CA2511925A1 - Heterocyclic inhibitors of phosphatases, compositions and uses thereof - Google Patents

Heterocyclic inhibitors of phosphatases, compositions and uses thereof Download PDF

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CA2511925A1
CA2511925A1 CA002511925A CA2511925A CA2511925A1 CA 2511925 A1 CA2511925 A1 CA 2511925A1 CA 002511925 A CA002511925 A CA 002511925A CA 2511925 A CA2511925 A CA 2511925A CA 2511925 A1 CA2511925 A1 CA 2511925A1
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alkyl
nr6c
straight
substituents
independently selected
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CA2511925C (en
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Jeffrey O. Saunders
Gregory F. Miknis
Alexandre J. Buckmelter
Kevin W. Hunt
James F. Blake
Guy P. A. Vigers
Xicheng Sun
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Vertex Pharmaceuticals Inc
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Abstract

The present invention relates to compounds that inhibit phosphatases, compositions thereof, and methods of using those compounds and compositions for treating diseases.

Claims (16)

1. A compound having formula (I):
wherein:
ring A is an optionally substituted aryl or heteroaryl ring;
R a is -COOH;
n is 0-4;
R1 is H, or an optionally substituted hydroxyaliphatic, aminoaliphatic, aliphatic-COOH, aliphatic-CONH2, or arylaliphatic;
R2 is an optionally substituted aliphatic, arylaliphatic, cycloaliphatic-aliphatic, heteroarylaliphatic, or heterocyclylaliphatic;
R3 and R4 are independently selected from R11, R12, R14 or R15;
wherein:
each R11 is independently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, R6 or (CH2)m-Y;
wherein m is 0, 1 or 2; and Y is selected from halogen, CN, NO2, CF3, OCF3, OH, SR6, S(O)R6, SO2R6, NH2, NHR6, N(R6)2, NR6R8, COOH, COOR6 or OR6;
each R12 is independently selected from (C1-C6)-straight or branched alkyl, or (C2-C6)-straight or branched alkenyl or alkynyl; and each R12 optionally comprises up to 2 substituents, wherein:
the first of said substituents, if present, is selected from R11, R14 and R15, and the second of said substituents, if present, is R11;
each R14 is independently selected from OR15, OC(O)R6, OC(O)R15, OC(O)OR6, OC(O)OR15, OC(O)N(R6)2, OP(O)(OR6)2, SR6, SR15, S(O)R6, S(O)R15, SO2R6, SO2R15, SO2N(R6)2, SO2NR15R6, SO3R6, C(O)R15, C(O)OR15, C(O)R6, C(O)OR6, NC(O)C(O)R6, NC(O)C(O)R15, NC(O)C(O)OR6, NC(O)C(O)N(R6)2, C(O)N(R6)2, C(O)N(OR6)R6, C(O)N(OR6)R15, C(NOR6)R6, C(NOR6)R15, N(R6)2, NR6C(O)R11, NR6C(O)R6, NR6C(O)R15, NR6C(O)OR6, NR6C(O)OR15, NR6C(O)N(R6)2, NR6C(O)NR15R6, NR6SO2R6, NR6SO2R15, NR6SO2N(R6)2, NR6SO2NR15R6, N(OR6)R6, N(OR6)R15, P(O)(OR6)N(R6)2, and P(O)(OR6)2;
each R15 is a cycloaliphatic, aryl, heterocyclyl, or heteroaromatic; and each R15 optionally comprises up to 3 substituents, each of which, if present, is R11;
each R6 is independently selected from H, (C1-C6)-straight or branched alkyl, or (C2-C6) straight or branched alkenyl; and each R6 optionally comprises a substituent that is R7;
R7 is a cycloaliphatic, aryl, heterocyclyl, or heteroaromatic; and each R7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C2-C6) straight or branched alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH2)p-Z;
wherein p is 0, 1 or 2; and Z is selected from halogen, CN, NO2, CF3, OCF3, OH, S(C1-C6)-alkyl, SO(C1-C6)-alkyl, SO2(C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, N((C1-C6)-alkyl)R8, COOH, C(O)O(C1-C6)-alkyl or O(C1-C6)-alkyl; and R8 is an amino protecting group;
provided that:
R3 and R4 are not simultaneously hydrogen;
when R3 is H, then R4 is not chloro; and when R4 is H, then R3 is not -SCH3 or -NH-C(O)CH3.
2. The compound according to claim 1, wherein ring A is an optionally substituted 5 or 6 membered aryl or heteroaryl ring, wherein said heteroaryl ring contains up to 2 ring heteroatoms independently selected from O, S, or NH.
3. The compound according to claim 2, wherein ring A is phenyl.
4. The compound according to claim 1, wherein R1 is hydrogen, -(CH2)q-X, wherein q is 1-4, and X is OH, NH2, COOH or CONH2, (C1-C6)-alkyl, or benzyl.
5. The compound according to claim 4, wherein R1 is hydrogen, hydroxymethyl, methyl, -CH2COOH, -CH2CONH2, aminobutyl, methyl, or isopentyl.
6. The compound according to claim 1, wherein R2 is selected from butyl, isobutyl, methoxypropyl, cyclopentyl, cyclohexylmethyl, phenyl, trifluorophenyl, benzyl, fluorobenzyl, methylenedioxybenzyl, pyridylmethyl, furanylmethyl, tetrahydrofuranylmethyl, N-morpholinylmethyl, thienylmethyl, 2-oxo-pyrrolodinylpropyl, phenylethyl, chlorophenylethyl, methoxyphenylethyl, or dimethoxyphenylethyl.
7. The compound according to claim 6, wherein R2 is selected from 2-furanylmethyl or methyl.
According to another preferred embodiment, R3 and R4 are independently selected from hydrogen, halo, acetamido, allyloxy, thiophenyl, sulfoxyalkyl, or sulfoxyphenyl.
8. A compound of formula (II):
wherein:
X is -(CH2)n-, or -C(O)-;
n is 1-3;
Y is O, S, NH, or N(C1-C6 aliphatic);
Z is H or C1-C6 aliphatic;
Q is 0 or 1;
A, R x, R y, and R z are independently selected from R11, R12, R14 or R15;
wherein:
each R11 is independently selected from 1,2-methylenedioxy, 1,2-ethylenedioxy, R6 or (CH2)m-Y;
wherein m is 0, 1 or 2; and Y is selected from halogen, CN, NO2, CF3, OCF3, OH, SR6, S(O)R6, SO2R6, NH2, NHR6, N(R6)2, NR6R8, COOH, COOR6 or OR6;

each R12 is independently selected from (C1-C6)-straight or branched alkyl, or (C2-C6)-straight or branched alkenyl or alkynyl; and each R12 optionally comprises up to 2 substituents, wherein:
the first of said substituents, if present, is selected from R11, R14 and R15, and the second of said substituents, if present, is R11;
each R14 is independently selected from OR15, OC(O)R6, OC(O)R15, OC(O)OR6, OC(O)OR15, OC(O)N(R6)2, OP(O)(OR6)2, SR6, SR15, S(O)R6, S(O)R15, SO2R6, SO2R15, SO2N(R6)2, SO2NR15R6, SO3R6, C(O)R15, C(O)OR15, C(O)R6, C(O)OR6, NC(O)C(O)R6, NC(O)C(O)R15, NC(O)C(O)OR6, NC(O)C(O)N(R6)2, C(O)N(R6)2, C(O)N(OR6)R6, C(O)N(OR6)R15, C(NOR6)R6, C(NOR6)R15, N(R6)2. NR6C(O)R11, NR6C(O)R6.
NR6C(O)R15, NR6C(O)OR6, NR6C(O)OR15, NR6C(O)N(R6)2, NR6C(O)NR15R6, NR6SO2R6, NR6SO2R15, NR6SO2N(R6)2.
NR6SO2NR15R6, N(OR6)R6, N(OR6)R15, P(O)(OR6)N(R6)2, and P(O)(OR6)2, each R15 is a cycloaliphatic, aryl, heterocyclyl, or heteroaromatic; and each R15 optionally comprises up to 3 substituents, each of which, if present, is R11;
each R6 is independently selected from H, (C1-C6)-straight or branched alkyl, or (C2-C6) straight or branched alkenyl; and each R6 optionally comprises a substituent that is R7;
R7 is a cycloaliphatic, aryl, heterocyclyl, or heteroaromatic; and each R7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C2-C6) straight or branched alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH2)p-Z;

wherein p is 0, 1 or 2; and Z is selected from halogen, CN, NO2, CF3, OCF3, OH, S(C1-C6)-alkyl, SO(C1-C6)-alkyl, SO2(C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, N((C1-C6)-alkyl)R8, COOH, C(O)O(C1-C6)-alkyl or O(C1-C6)-alkyl; and R8 is an amino protecting group;
or R x and R y, taken together, form an optionally substituted heterocyclic ring having up to 3 substituents.
9. A pharmaceutical composition comprising a compound according to any one of claims 1-8 and a pharmaceutically acceptable adjuvant or carrier.
10. A method for treating or lessening the severity of a disease in a patient, wherein said disease is selected from autoimmune diseases, proliferative diseases, angiogenic disorders, or cancers, said method comprising the step of administering to said patient a composition according to claim 9.
11. A method for treating or lessening the severity of a SHP-2-mediated disease or condition in a patient comprising the step of administering to said patient a composition according to claim 9.
12. The method according to claim 10, wherein said autoimmune disease is selected from glomerulo-nephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, or graft vs. host disease.
13. The method according to claim 10, wherein said proliferative disease is selected from acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma or HTLV-1-mediated tumorigenesis.
14. The method according to claim 10, wherein said angiogenic disorder is selected from solid tumors, ocular neovasculization, or infantile haemangiomas.
15. The method according to claim 10, wherein said cancers is selected from colon cancer, breast cancer, stomach cancer, or ovarian cancers.
16. An implantable medical device coated with a compound according to any one of claims 1-8, wherein said device is selected from prostheses, artificial valves, vascular grafts, stems or catheters.
CA2511925A 2002-12-31 2003-12-31 Heterocyclic inhibitors of phosphatases, compositions and uses thereof Expired - Fee Related CA2511925C (en)

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US43757602P 2002-12-31 2002-12-31
US60/437,576 2002-12-31
PCT/US2003/041661 WO2004060878A2 (en) 2002-12-31 2003-12-31 Inhibitors of phosphatases

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CA2511925A1 true CA2511925A1 (en) 2004-07-22
CA2511925C CA2511925C (en) 2012-11-13

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