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US 2004/0106615 A1Published application
Protein kinase inhibitors and uses thereof
AssigneeVertex Pharmaceuticals Incorporated
InventorsJohn Cochran, Jeremy Green, Michael R. Hale, Brian Ledford, Francois Maltais, Suganthini Nanthakumar
Life of this patent
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Abstract
Described herein are compounds that are useful as protein kinase inhibitors having the formulae I and V: 1 or a pharmaceutically acceptable salt thereof, wherein Ring B, Z1, Z2, U, T, m, n, p, Q, Q′, R1, R2, Rx, R3, and R6 are as defined herein. These compounds, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of a variety of disorders, including stroke, inflammatory disorders, autoimmune diseases such as SLE lupus and psoriasis, proliferative disorders such as cancer, and conditions associated with organ transplantation.
Claims85
A compound of formula I:
- 254
- or a pharmaceutically acceptable salt thereof, wherein:
- Ring B is a 6-membered aryl ring having 0-3 nitrogens;
- Z1 and Z2 are each independently selected from N or CH;
- T and Q are each independently selected from a saturated or unsaturated C1-6 alkylidene chain wherein:
- up to two methylene units of the chain are optionally and independently replaced by —C(O)—, —C(O)C(O)—, —C(O)NR—, —C(O)NRNR—, —CO2—, —OC(O)—, —NRCO2—, —O—, —NRC(O)NR—, —OC(O)NR—, —NRNR—, —NRC(O)—, —S—, —SO—, —SO2—, —NR—, —SO2NR—, or —NRSO2—;
- each R is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or:
- two R on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- U is selected from —NR—, —NRC(O)—, —NRC(O)NR—, —NRCO2—, —O—, —C(O)NR—, —C(O)—, —CO2—, —OC(O)—, —NRSO2—, —SO2NR—, —NRSO2NR—, or —SO2—;
- m and n are each independently selected from zero or one;
- p is selected from 0, 1, 2, 3, or 4;
- R1 is selected from R or Ar;
- each Ar is an optionally substituted ring selected from a 6-10 membered aryl ring, a 5-10 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3-10 membered heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- R2 is selected from —(CH2)yCH(R5)2 or —(CH2),CH(R4)CH(R5)2;
- y is 0-6;
- R3 is selected from R, Ar, —(CH2)yCH(R5)2, or CN;
- R4 is selected from R, (CH2)wOR, (CH2)wN(R)2, or (CH2)wSR;
- w is 0-4;
- each R5 is independently selected from optionally substituted C1-6 aliphatic, Ar, OR, CO2R, (CH2)yN(R)2, N(Ar)(R), SR, NRC(O)R, NRC(O)N(R)2, CON(R)2, SO2R, NRSO2R, C(O)R, CN, or SO2N(R)2;
- and
- each R6 is independently selected from R, F, Cl, N(R)2, OR, SR, NRC(O)R, NRC(O)N(R)2, C(O)N(R)2, SO2R, NRSO2R, C(O)R, CN, or SO2N(R)2.
18 more elements
A compound of formula V:
- 455
- or a pharmaceutically acceptable salt thereof, wherein:
- Ring B is a 6-membered aryl ring having 0-3 nitrogens;
- Z1 and Z2 are each independently selected from N or CH;
- T is a saturated or unsaturated C1-6 alkylidene chain wherein:
- up to two methylene units of the chain are optionally and independently replaced by —C(O)—, —C(O)C(O)—, —C(O)NR—, —C(O)NRNR—, —CO2—, —OC(O)—, —NRCO2—, —O—, —NRC(O)NR—, —OC(O)NR—, —NRNR—, —NRC(O)—, —S—, —SO—, —SO2—, —NR—, —SO2NR—, or —NRSO2—;
- each R is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or:
- two R on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- Q′ is a saturated or unsaturated C1-6 alkylidene chain wherein:
- one or two methylene units of the chain are optionally and independently replaced by —C(O)NR′—, —NR′CO2—, —OC(O)NR′—, —NR′C(O)—, —NR′—, —SO2NR′—, or —NR′SO2—;
- each R′ is independently selected from a C1-6 aliphatic group, wherein said aliphatic group is substituted with one Ar group and optionally substituted with 1-2 additional groups independently selected from halogen, —OR, —SR, —NO2, —CN, —N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRCO2R, —NRNRC(O)R, —NRNRC(O)N(R)2, —NRNRCO2R, —C(O)C(O)R, —C(O)CH2C(O)R, —CO2R, or —C(O)R;
- U is selected from —NR—, —NRC(O)—, —NRC(O)NR—, —NRCO2—, —O—, —C(O)NR—, —C(O)—, —CO2—, —OC(O)—, —NRSO2—, —SO2NR—, —NRSO2NR—, or —SO2—;
- m and n are each independently selected from zero or one;
- p is selected from 0, 1, 2, 3, or 4;
- R1 is selected from R or Ar;
- each Ar is an optionally substituted ring selected from a 6-10 membered aryl ring, a 5-10 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3-10 membered heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- y is 0-6;
- Rx is —(CH2)yR5 R3 is selected from R, Ar, —(CH2)yCH(R5)2, or CN;
- w is 0-4;
- each R5 is independently selected from optionally substituted C1-6 aliphatic, Ar, OR, CO2R, (CH2)YN(R)2, N(Ar)(R), SR, NRC(O)R, NRC(O)N(R)2, C(O)N(R)2, SO2R, NRSO2R, C(O)R, CN, or SO2N(R)2;
- and
- each R6 is independently selected from R, F, Cl, N(R)2, OR, SR, NRC(O)R, NRC(O)N(R)2, C(O)N(R)2, SO2R, NRSO2R, C(O)R, CN, or SO2N(R)2.
19 more elements
Dependencies are inferred from the claim text.