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Details for Patent: 7,439,249

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Details for Patent: 7,439,249

Title:Inhibitors of phosphatases
Abstract: The present invention relates to compounds that inhibit phosphatases, compositions thereof, and methods of using those compounds and compositions for treating diseases.
Inventor(s): Saunders; Jeffrey O. (Acton, MA), Miknis; Gregory F. (Broomfield, CO), Buckmelter; Alexandre J. (Superior, CO), Hunt; Kevin W. (Longmont, CO), Blake; James F. (Longmont, CO), Vigers; Guy P. A. (Boulder, CO), Sun; Xicheng (Superior, CO)
Assignee: Vertex Pharmaceuticals Incorporated (Cambridge, MA)
Filing Date:Dec 31, 2003
Application Number:10/750,326
Claims:1. A compound having formula (I): ##STR00057## wherein: ring A is an aryl ring wherein said aryl ring is either unsubstituted or substituted with one or more substituents selected from halogen, --R.degree., --OR.degree., --SR.degree., 1,2-methylene-dioxy, 1,2-ethylenedioxy; unsubstituted phenyl (Ph), unsubstituted --O(Ph), unsubstituted --CH.sub.2(Ph), unsubstituted --CH.sub.2CH.sub.2(Ph) or (Ph), --O(Ph), --CH.sub.2(Ph), or --CH.sub.2CH.sub.2(Ph) substituted with one or more --R.degree. groups; --NO.sub.2, --CN, --N(R.degree.).sub.2, --NR.degree.C(O)R.degree., --NR.degree.C(O)N(R.degree.).sub.2, --NR.degree.CO.sub.2R.degree., --NR.degree.NR.degree.C(O)R.degree., --NR.degree.NR.degree.C(O)N(R.degree.).sub.2, --NR.degree.NR.degree.CO.sub.2R.degree., --C(O)C(O)R.degree., --C(O)CH.sub.2C(O)R.degree., --CO.sub.2R.degree., --C(O)R.degree., --C(O)N(R.degree.).sub.2, --OC(O)N(R.degree.).sub.2, --S(O).sub.2R.degree., --SO.sub.2N(R.degree.).sub.2, --S(O)R.degree., --NR.degree.SO.sub.2N(R.degree.).sub.2, --NR.degree.SO.sub.2R.degree., --C(.dbd.S)N(R.degree.).sub.2, --C(.dbd.NH)--N(R.degree.).sub.2, or --(CH.sub.2).sub.qNHC(O)R.degree.; wherein: q is 0-2; and wherein: each R.degree. is independently selected from hydrogen, a C.sub.1-6 aliphatic, wherein said C.sub.1-6 aliphatic group is either unsubstituted or substituted with one or more substituents selected from .dbd.O, .dbd.S, .dbd.NNHR*, .dbd.NN(R*).sub.2, .dbd.NNHC(O)R*, .dbd.NNHCO.sub.2(alkyl), .dbd.NNHSO.sub.2(alkyl), .dbd.NR*NH.sub.2, NH(C.sub.1-4 aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4 aliphatic), or halo C.sub.1-4 aliphatic; an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, --O(Ph), or --H.sub.2(Ph), or wherein two occurrences of R.degree., on the same substituent or different substituents, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein: each R* is independently selected from hydrogen or a C.sub.1-6 aliphatic group wherein said aliphatic group of R* is either unsubstituted or substituted with one or more substituents selected from NH.sub.2, NH(C.sub.1-4 aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4 aliphatic), or halo(C.sub.1-4 aliphatic); the nitrogen of any non-aromatic heterocyclic ring is either unsubstituted or substituted with one or more groups selected from --R.sup.+, --N(R.sup.+).sub.2, --C(O)R.sup.+, --OR.sup.+, --CO.sub.2R.sup.+, --C(O)C(O)R.sup.+, --C(O)CH.sub.2C(O)R.sup.+, --SO.sub.2R.sup.+, --SO.sub.2N(R.sup.+).sub.2, --C(.dbd.S)N(R.sup.+).sub.2, --C(.dbd.NH)--N(R.sup.+).sub.2, or --NR.sup.+SO.sub.2R.sup.+; wherein: R.sup.+ is hydrogen, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, an unsubstituted C.sub.1-6 aliphatic, unsubstituted phenyl (Ph), unsubstituted --O(Ph), unsubstituted --CH.sub.2(Ph), unsubstituted --CH.sub.2CH.sub.2(Ph); or C.sub.1-6 aliphatic, phenyl (Ph), --O(Ph), --CH.sub.2(Ph), or --CH.sub.2CH.sub.2(Ph) substituted with one or more groups selected from NH.sub.2, NH(C.sub.1-4 aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4 aliphatic), or halo (C.sub.1-4 aliphatic) or wherein two occurrences of R.sup.+, on the same substituent or different substituents, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sub.a is --COOH; n is 1; R.sub.1 is a hydroxyaliphatic, aminoaliphatic, aliphatic-COOH, aliphatic-CONH.sub.2, or arylaliphatic wherein said hydroxyaliphatic, aminoaliphatic, aliphatic-COOH, aliphatic-CONH.sub.2, or arylaliphatic is either unsubstituted or substituted with one or more substituents selected from halogen, --R.degree., --OR.degree., --SR.degree., 1,2-methylene-dioxy, 1,2-ethylenedioxy; unsubstituted phenyl (Ph), unsubstituted --O(Ph), unsubstituted --CH.sub.2(Ph), unsubstituted --CH.sub.2CH.sub.2(Ph) or (Ph), --O(Ph), --CH.sub.2(Ph), or --CH.sub.2CH.sub.2(Ph) substituted with one or more --R.degree. groups; --NO.sub.2, --CN, --N(R.degree.).sub.2, --NR.degree.C(O)R.degree., --NR.degree.C(O)N(R.degree.).sub.2, --NR.degree.CO.sub.2R.degree., --NR.degree.NR.degree.C(O)R.degree., --NR.degree.NR.degree.C(O)N(R.degree.).sub.2, --NR.degree.NR.degree.CO.sub.2R.degree., --C(O)C(O)R.degree., --C(O)CH.sub.2C(O)R.degree., --CO.sub.2R.degree., --C(O)R.degree., --C(O)N(R.degree.).sub.2, --OC(O)N(R.degree.).sub.2, --S(O).sub.2R.degree., --SO.sub.2N(R.degree.).sub.2, --S(O)R.degree., ----NR.degree.SO.sub.2N(R.degree.).sub.2, --NR.degree.SO.sub.2R.degree., --C(.dbd.S)N(R.degree.).sub.2, --C(.dbd.NH)--N(R.degree.).sub.2, or --(CH.sub.2).sub.qNHC(O)R.degree.; wherein: q is 0-2; and wherein: each R.degree. is independently selected from hydrogen, a C.sub.1-6 aliphatic, wherein said C.sub.1-6 aliphatic group is either unsubstituted or substituted with one or more substituents selected from .dbd.O, .dbd.S, .dbd.NNHR*, .dbd.NN(R*).sub.2, .dbd.NNHC(O)R*, .dbd.NNHCO.sub.2(alkyl), .dbd.NNHSO.sub.2(alkyl), .dbd.NR*NH.sub.2, NH(C.sub.1-4 aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4 aliphatic), or halo C.sub.1-4 aliphatic; an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, --O(Ph), or --CH.sub.2(Ph), or wherein two occurrences of R.degree., on the same substituent or different substituents, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein: each R* is independently selected from hydrogen or a C.sub.1-6 aliphatic group wherein said aliphatic group of R* is either unsubstituted or substituted with one or more substituents selected from NH.sub.2, NH(C.sub.1-4 aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4 aliphatic), or halo(C.sub.1-4 aliphatic); the nitrogen of any non-aromatic heterocyclic ring is either unsubstituted or substituted with one or more groups selected from --R.sup.+, --N(R.sup.+).sub.2, --C(O)R.sup.+, --OR.sup.+, --CO.sub.2R.sup.+, --C(O)C(O)R.sup.+, --C(O)CH.sub.2C(O)R.sup.+, --SO.sub.2R.sup.+, --SO.sub.2N(R.sup.+).sub.2, --C(.dbd.S)N(R.sup.+).sub.2, --C(.dbd.NH)--N(R.sup.+).sub.2, or --NR.sup.+SO.sub.2R.sup.+; wherein: R.sup.+ is hydrogen, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, an unsubstituted C.sub.1-6 aliphatic, unsubstituted phenyl (Ph), unsubstituted --O(Ph), unsubstituted --CH.sub.2(Ph), unsubstituted --CH.sub.2CH.sub.2(Ph); or C.sub.1-6 aliphatic, phenyl(Ph), --O(Ph), --CH.sub.2(Ph), or --CH.sub.2CH.sub.2(Ph) substituted with one or more groups selected from NH.sub.2, NH(C.sub.1-4 aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4 aliphatic), or halo (C.sub.1-4 aliphatic) or wherein two occurrences of R.sup.+, on the same substituent or different substituents, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sub.2 is an unsubstituted aliphatic, or a cycloaliphatic-aliphatic or heteroarylaliphatic, wherein said cycloaliphatic-aliphatic or heteroarylaliphatic is either unsubstituted or substituted with one or more substituents selected from halogen, --R.degree., --OR.degree., --SR.degree., 1,2-methylene-dioxy, 1,2-ethylenedioxy; unsubstituted phenyl (Ph), unsubstituted --O(Ph), unsubstituted --CH.sub.2(Ph), unsubstituted --CH.sub.2CH.sub.2(Ph) or (Ph), --O(Ph), --CH.sub.2(Ph), or --CH.sub.2CH.sub.2(Ph) substituted with one or more --R.degree. groups; --NO.sub.2, --CN, --N(R.degree.).sub.2, --NR.degree.C(O)R.degree., --NR.degree.C(O)N(R.degree.).sub.2, --NR.degree.CO.sub.2R.degree., --NR.degree.NR.degree.C(O)R.degree., --NR.degree.NR.degree.C(O)N(R.degree.).sub.2, --NR.degree.NR.degree.CO.sub.2R.degree., --C(O)C(O)R.degree., --C(O)CH.sub.2C(O)R.degree., --CO.sub.2R.degree., --C(O)R.degree., --C(O)N(R.degree.).sub.2, --OC(O)N(R.degree.).sub.2, --S(O).sub.2R.degree., --SO.sub.2N(R.degree.).sub.2, --S(O)R.degree., --NR.degree.SO.sub.2N(R.degree.).sub.2, --NR.degree.SO.sub.2R.degree., --C(.dbd.S)N(R.degree.).sub.2, --C(.dbd.NH)--N(R.degree.).sub.2, or --(CH.sub.2).sub.qNHC(O)R.degree.; wherein: q is 0-2; and wherein: each R.degree. is independently selected from hydrogen, a C.sub.1-6 aliphatic, wherein said C.sub.1-6 aliphatic group is either unsubstituted or substituted with one or more substituents selected from .dbd.O, .dbd.S, .dbd.NNHR*, .dbd.NN(R*).sub.2, .dbd.NNHC(O)R*, .dbd.NNHCO.sub.2(alkyl), .dbd.NNHSO.sub.2(alkyl), .dbd.NR*NH.sub.2, NH(C.sub.1-4 aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4 aliphatic), or halo C.sub.1-4 aliphatic; an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, --O(Ph), or --CH.sub.2(Ph), or wherein two occurrences of R.degree., on the same substituent or different substituents, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein: each R* is independently selected from hydrogen or a C.sub.1-6 aliphatic group wherein said aliphatic group of R* is either unsubstituted or substituted with one or more substituents selected from NH.sub.2, NH(C.sub.1-4 aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4 aliphatic), or halo(C.sub.1-4 aliphatic); the nitrogen of any non-aromatic heterocyclic ring is either unsubstituted or substituted with one or more groups selected from --R.sup.+, --N(R.sup.+).sub.2, --C(O)R.sup.+, --OR.sup.+, --CO.sub.2R.sup.+, --C(O)C(O)R.sup.+, --C(O)CH.sub.2C(O)R.sup.+, --SO.sub.2R.sup.+, --SO.sub.2N(R.sup.+).sub.2, --C(.dbd.S)N(R.sup.+).sub.2, --C(.dbd.NH)--N(R.sup.+).sub.2, or --NR.sup.+SO.sub.2R.sup.+; wherein: R.sup.+ is hydrogen, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, an unsubstituted C.sub.1-6 aliphatic, unsubstituted phenyl (Ph), unsubstituted --O(Ph), unsubstituted --CH.sub.2(Ph), unsubstituted --CH.sub.2CH.sub.2(Ph); or C.sub.1-6 aliphatic, phenyl(Ph), --O(Ph), --CH.sub.2(Ph), or --CH.sub.2CH.sub.2(Ph) substituted with one or more groups selected from NH.sub.2, NH(C.sub.1-4 aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, OH, O(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), O(halo C.sub.1-4 aliphatic), or halo (C.sub.1-4 aliphatic) or wherein two occurrences of R.sup.+, on the same substituent or different substituents, taken together, form a 5-8-membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sup.3 and R.sup.4 are independently selected from R.sup.11, R.sup.12, R.sup.14 or R.sup.15; wherein: each R.sup.11 is independently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, R.sup.6 or (CH.sub.2).sub.m--Y; wherein m is 0, 1 or 2; and Y is selected from halogen, CN, NO.sub.2, CF.sub.3, OCF.sub.3, OH, SR.sup.6, S(O)R.sup.6, SO.sub.2R.sup.6, NH.sub.2, NHR.sup.6, N(R.sup.6).sub.2, NR.sup.6R.sup.8, COOH, COOR.sup.6 or OR.sup.6; each R.sup.12 is independently selected from (C.sub.1-C.sub.6)-straight or branched alkyl, or (C.sub.2-C.sub.6)-straight or branched alkenyl or alkynyl; and each R.sup.12 optionally comprises up to 2 substituents, wherein: the first of said substituents, if present, is selected from R.sup.11, R.sup.14 and R.sup.15, and the second of said substituents, if present, is R.sup.11; each R.sup.14 is independently selected from OR.sup.15, OC(O)R.sup.6, OC(O)R.sup.15, OC(O)OR.sup.6, OC(O)OR.sup.15, OC(O)N(R.sup.6).sub.2, OP(O) (OR.sup.6).sub.2, SR.sup.6, SR.sup.15, S(O)R.sup.6, S(O)R.sup.15, SO.sub.2R.sup.6, SO.sub.2R.sup.15, SO.sub.2N(R.sup.6).sub.2, SO.sub.2NR.sup.15R.sup.6, SO.sub.3R.sup.6, C(O)R.sup.15, C(O)OR.sup.15, C(O)R.sup.6, C(O)OR.sup.6, NC(O)C(O)R.sup.6, NC(O)C(O)R.sup.15, NC(O)C(O)OR.sup.6, NC(O)C(O)N(R.sup.6).sub.2, C(O)N(R.sup.6).sub.2, C(O)N(OR.sup.6)R.sup.6, C(O)N(OR.sup.6)R.sup.15, C(NOR.sup.6)R.sup.6, C(NOR.sup.6)R.sup.15, N(R.sup.6).sub.2, NR.sup.6C(O)R.sup.11, NR.sup.6C(O)R.sup.6, NR.sup.6C(O)R.sup.15, NR.sup.6C(O)OR.sup.6, NR.sup.6C(O)OR.sup.15, NR.sup.6C(O)N(R.sup.6).sub.2, NR.sup.6C(O)NR.sup.15R.sup.6, NR.sup.6SO.sub.2R.sup.6, NR.sup.6SO.sub.2R.sup.15, NR.sup.6SO.sub.2N(R.sup.6).sub.2, NR.sup.6SO.sub.2NR.sup.15R.sup.6, N(OR.sup.6)R.sup.6, N(OR.sup.6)R.sup.15, P(O) (OR.sup.6)N(R.sup.6).sub.2, and P(O) (OR.sup.6).sub.2; each R.sup.15 is a cycloaliphatic, aryl, heterocyclyl, or heteroaromatic; and each R.sup.15 optionally comprises up to 3 substituents, each of which, if present, is R.sup.11; each R.sup.6 is independently selected from H, (C.sub.1-C.sub.6)-straight or branched alkyl, or (C.sub.1-C.sub.6) straight or branched alkenyl; and each R.sup.6 optionally comprises a substituent that is R.sup.7; R.sup.7 is a cycloaliphatic, aryl, heterocyclyl, or heteroaromatic; and each R.sup.7 optionally comprises up to 2 substituents independently chosen from H, (C.sub.1-C.sub.6)-straight or branched alkyl, (C.sub.2-C.sub.6) straight or branched alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH.sub.2).sub.p-Z; wherein p is 0, 1 or 2; and Z is selected from halogen, CN, NO.sub.2, CF.sub.3, OCF.sub.3, OH, S(C.sub.1-C.sub.6)-alkyl, SO(C.sub.1-C.sub.6)-alkyl, SO.sub.2(C.sub.1-C.sub.6)-alkyl, NH.sub.2, NH(C.sub.1-C.sub.6)-alkyl, N((C.sub.1-C.sub.6)-alkyl).sub.2, N((C.sub.1-C.sub.6)-alkyl)R.sup.8, COOH, C(O)O(C.sub.1-C.sub.6)-alkyl or O(C.sub.1-C.sub.6)-alkyl; and R.sup.8 is --C(O)CH.sub.3, --C(O)Ph or --SO.sub.2Ph; provided that: R.sup.3 and R.sup.4 are not simultaneously hydrogen; when R.sup.3 is H, then R.sup.4 is not chloro; and when R.sup.4 is H, then R.sup.3 is not --SCH.sub.3 or --NH--O(O)CH.sub.3.

2. The compound according to claim 1, wherein ring A is an optionally substituted 6 membered aryl.

3. The compound according to claim 2, wherein ring A is phenyl.

4. The compound according to claim 1, wherein R.sub.1 is --(CH.sub.2).sub.q--X, wherein q is 1-4, and X is OH, NH.sub.2, COOH or CONH.sub.2, (C1-C6)-alkyl, or benzyl.

5. The compound according to claim 4, wherein R.sub.1 is hydroxymethyl, methyl, --CH.sub.2COOH, --CH.sub.2CONH.sub.2, aminobutyl, or isopentyl.

6. The compound according to claim 1, wherein R.sub.2 is selected from butyl, isobutyl, cyclopentyl, cyclohexylmethyl, pyridylmethyl, furanylmethyl, or thienylmethyl.

7. The compound according to claim 6, wherein R.sub.2 is selected from 2-furanylmethyl.

8. The compound according to claim 1 wherein R.sub.3 and R.sub.4 are independently selected from hydrogen, halo, acetamido, allyloxy, thiophenyl, sulfoxyalkyl, or sulfoxyphenyl.

9. A compound selected from: ##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062##

10. A pharmaceutical composition comprising a compound according to any one of claims 1-7 and 8-9 and a pharmaceutically acceptable adjuvant or carrier.
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