alkylene is optionally substituted with C1-C4 alkyl
each m is individually and independently 0, 1, 2, or 3;
and
each p is 0, 1, 2, or 3.

20 more elements

Facts

Application

14/214,171Filed 14 Mar 2014

Priority

15 Mar 2013

Published

18 Sep 2014

Term ends

Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents