Phenyl amino pyrimidine compounds and uses thereof
The present invention relates to phenyl amino pyrimidine compounds which are inhibitors of protein kinases including JAK kinases. In particular the compounds are selective for JAK2 kinases. The kinase inhibitors can be used in the treatment of kinase associated diseases such as immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases.
1 . A process for the preparation of a compound of formula I,
wherein:
Q and Z are independently selected from N and CR 1 ;
each n is independently 1, 2, or 3;
R 1 is independently selected from hydrogen, halogen, R 2 , OR 2 , OH, R 4 , OR 4 , CN, CF 3 , (CH 2 ) n N(R 2 ) 2 , NO 2 , R 2 R 4 , SO 2 R 4 , NR 2 SO 2 R 3 , COR 4 , NR 2 COR 3 , CO 2 H, CO 2 R 2 , NR 2 COR 4 , R 2 CN, R 2 OH, R 2 OR 3 , and OR 5 R 4 ; or
two R 1 substituents together with the carbons which they are attached to form an unsaturated 5 or 6 membered heterocyclyl;
R 2 is substituted or unsubstituted C 1-4 alkyl or substituted or unsubstituted C 1-4 alkylene, wherein up to 2 carbon atoms can be optionally replaced with CO, NR Y , CONR Y , S, SO 2 , or O;
R 3 is R 2 , C 2-4 alkenyl or substituted or unsubstituted aryl;
R 4 is NH 2 , NHR 2 , N(R 1 ) 2 , substituted or unsubstituted morpholino, substituted or unsubstituted thiomorpholino, substituted or unsubstituted thiomorpholino-1-oxide, substituted or unsubstituted thiomorpholino-1,1-dioxide, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted tetrahydrofuranyl, or substituted or unsubstituted tetrahydropyranyl;
R 5 is substituted or unsubstituted C 1-4 alkylene;
R 6 -R 10 are independently selected from H, R X CN, halogen, substituted or unsubstituted C 1-4 alkyl, OR 1 , CO 2 R 1 , N(R 1 ) 2 , NO 2 , CON(R 1 ) 2 , SO 2 N(R Y ) 2 , N(SO 2 R 1 ) 2 , substituted or unsubstituted piperazinyl, N(R Y )SO 2 R 2 , and CF 3 , wherein R 7 , R 8 , or R 9 is R X CN;
R X is substituted or unsubstituted C 1-6 alkylene, wherein up to 2 carbon atoms can be optionally replaced with CO, NSO 2 R 1 , NR Y , CONR Y , S, SO 2 , or O;
R Y is H or substituted or unsubstituted C 1-4 alkyl; and
R 11 is selected from H, halogen, substituted or unsubstituted C 1-4 alkyl, OR 2 , CO 2 R 2 , CN, CON(R 1 ) 2 , and CF 3 ,
or an enantiomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof,
wherein the process comprises coupling a compound of formula II
wherein each X is a leaving group,
with compounds of formulae III and IV
and wherein M comprises boron or a metal.
2 . The process according to claim 1 , wherein X is chloro which is converted to iodo prior to the coupling with the compounds of formulae III and IV.
3 . The process of claim 1 , wherein M is boronic acid or 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl and the coupling of the compound of formula II with the compound of formula III comprises contacting the compound of formula II with the compound of formula III in the presence of a palladium catalyst.
4 . The process of claim 3 , wherein the palladium catalyst is selected from the group consisting of: Pd(PPh 3 ) 4 , Pd(OAc) 2 , [PdCl 2 (dppf)], and Pd 2 (dba) 3 /P(t-Bu) 3 .
5 . The process of claim 1 , wherein the coupling of the compound of formula II with the compound of formula IV comprises contacting the compound of formula II with the compound of formula IV at an elevated temperature in the presence of an acid.
6 . The process of claim 5 , wherein the acid is hydrogen chloride or p-toluenesulfonic acid.
7 . The process of claim 5 , wherein the contacting of the compound of formula II with the compound of formula IV at an elevated temperature comprises refluxing the compound of formula II and the compound of formula IV in a solvent.
8 . The process of claim 1 , wherein the coupling of the compound of formula II with the compound of formula IV comprises contacting the compound of formula II with the compound of formula IV in the presence of a palladium catalyst and a base.
9 . The process of claim 8 , wherein the palladium catalyst is selected from the group consisting of: Pd(OAc) 2 /P(t-Bu) 3 , Pd 2 (dba) 3 /BINAP, and Pd(OAc) 2 /BINAP.
10 . The process of claim 8 , wherein the base is cesium carbonate, sodium tert-butoxide, or potassium tert-butoxide.
11 . The process of claim 1 , wherein the compound of formula I is a compound of formula Ia:
wherein:
Q and Z are independently selected from N and CR 1 ;
R 1 is independently selected from H, halogen, R 2 , OR 2 , OH, R 4 , CN, CF 3 , NO 2 , R 2 R 4 , SO 2 R 4 , NR 2 SO 2 R 3 , COR 4 , CO 2 H, CO 2 R 2 , NR 2 COR 3 , NR 2 COR 4 , R 2 CN, R 2 OH, R 2 OR 3 , and OR 5 R 3 ; or
two R 1 substituents together with the carbons which they are attached to form an unsaturated N-containing 5 or 6 membered heterocyclyl;
R 2 is C 1-4 alkyl;
R 3 is R 2 , C 2-4 alkenyl or aryl;
R 4 is NH 2 , NHR 2 N(R 2 ) 2 , morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, 4-carbonylmethyl piperazinyl, 4-methyl piperazinyl, 3- or 4-hydroxy piperidinyl, 4 hydroxymethyl piperidinyl, 4-pyrrolidinyl piperidinyl, 4 or 5-methyl oxazolyl, 4-hydroxy pyridinyl, 3-hydroxy pyrrolyl, 3-hydroxy pyrrolidinyl, pyridinyl, pyrazolyl, or imidazolyl;
R 5 is C 2-4 alkylene;
R 6 -R 9 are independently selected from H, R X CN, halogen, substituted or unsubstituted C 1 -4alkyl, substituted or unsubstituted aryl, OR 1 , CO 2 R 1 , N(R 1 ) 2 , NO 2 , CON(R 1 ) 2 , and CON(R 1 ) 2 , wherein R 7 , R 8 , or R 9 is R X CN;
R X is substituted or unsubstituted C 1-4 alkylene, wherein up to 2 carbon atoms can be optionally replaced with CO, NSO 2 R 1 , NR Y , CONR Y , SO, SO 2 , or O;
R Y is H or substituted or unsubstituted C 1-4 alkyl; and
R 11 is selected from H, halogen, substituted or unsubstituted C 1-4 alkyl, OR 2 , CO 2 R 2 , CN, CON(R 1 ) 2 , and CF 3 ,
or an enantiomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
12 . The process of claim 1 , wherein Q is N and Z is CR 1 .
13 . The process of claim 1 , wherein R 1 is hydrogen, morpholinyl, CH 2 morpholinyl, C 1-4 alkoxy, thiomorpholinyl, 3-hydroxypyrrolidinyl, iodo, fluoro, OH, 4-hydroxy piperidinyl, 4 hydroxymethyl piperidinyl, N-methyl piperidinyl, 3-hydroxy piperidinyl, carbonyl 4-pyrrolidinyl piperidinyl, oxy-4-piperidinyl, 4-carbonylmethyl piperazinyl, 4-methyl piperazinyl, 4-NHSO 2 CH 3 -piperidinyl, 4-oxy piperidinyl, imidazolyl, CON(R 1 ) 2 , CF 3 , or R 2 OR 3 .
14 . The process of claim 1 , wherein R 6 is H or methyl.
15 . The process of claim 1 , wherein R 7 is H, methyl, methoxy, halogen, or hydroxy.
16 . The process of claim 1 , wherein R 8 is H, CONHCN, CH 2 NHCOCN, CN, CONHC(CH 3 ) 2 CN, NCNSO 2 CH 3 , SO 2 NHCH 2 CN, NH(SO 2 CH 3 )CH 2 CN, OH, CO 2 CH 2 CH 3 , CON(R 1 ) 2 , N(R 1 ) 2 , or CO 2 R 1 .
17 . The process of claim 1 , wherein R 9 is H, R X CN, methoxy, halogen, OCF 3 , or CF 3 .
18 . The process of claim 1 , wherein R 11 is H, halogen, substituted or unsubstituted C 1-4 alkyl, OR 2 , CO 2 R 2 , CN, or CF 3 .
19 . The process of claim 1 , wherein R 11 is methyl, methoxy, Cl, Br, F, or CO 2 R 2 .
20 . The process of claim 1 , wherein the compound of formula I is a compound of formula Ib
wherein:
Z is independently selected from N and CH;
R 1 is independently selected from H, halogen, OH, CONHR 2 , CON(R 2 ) 2 , CF 3 , R 2 OR 2 , CN, morpholino, thiomorpholinyl, thiomorpholino-1,1-dioxide, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, imidazolyl, substituted or unsubstituted pyrrolidinyl, and C 1-4 alkylene, wherein the carbon atoms are optionally replaced with NR Y and/or O, or substituted with morpholino, thiomorpholinyl, thiomorpholino-1,1-dioxide, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, imidazolyl, or substituted or unsubstituted pyrrolidinyl;
R 2 is substituted or unsubstituted C 1-4 alkyl;
R Y is H or substituted or unsubstituted C 1-4 alkyl;
R 8 is R X CN;
R X is substituted or unsubstituted C 1-4 alkylene, wherein up to 2 carbon atoms can be optionally replaced with CO, NSO 2 R 1 , NR Y , CONR Y , SO, SO 2 , or O; and
R 11 is H or C 1-4 alkyl,
or an enantiomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
21 . The process of claim 1 , wherein the compound of formula I is a compound of the following formula:
or an enantiomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof.