US 6,642,227 B2Granted

Inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases

AssigneeVertex Pharmaceuticals Incorporated

InventorsJingrong Cao, Jeremy Green, Young-Choon Moon, Jian Wang, Mark Ledeboer, Edmund Harrington, Huai Gao

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Abstract

The present invention provides compounds of formula I: or a pharmaceutically acceptable derivative o thereof, wherein A, B, Ra, R1, R2, R3, and R4 are as described in the specification. These compounds are inhibitors of protein kinase, particularly inhibitors of JNK, a mammalian protein kinase involved cell proliferation, cell death and response to extracellular stimuli; Lck and Src kinase. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.

Claims31

Dependent claims

A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
A is N and B is CH;
R1 and R2 are each independently selected from halogen, CN, NO2, N(R)2, OR, SR, or (T)n—R5;
R3 is selected from a 3-6 membered carbocyclic or heterocyclic ring having one to two heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroaryl ring having one to three heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said phenyl or heteroaryl ring is optionally substituted with one (T)n—Ar and one to two R7;
each n is independently selected from zero or one;
T is a C1-C6 alkylidene chain, wherein one methylene unit of T is optionally replaced by CO, CO2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO2, NRCONR, SO2, NRSO2, SO2NR, NRSO2NR, O, S, or NR;
each R is independently selected from hydrogen or an optionally substituted C1-C6 aliphatic group;
or two R on the same nitrogen atom may be taken together with the nitrogen to form a four to eight membered, saturated or unsaturated heterocyclic ring containing one to three heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R4 is (T)n—R, (T)n—Ar, or (T)n—Ar1;
Ra is selected from Rb, halogen, NO2, ORb, SRb, or N(Rb)2;
Rb is selected from hydrogen or a C1-C4 aliphatic group optionally substituted with oxo, OH, SH, NH2, halogen, NO2, or CN;
R5 is an optionally substituted C1-C6 aliphatic or Ar;
Ar is a 5-6 membered saturated, partially unsaturated, or aryl monocyclic ring having zero to three heteroatoms independently selected from nitrogen, sulfur, or oxygen, or an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having zero to four heteroatoms independently selected from nitrogen, sulfur, or oxygen, wherein Ar is optionally substituted with one to three R7;
Ar1 is a 6-membered aryl ring having zero to two nitrogens, wherein said ring is substituted with one Z—R6 group and optionally substituted with one to three R7;
Z is a C1-C6 alkylidene chain wherein up to two non-adjacent methylene units of Z are optionally replaced by CO, C2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRC2, NRCONR, SO, SO2, NRSO2, SO2NR, NRSO2NR, O, S, or NR;
provided that said optionally replaced methylene unit of Z is a methylene unit non-adjacent to R6;
R6 is selected from Ar, R, halogen, NO2, CN, OR, SR, N(R)2, NRC(O)R, NRC(O)N(R)2, NRC2R, C(O)R, CO2R, OC(O)R, C(O)N(R)2, OC(O)N(R)2, SOR, SO2R, SO2N(R)2, NRSO2R, NRSO2N(R)2, C(O)C(O)R, or C(O)CH2C(O)R;
and
each R7 is independently selected from R, halogen, NO2, CN, OR, SR, N(R)2, NRC(O)R, NRC(O)N(R)2, NRCO2R, C(O)R, CO2R, C(O)N(R)2, OC(O)N(R)2, SOR, SO2R, SO2N(R)2, NRSO2R, NRSO2N(R)2, C(O)C(O)R, or C(O)CH2C(O)R;
or two R7 on adjacent positions of Ar1 may be taken together to form a saturated, partially unsaturated, or fully unsaturated five to seven membered ring containing zero to three heteroatoms selected from O, S, or N.

17 more elements

A compound selected from the following Table 1, Table 2, Table 7, or Table 8 compounds:

TABLE 1 Compounds of Formula IIa No. IIa- R1 R2 R3 R4 1 SMe CN 4-CO2H-phenyl H 2 SMe CN 4-Cl-phenyl H 3 SMe CN 4-CF3-phenyl H 4 SMe CN 4-CH3-phenyl H 5 SMe CN 2-Cl-phenyl H 6 SMe CN 4-OCH3-phenyl H 7 NHCH2Ph CN 4-CF3-phenyl H 8 NHCH2Ph CN 2-Cl-phenyl H 9 NHCH2Ph CN 4-OCH3-phenyl H 10 SMe CN 4-Cl-phenyl Ph 11 OEt CN 4-Cl-phenyl Ph 12 SMe CN 4-CF3-phenyl Ph 13 OEt CN 4-CF3-phenyl Ph 14 SMe CN 4-CH3-phenyl Ph 15 OEt CN 4-CH3-phenyl Ph 16 SMe CN H H 17 CH2CH2OH CN OPh Et 18 CONHEt CF3 pyridine-3-yl CH2Ph 19 SCH2Ph NHEt CONHCH2Ph COPh 20 CH2NO2 CONHEt NH(4-Cl-phenyl) H 21 NHCONH2 OMe CH2Ph SO2Me 22 Et CN thiazol-2-yl Ph 23 SMe CN piperidin-1-yl cyclohexyl 24 OCH2Ph Cl 4-CONHMe-phenyl cyclohexyl 25 NHMe NO2 NHPh H 26 SMe NO2 NH2 H 27 OEt NO2 NHCH2Ph H 28 NHMe NH2 NHPh Ph 29 SMe NH2 NH2 Me 30 OEt NH2 NHCH2Ph Me 31 NHMe NHCOEt Ph Ph 32 SME NHCOEt CH2Ph CH2Ph 33 OEt NHCOEt CH2Ph H 34 NHMe CONHMe Ph H 35 SMe CONHMe Ph Ph 36 OEt CONHMe 4-Cl—Ph Ph 37 SMe CN Ph 3-OBn—Ph 38 SMe CN Ph 3-SO2NH2—Ph 39 S—CH2- CN Ph Ph phenol-4-ol 40 SMe CN Ph 3-OH—Ph 41 SMe CN Ph 4-OBn—Ph 42 OH CN Ph 3-OBn—Ph 43 SMe CN cyclohexyl 3,5-OMe—Ph 44 SMe CN cyclohexyl 3-SO2NH2—Ph 45 SMe CN cyclohexyl 3-OBn—Ph 46 SMe CN cyclohexyl Ph 47 SMe CN cyclohexyl 4-CO2Et—Ph 48 SMe CN cyclohexyl 3-OH—Ph 49 SMe CN 3-OMe—Ph 3-NO2—Ph 50 SMe CN 3-OMe—Ph 3-NH2—Ph 51 SMe CN 3-OH—Ph 3-NO2—Ph 52 SMe CN 3-OBn—Ph Ph 53 SMe CN 3-OBn—Ph 3-NO2—Ph 54 N(Me)2 CN 3-OBn—Ph Ph 55 N(Me)2 CN 3-OBn—Ph 3-NO2—Ph 56 SMe CN 3-pyridyl 3-OBn—Ph 57 SMe CN 3-pyridyl 3-OH—Ph 58 OEt CN Ph Ph 59 SMe CN 3-Br—Ph 3-NH2—Ph 60 N(Me)2 CN 3-OPh—Ph 3-NH2—Ph 61 SMe CN 3-OPh—Ph 3-NH2—Ph 62 SMe CN 5-Br-3-pyridyl 3-OBn—Ph 63 4-Me-piper- CN 3-OPh—Ph Ph idin-1-yl 64 OH CN 4-tolyl Ph 65 SMe CN 3-OBn—Ph 3-OH—Ph 66 SMe CN 3-OPh—Ph 3-OH—Ph 67 SMe CN 3-OH—Ph 3-OH—Ph 68 SMe CN 3-Br—Ph 3-OH—Ph 69 SMe CN 3-Br—Ph 3-OBn—Ph 70 NHEt CN Ph 3-OH—Ph 71 SMe CN 3-(3-OH—Ph)—Ph 3-OH—Ph 72 SMe CN 3-(3-OEt—Ph)—Ph 3-OH—Ph 73 SMe CN 3-(3-pyridyl)-Ph 3-OH—Ph 74 SMe CN 5-Ph-pyridin-3-yl 3-OBn—Ph 75 N(Me)2 CN 5-Br-3-pyridyl 3-OBn—Ph 76 N(Me)2 CN 5-Ph-3-pyridyl 3-OBn—Ph 77 SMe CO2Et Ph 3-OH—Ph 78 SMe CO2Et Ph Ph 79 NHEt CN Ph 4-OH—Ph 80 N(Me)2 CN 5-Ph-pyridin-3-yl 3-OH—Ph 81 SMe CN 3-(3-NH2—Ph)—Ph 3-OH—Ph 82 SMe CN 3-(3-Cl,4-F—Ph)—Ph 3-OH—Ph 83 SMe CN 3-(4-iPr—Ph)—Ph 3-OH—Ph 84 SMe CN 5-Ph-pyridin-3-yl 3-OH—Ph 85 SMe CN 5-Ph-pyridin-3-yl 3-NO2—Ph 86 SMe CN 3-(3-N—Boc-pyrrol-2- 3-OH—Ph yl)-Ph 87 SMe CN 3-(4-iPr—Ph)—Ph 3-OH—Ph 88 SMe CN 3-pyridyl 3-NHSO2Me—Ph 89 SMe CN 3-pyridyl 3-NHSO2Et—Ph 90 NHEt CO2Et Ph 3-OMe—Ph 91 SMe CN 3-pyridyl 3-SO2NH2—Ph 92 SMe CN 3-(2-OH—Ph)—Ph 3-OH—Ph 93 SMe CN 3-(3-pyrrol-2-yl)-Ph 3-OH—Ph 94 SMe CN 3-(6-OMe-pyridin-2- 3-OH—Ph yl)-Ph 95 SMe CN 3-(5-OMe-pyridin-2- 3-OH—Ph yl)-Ph 96 SMe CN 3-(2,5-Me2-isoxazol-4- 3-OH—Ph yl)-Ph 97 NH(CH3)2mor- CN Ph 3-OH—Ph pholin-4-yl 98 NH(CH3)2mor- CN Ph 3-SO2NH2—Ph pholin-4-yl 99 NH(CH3)2mor- CN Ph 4-OH—Ph pholin-4-yl 100 NH(CH3)3N(Et)2 CN Ph 3-OH—Ph 101 NH(CH3)3N(Et)2 CN Ph 4-OH—Ph 102 NH(CH3)2piperidin- CN Ph 3-OH—Ph 1-yl 103 NH(CH3)2piperidin- CN Ph 3-SO2NH2—Ph 1-yl 104 NH(CH3)2piperidin- CN Ph 4-OH—Ph 1-yl 105 SMe CN 3-(pyridin-4-yl)-Ph 3-OH—Ph TABLE 2 Compounds of Formula IIb No. IIb- R1 R2 R3 R4 1 SMe 4-CH3thiazol-2-yl Me Ph 2 SMe 4-CH3thiazol-2-yl Me 4-F—Ph 3 SMe 4-CH3thiazol-2-yl Me 6-Cl-pyridin-3-yl 4 SMe 4-CH3thiazol-2-yl Me 3-Cl—Ph 5 SMe 4-CH3thiazol-2-yl Me 3-CH3O—Ph 6 SMe 4-CH3thiazol-2-yl Me 3-BnO—Ph 7 SMe CN Me Ph 8 SMe CN Me 4-F—Ph 9 SMe CN Me 6-Cl-pyridin-3-yl 10 SMe CN Me 3-Cl—Ph 11 SMe CN Me 3-CH3O—Ph 12 SMe CN Me 3-BnO—Ph TABLE 7 Compounds of Formula V No.V- R1 Ra R3 R4 1 SCH2phen-4-ol Me 3-Cl phenyl Ph 2 OH Me Ph 3-OBn—Ph 3 OEt Me Ph 3-OBn—Ph 4 SMe Me Ph 3-OBn—Ph 5 SMe Me Ph 3-SO2NH2—Ph 6 SMe Me Ph 3-OH—Ph 7 SMe Me Ph 3-NO2—Ph 8 SMe Me Ph 3-NH2—Ph 9 SMe Me 2-CF3—Ph 3-OBn—Ph 10 SMe Me 2-CF3—Ph 3-OH—Ph 11 SCH2phen-4-ol Me 3-Cl—Ph Ph 12 SMe Me 4-Me—Ph 3-OBn—Ph 13 SMe Me 4-Me—Ph 3-OH—Ph 14 SMe Me 4-Me—Ph pyrid-3-yl 15 SMe Me pyrid-3-yl 3-OBn—Ph 16 SMe Me pyrid-3-yl Ph 17 SMe Me pyrid-3-yl 3-OMe—Ph 18 SMe Me pyrid-3-yl 3,5-OMe—Ph 19 SMe Me pyrid-3-yl 3-Br—Ph 20 SMe Me pyrid-3-yl 3-Cl—Ph 21 SMe Me pyrid-3-yl 3-CO2Me—Ph 22 SMe Me pyrid-3-yl 6-Cl-pyrid-3-yl 23 SMe Me pyrid-3-yl CH2Ph 24 SMe Me pyrid-3-yl 3-OH—Ph 25 SMe Me furan-2-yl pyrid-3-yl 26 SMe Me furan-2-yl 3-OH—Ph 27 SMe Me furan-2-yl 3-OBn—Ph 28 SMe Me furan-2-yl 3-NO2—Ph 29 N(Me)2 Me 3-OPh—Ph 3-NO2—Ph 30 N(Me)2 Me 3-OPh—Ph 3-OH—Ph 31 SMe Me 3-Ph—Ph 3-OBn—Ph 32 SMe Me 3-Ph—Ph 3-OH—Ph TABLE 8

Dependencies are inferred from the claim text.

Facts

Application: 10/121,035Filed 10 Apr 2002 · us provisional application
Priority: 13 Apr 2001
Published: US 2003/0096816 A122 May 2003
Granted: 4 Nov 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification40 codes

C07D 409/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms: containing three…
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 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…

Family

Application60/283,621Us provisional application · filed 13 Apr 2001
Application60/292,974Us provisional application · filed 23 May 2001
Application60/329,440Us provisional application · filed 15 Oct 2001
US 2003/0096816 A1Pre-grant publication · published 22 May 2003
US 6,642,227 B2This patent

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