Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• R 1 is selected from halo, C 6-10 aryl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from N, C(O), O, and S;
• R4, R5, R8, and R9 are independently selected from hydrogen, cyano, C1-4alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl, halo, and C 1-4 alkylamino;
• R6 is selected from amino, C1-4aminoalkyl, and C1-4alkylamino
• each R 17 and R 18 is independently selected from amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4alkyl, and C1-4alkoxy.
• Certain compounds disclosed herein may possess useful PTPN11 inhibiting activity, and may be used in the treatment or prophylaxis of a disease or condition in which PTPN11 plays an active role.
• certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions.
• Certain embodiments provide methods for inhibiting PTPN11.
• each R 17 is independently selected from amino, halo, hydroxy, and cyano.
• each R 17 is independently selected from amino, hydroxy, and cyano.
• R1 is selected from C6-10aryl and a 5- to 9- membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from N, C(O), O, and S;
• R1 is selected from C6-10aryl and a 5- to 9- membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from N, C(O), O, and S; said aryl or heteroaryl of R1 is optionally substituted with 1 to 5 R12 groups independently selected from halo, hydroxy, alkoxy, amino, C 1-4 alkyl, C 1-4 haloalkyl, and C 1- 4aminoalkyl; and
• R 4 , R 5 , R 8 , and R 9 are independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C3-8cycloalkyl, and C1-4alkylamino.
• said aryl or heteroaryl of R 1 is optionally substituted with 1 to 5 R 12 groups independently selected from halo, hydroxy, amino, C1-4alkylamino, C1-4dialkylamino, C1- 4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 aminoalkyl;
• R 7 is selected from hydroxy, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl, and 5- or 6- membered heteroaryl.
• said aryl or heteroaryl of R 1 is optionally substituted with 1 to 5 R 12 groups independently selected from halo, hydroxy, alkoxy, amino, C1-4alkylamino, C1-4dialkylamino, cyano, and C 1-4 alkyl.
• said aryl or heteroaryl of R1 is optionally substituted with 1 to 5 R12 groups independently selected from halo, hydroxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, cyano, C1-4alkyl, C1-4alkoxy, C1-4hydroxyalkyl, C1-4haloalkyl, C1-4aminoalkyl, C3-8cycloalkyl, C3- 8 cycloalkenyl, NR 15 C(O)R 13 , NR 15 C(O)OR 13 , NR 13 C(O)NR 15 R 16 , NR 15 S(O)R 13 ,
• each R 17 is independently selected from amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4alkyl, and C1-4alkoxy.
• said aryl or heteroaryl of R 1 is optionally substituted with 1 to 5 R 12 groups independently selected from halo, hydroxy, amino, C1-4alkylamino, C1-4dialkylamino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 aminoalkyl, C 3-8 cycloalkyl, C 3- 8cycloalkenyl, NR15C(O)R13, NR15C(O)OR13, NR13C(O)NR15R16, NR15S(O)R13,
• R 1 is selected from halo, C 6-10 aryl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from N, C(O), O, and S;
• said aryl or heteroaryl of R1 is optionally substituted with 1 to 5 R12 groups independently selected from halo, hydroxy, amino, C1-4alkylamino, C1-4dialkylamino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 aminoalkyl, C 3-8 cycloalkyl, C 3- 8cycloalkenyl, NR15C(O)R13, NR15C(O)OR13, NR13C(O)NR15R16, NR15S(O)R13,
• R 13 , R 15 , and R 16 are independently selected from hydrogen, C 1-4 alkyl, and
• R1 is selected from halo, C6-10aryl, C3-8cycloalkyl, C3-8cycloalkenyl, and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from N, C(O), O, and S;
• R1 is selected from halo, C6-10aryl, C3-8cycloalkyl, C3-8cycloalkenyl, and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from N, C(O), O, and S;
• R13, R15, and R16 are independently selected from hydrogen, C1-4alkyl, and
• R 17 is selected from amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4alkyl, and C1-4alkoxy.
• each R 12 group is independently selected from halo, hydroxy, cyano, C1-4alkyl, C1-4alkoxy, and C1-4hydroxyalkyl. [067] Also provided are embodiments wherein any embodiment above may be combined with any one or more of these embodiments, provided the combination is not mutually exclusive.
• two embodiments are“mutually exclusive” when one is defined to be something which is different than the other.
• an embodiment wherein two groups combine to form a cycloalkyl is mutually exclusive with an embodiment in which one group is ethyl the other group is hydrogen.
• an embodiment wherein one group is CH2 is mutually exclusive with an embodiment wherein the same group is NH.
• the present invention also relates to a method of inhibiting at least one PTPN11 function comprising the step of contacting PTPN11 with a compound as described herein.
• the cell phenotype, cell proliferation, activity of PTPN11, change in biochemical output produced by active PTPN11, expression of PTPN11, or binding of PTPN11 with a natural binding partner may be monitored.
• Such methods may be modes of treatment of disease, biological assays, cellular assays, biochemical assays, or the like.
• the disease is selected from Noonan Syndrome and Cartoon Syndrome.
• the cancer is selected from breast cancer, colon cancer, leukemia, or melanoma.
• a method of treatment of a PTP-mediated disease comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a salt or tautomer thereof, to a patient in need thereof.
• the disease is cancer.
• the cancer is selected from breast cancer, colon cancer, leukemia, or melanoma.
• Also provided herein is a compound as disclosed herein for use as a medicament.
• Also provided herein is a compound as disclosed herein for use as a medicament for the treatment of a PTPN11-mediated disease.
• Also provided herein is a method of inhibition of PTPN11 comprising contacting PTPN11 with a compound as disclosed herein, or a salt or tautomer thereof.
• Also provided herein is a method of inhibition of PTP comprising contacting PTP with a compound as disclosed herein, or a salt or tautomer thereof.
• the PTPN11-mediated disease is selected from Noonan Syndrome and Leopard Syndrome.
• the PTPN11-mediated disease is cancer.
• the PTPN11-mediated disease is selected from breast cancer, colon cancer, leukemia, or melanoma.
• Also provided is a method of modulation of a PTPN11-mediated function in a subject comprising the administration of a therapeutically effective amount of a compound as disclosed herein.
• composition comprising a compound as disclosed herein, together with a pharmaceutically acceptable carrier.
• the pharmaceutical composition is formulated for oral administration.
• the pharmaceutical composition is formulated for parenteral administration.
• the pharmaceutical composition is formulated for intravenous administration.
• the pharmaceutical composition is formulated for subcutaneous administration.
• the oral pharmaceutical composition is selected from a tablet and a capsule.
• acyl refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon.
• An“acetyl” group refers to a–C(O)CH3 group.
• An“alkylcarbonyl” or“alkanoyl” group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include
• acyl groups include formyl, alkanoyl and aroyl.
• alkenyl refers to a straight- chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms.
• alkylthio refers to an alkyl thioether (R–S–) radical wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized.
• suitable alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.
• acylamino as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group.
• An example of an “acylamino” group is acetylamino (CH3C(O)NH-).
• aryl as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together.
• aryl embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.
• N-carbamyl refers to a ROC(O)NR’- group, with R and R’ as defined herein.
• carbonyl when alone includes formyl [-C(O)H] and in combination is a -C(O)- group.
• cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H- indenyl, adamantyl and the like.
• “Bicyclic” and“tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type.
• the latter type of isomer is exemplified in general by, bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.
• ether refers to an oxy group bridging two moieties linked at carbon atoms.
• halo refers to fluorine, chlorine, bromine, or iodine.
• haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
• haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
• Haloalkylene refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene
• heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings.
• mercaptyl as used herein, alone or in combination, refers to an RS- group, where R is as defined herein.
• perhaloalkoxy refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.
• perhaloalkyl refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
• ring or equivalently,“cycle,” as used herein, in reference to a chemical structure or portion thereof, means a group in which every atom is a member of a common cyclic structure.
• a ring can be saturated or unsaturated, including aromatic, unless otherwise provided, and may have between 3 and 9 members. If the ring is a heterocycle, it may contain between 1 and 4 heteroatoms or heteroatom-comprising groups selected from B, N, O, S, C(O), S(O)m. Unless specifically prohibited, a ring is optionally substituted.
• Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
• Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
• the compounds disclosed herein may exist as geometric isomers.
• the present invention includes all cis, trans, syn, anti,
• cytotoxic antibiotics including but not limited to actinomycin D (dactinomycin, COSMEGEN), bleomycin (BLENOXANE) doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin (MITOSOL), mitoxantrone (NOVANTRONE), plicamycin; (7) aromatase inhibitors, including but not limited to aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIVIZOR), exemestane
• methods described herein are used to treat a disease condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof, wherein the condition is cancer which has developed resistance to chemotherapeutic drugs and/or ionizing radiation.
• certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
• reaction mixture was stirred for another hour, then quenched with HCl (1.8 mL) / EtOH (7.5 mL) / THF (9.0 mL) mixture, and warmed to RT.
• tert-butyl 4-amino-4-carbamoylpiperidine-1-carboxylate To a solution of tert-butyl 4-amino-4-cyanopiperidine-1-carboxylate (50 mg, 0.22 mmol) and K2CO3 (61 mg, 0.44 mmol) in DMSO (1 mL) was added H 2 O 2 (30% in water, 25 mg, 0.44 mmol) slowly. The resulting mixture was stirred at RT for 72h.
• Examples disclosed herein can be synthesized using the general synthetic procedure set forth in Scheme II.
• Ortho metalation of the pyrazine 201 can be accomplished with a metalated secondary amine (R106)2NLi, which can be prepared from (R106)2NH and BuLi (not shown).
• suitable secondary amines (R106)2NH for this transformation include diiosopropylamine and 2,2,6,6-tetramethylpiperidine.
• the metalated pyrazine is condensed with a substituted aryl carboxaldehyde to give benzylic alcohol 202.
• Oxidation to the ketone 203 is followed by substitution of the aryl halide with an appropriately substituted piperidine to give amine 204.
• Reaction with hydrazine gives the pyrazolo[3,4-b]pyrazine ring of 205.
• Scheme II can be modified to accommodate functionality in the piperidine.
• a protected amine can be incorporated into the piperidine as an–NHP 1 group.
• the group“P1” is an appropriate amino protecting group.
• P 1 can be a carbamate protecting group such as Boc or CBz, or a labile aromatic protecting group, such as p-methoxybenzyl.
• the protecting group P1 is removed from 205 to afford the product.
• a carbamate protecting group can be removed under acid conditions to afford the product.
• reaction mixture was stirred for another hour, then quenched with hydrochloric acid (1.8 mL) / EtOH (7.5 mL) / THF (9.0 mL) mixture, and warmed to rt.
• reaction mixture was stirred for another hour, then quenched with hydrochloric acid (1.8 mL) / EtOH (7.5 mL) / THF (9.0 mL) mixture, and warmed to RT
• the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with EtOAc.
• the organic layer was separated and washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
• tert-Butyl 2,2-difluoro-1-oxo-8-azaspiro[4.5]decane-8-carboxylate To a solution of NaHMDS (2 M in THF, 21.7 mL, 43.4 mmol) was added a solution of tert-butyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate (10.0 g, 39.5 mmol) in THF (25 mL) at -78 °C. After stirring for 30 min at this temperature, a solution of N-fluorobenzenesulfonamide (12.5 g, 39.5 mmol) in THF (50 mL) was added.

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