N-acyl-N′-(pyridin-2-yl) ureas and analogs exhibiting anti-cancer and anti-proliferative activities

Patent metadata

Field	Value
Publication number	US-9309224-B2
Application number	US-201414214179-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

Described are compounds of Formula 1

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.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof,
wherein
A is selected from the group consisting of C1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain is partially or completely deuterated, branched C3-C8alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, and C3-C8carbocyclyl, and wherein each A moiety may be further substituted with one, two, or three R3 moieties;
W is —NHC(O)R5, —NHC(O)R6, —NHC(O)N(R7)R8 or —C(O)N(R7)R8;
X1 and X2 are individually and independently hydrogen, C1-C6 alkyl, fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated;
each R1 and R2 is individually and independently H, C1-C6 alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated, hydroxyl, C1-C6 alkoxy, fluoroC1-C6alkoxy wherein the alkyl group is fully or partially fluorinated, or cyano;
each R3 is individually and independently H, halogen, C1-C6 alkyl, fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluoro-C1-C6 alkoxy wherein the alkyl chain is partially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano;
each R4 is individually and independently hydrogen, C1-C6 alkyl, or branched C3-C8 alkyl;
each R5 is individually and independently hydrogen, C1-C6 alkyl, branched C3-C8 alkyl, C3-C8 cycloalkyl, —(CH 2 ) m —CN, —(CH 2 ) m —OR7, —(CH 2 ) m —NR7(R8), or —(CH 2 ) m —R6, wherein each alkylene of R5 may be further substituted with one or more C1-C6alkyl;
each R6 is independently and individually selected from the group consisting of

 and wherein the symbol (##) is the point of attachment to respective R5 or W moieties containing a R6 moiety;
each R6 is optionally substituted with —(R9) p ;
each R7 and R8 is individually and independently H, C1-C6 alkyl, fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated, branched C3-C8 alkyl, —(CH 2 ) m —CN, —(CH 2 ) m —OR7, —(CH 2 ) m —NR7(R8), or —(CH 2 ) m —R6,
each R9 is individually and independently C1-C6 alkyl, —(CH 2 ) m —CN, —(CH 2 ) m —OR3, —(CH 2 ) m —NR7(R8), or —(CH 2 ) m —C(O)—R5, wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl;
each R10 is H, 4-(C1-C4alkyl)-piperazin-1-yl, morpholinyl, piperidinyl, pyrrolidinyl or azetidinyl;
each m is individually and independently 0, 1, 2, or 3;
each n is individually and independently 0, 1, 2, or 3;
each p is 0, 1, 2, or 3; and
each q is 0, 1, 2, or 3.

2. The compound of claim 1 , wherein X1 and X2 are individually and independently hydrogen or C1-C6 alkyl.

3. The compound of claim 2 , wherein the compound is a compound of Formula Ia,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

4. The compound of claim 3 , wherein R3 is C1-C6alkyl, hydrogen or C1-C6alkoxy.

5. The compound of claim 4 , wherein W is —NHC(O)R5, —NHC(O)R6 or —NHC(O)N(R7)R8.

6. The compound of claim 4 , wherein W is —C(O)N(R7)R8.

7. The compound of claim 2 , wherein the compound is a compound of Formula Ib:

wherein A is C3-C8 carbocyclyl.

8. The compound of claim 7 , wherein R3 is C1-C6alkyl, hydrogen, C1-C6alkoxy or fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completely fluorinated.

9. The compound of claim 8 , wherein W is —NHC(O)R5, —NHC(O)R6 or —NHC(O)N(R7)R8.

10. The compound of claim 8 , wherein W is —C(O)N(R7)R8.

11. The compound of claim 1 selected from the group consisting of N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclohexanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclopentanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-2-cyclohexylacetamide, N-((5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)cyclopentanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)isobutyramide, N-(4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide, N-((6-methyl-5-((2-propionamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-isobutyramidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)propionamide, N-((5-((2-isobutyramidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-methylcyclopropanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)-2-methoxy-2-methylpropanamide, 1-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, N-((5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-propionamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-(trifluoromethyl)cyclobutanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-2-methoxy-2-methylpropanamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-methoxycyclopropanecarboxamide, N-((5-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-methylcyclopropanecarboxamide, N-(4-((6-(3-(2-methoxy-2-methylpropanoyl)ureido)pyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide, 1-methyl-N-(4-((6-(3-(1-methylcyclopropanecarbonyl)ureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-4-carboxamide, N-methyl-4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)picolinamide, 1-methyl-N-((5-((2-propionamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclopropanecarboxamide, 2-methoxy-2-methyl-N-((5-((2-propionamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)propanamide, N-((5-((2-acetamidopyridin-4-yl)oxy)-4-methylpyridin-2-yl)carbamoyl)-2-methoxy-2-methylpropanamide, 1-methoxy-N-((5-((2-propionamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclopropanecarboxamide, N-(4-((6-(3-(2-methoxy-2-methylpropanoyl)ureido)pyridin-3-yl)oxy)pyridin-2-yl)-1-methylpiperidine-4-carboxamide, N-((5-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-methoxycyclopropanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)-4-methylpyridin-2-yl)carbamoyl)pivalamide, N-((5-(2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)-1-methylcyclobutanecarboxamide, N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-1-methylcyclobutanecarboxamide, 4-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide, N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)morpholine-4-carboxamide, (S)-3-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide, N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)azetidine-1-carboxamide, N-(4-((6-(3-(1-methoxycyclopropanecarbonyl)ureido)pyridin-3-yl)oxy)pyridin-2-yl)-1-met

Assignees

• Deciphera Pharmaceuticals Llc
• Deciphera Pharmaceuticals Llc

Inventors

• Flynn Daniel L
• Caldwell Timothy Malcolm
• Samarakoon Thiwanka
• Vogeti Lakshminarayana
• Kaufman Michael D
• Patt William C
• Ahn Yumi

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D493/08

  Bridged systems · CPC title