US 2006/0142250 A1Published application

Protein tyrosine phosphatase inhibitors and methods of use thereof

AssigneeCEPTYR, Inc.

InventorsMark Blaskovich, Ted Baughman, Thomas Little, William Patt, Maher Qabar, Lauri Schultz, Feng Hong, Gangadhar Nagula, Jennifer Gage, James Howbert

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Abstract

The present invention provides compounds of Formula (I) and Formula (II) that are useful for modulating the biological activity of the protein tyrosine phosphatase-1b (PTP1B) enzyme. Compounds of this invention can be used to treat diseases and/or conditions in which the PTP1B enzyme is a factor. Such diseases and/or conditions include, but are not limited to, Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, insulin resistance, obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, atherosclerosis, vascular restenosis, inflammatory bowel disease, pancreatitis, adipose cell tumors, adipose cell carcinoma, liposarcoma, dyslipidemia, cancer, and neurodegenerative diseases.

Claims63

Dependent claims

A compound of formula (I):

wherein:
X1 is a linker group or absent;
X2 is H or optionally substituted C1-8 straight-chained or branched aliphatic, optionally containing 1 or more double or triple bonds, wherein one or more carbons are optionally replaced by R* wherein R* is optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
—C(O)—, —C(O)C(O)—, —C(O)NR11—,—C(O)NR11NR12—, —C(O)O—, —OC(O)—, —NR11CO2—, —O—, —NR11C(O)NR12—, —OC(O)NR11—, —NR11NR12—, —NR11C(O)—, —S—, —SO—, —SO2—, —NR11—, —SO2NR11— or —NR11SO2—, wherein R11 and R12 are independently selected from H and optionally substituted aliphatic, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or X2 is optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
—C(O)—, —C(O)C(O)—, —C(O)NR11—, —C(O)NR11NR12—, —C(O)O—, —OC(O)—, —NR11CO2—, —O—, —NR11C(O)NR12 —, —OC(O)NR11—, —NR11NR12—, —NR11C(O)—, —S—, —SO—, —SO2—, —NR11—, —SO2NR11— or —NR11SO2—;
provided that when X1 is —NH—, X2 is not —CH2C(O)— or substituted —CH2C(O)—;
R1 is H or optionally substituted aliphatic, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or R2 is absent when X2 is H;
R2 is absent, H, optionally substituted C1-8 aliphatic, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
R3 and R4 are independently H, alkyl or C5-6 aryl;
R5 and R6 are independently H or halo;
R7 and R8 are independently H, —OR23 or —NHR23, or optionally substituted aliphatic, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or together form an optionally substituted ring comprising 3 to 7 carbon or heteroatoms;
R9 is H or C1-3 alkyl;
R10 is H or alkyl;
or R8 and R10 together form a bond or an optionally substituted ring comprising 3 to 7 carbon or heteroatoms;
and
each Rm is independently H, halo, —OH, —NO2, —CN, optionally substituted C1-3, —OR23, —C(O)R23, —C(O)OR23, —C(O)N(R23)(R24), —OC(O)R23, —OC(O)OR23, —OC(O)N(R23)(R24), —N(R23)(R24), —S(O)2R23, —S(O)R23, —SR23, —S(O)2N(R23)(R2);
NR23C(O)R24, —NR23C(O)OR23, —NR23SOOR24, —NR23C(O)N(R24)(R25) or —NR23SO2N(R24)(R25);
where R23, R24 and R25 are each independently H, C1-4 alkyl or 3 to 8 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two adjacent Rm groups together form an optionally substituted aromatic or non-aromatic ring comprising 5 to 7 carbon or heteroatoms;
where n is 0, 1, 2, 3 or 4;
or Rm and R7 together form an optionally substituted aromatic or non-aromatic ring;
wherein each of the phenyl ring A carbon atoms 2-6 is optionally replaced by N;
or any pair of adjacent phenyl ring A carbons atoms 2-6 is optionally replaced by N, S or O;
or a pharmaceutically acceptable salt, ester or prodrug thereof.

24 more elements

A compound of Formula IIa:

wherein Ra and Rb are independently H or halogen;
R26, R27, R29 and R30 are each independently H, halo, —OH, —NO2, —CN, —CF3, —CHF2, —CH2CH3, —CH2CF3, —CF2CF3, —CH2Cl, —CH2OH, —CH2CH2OH, —CH2NH2, —CH2CH2NH2, —CH2SO2CH3, —OR23, —C(O)R23, —C(O)OR23, —C(O)N(R23)(R24), —OC(O)R23, —OC(O)R23, —OC(O)N(R23)(R24), —N(R23)(R24), —S(O)2R23, —S(O)R23,—SR23, —S(O)2N(R23)(R24), —NR23C(O)R24, —NR23C(O)OR24, —NR23SOOR24, —NR23C(O)N(R24)(R25), —NR23SO2R24, —NR23SO2N(R24)(R25) or optionally substituted C1-6 alkyl, C1-6 alkoxy, or aryl;
where R23, R24 and R25 are each independently H, C1-4 alkyl or C3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
R31 and R32 are each independently H, alkyl or C5-6 aryl;
R28 is H, halogen, —CN, —[CH2]n—[C(H)3-p]x(R33)p, —C(O)OH, —C(O)(CH2)nNH2, —C(O)NH(CH2)nR33, —C═N—N—S(O)2R33, —(CH2)n—CH(R34)(R35) or —CHNR34;
or R28 taken together with either R27 or R29 form an optionally substituted ring comprising 3 to 8 carbon or heteroatoms;
with the proviso that R27 and R28 are not both H;
each R33 is independently H, halogen, —C(O)OR39, —OH, —CN, —N═N—N, —N(R37)(R38), —C(O)NH(CH2)nR39, —C(R39)(NH2)C(O)O—R39, —CH2R35 or —CH(R35)(NHS(O)2—R39) or optionally substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl;
R34 is H or —N(R37)(R38);
R35 is H, —C(O)R34, —C(O)OR39 or —N(NH2)C(O)NH(CH2)nPh;
R37 and R38 are each independently H, —C(O)OR39, —C(O)cycloalkyl-Ph, —S(O)2R39, —C(O)R39, —OC(O)R39, —C(O)(CH2)qR39, —S(O)2, —S(O)2NHR39, —S(O)2N(R44)(R39), —N(R44)(R39), —C(O)N(R44)(R39) or —NHC(O)N(R44)(R39);
or optionally substituted C1-6 alkyl, C3-8 cycloalkyl, C5-8 aryl, 3 to 8 membered heterocycloalkyl or 5 to 8 membered heteroaryl;
and
R39 and R44 are each independently H or optionally substituted C1-6 alkyl, C3-8 cycloalkyl, C3-8 aryl, 3 to 8 membered heterocycloalkyl or 5 to 8 membered heteroaryl;
wherein each of the phenyl ring A carbon atoms 2-6 including its respective substituents are optionally replaced by N;
or any pair of adjacent phenyl ring A carbons atoms 2-6 and their respective substituents are optionally replaced by S, N or O;
and
wherein n is an integer from 0 to 4;
m is 0, 1 or 2;
p is an integer from 1 to 3;
q is an integer from 0 to 6;
and x is either 0 or 1, provided that when x is 0, p is 1;
or
a pharmaceutically acceptable salt, ester or prodrug thereof.

21 more elements

A compound of Formula IIb:

R26, R27 and R29 are each independently H, halo, —OH, —NO2, —CN, —CF3, —CHF2, —CH2CH3, —CH2CF3, —CF2CF3, —CH2Cl, —CH2OH, —CH2CH2OH, —CH2NH2, —CH2CH2NH2, —CH2SO2CH3, —OR23, —C(O)R23, —C(O)OR23, —C(O)N(R23)(R24), —OC(O)R23, —OC(O)OR23, —OC(O)N(R23)(R24), —N(R23)(R24), —S(O)2R23, —S(O)R23, —SR23, —S(O)2N(R23)(R24);
—NR23C(O)R24, —NR23C(O)OR24, —NR23SOOR24, —NR23C(O)N(R24)(R25), —NR23SO2R24 or —NR23SO2N(R24)(R25);
or optionally substituted C1-6 alkyl, C1-6 alkoxy, or aryl;
where R23, R24 and R25 are each independently H, C1-4 alkyl or C3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
R31 and R32 are each independently H, alkyl or C5-6 aryl;
R28 is halogen, —CN, —[CH2]n—[C(H)3-p]x(R33)p, —C(O)OH, —C(O)(CH2)nNH2, —C(O)NH(CH2)nR33, —C═N—N—S(O)2R33, —(CH2)n—CHR34R35 or —CHNR34;
or R28 taken together with either R27 or R29 form an optionally substituted ring comprising 3 to 8 carbon or heteroatoms;
each R33 is independently H, halogen, —C(O)OR39, —OH, —CN, —N═N—N, —N(R37)(R38), —C(O)NH(CH2)2Ph, —C(R39)(NH2)C(O)OR39, —CH2R35 or —CH—(R35)2—(NHS(O)2—R39);
or optionally substituted cycloalkyl, aryl, heterocycloalkyl or heteroaryl;
R34 is H or —NR37R38;
R35 is H, —C(O)R34, —C(O)OR39or —N(NH2)C(O)NH(CH2)nPh;
R37 and R38 are each independently H, —C(O)R39, —C(O)OR39, —OC(O)R39, —N(R39)(R44), —C(O)cycloalkyl-Ph, —S(O)2R39, —C(O)(CH2)qR39, —S(O)2NR44R39, —C(O)N(R44)(R39) or —NHC(O)N(R44)(R39);
or optionally substituted C1-6 alkyl, C3-8 cycloalkyl, 3-8 member heterocycloalkyl, C5-8 aryl, or 5-8 member heteroaryl;
R39 and R44 are each independently H, optionally substituted C1-6 alkyl, C3-8 cycloalkyl, 3-8 member heterocycloalkyl, C5-8 aryl, or 5-8 member heteroaryl;
each of the phenyl ring A carbon atoms 3-6 including its respective substituents are optionally replaced by N;
or any pair of adjacent phenyl ring A carbons atoms 3-6 and their respective substituents are optionally replaced by S, N or O;
and
wherein n is an integer from 0 to 4;
m is 0, 1 or 2;
p is an integer from 1 to 3;
q is an integer from 0 to 6;
and x is either 0 or 1, provided that when x is 0, p is 1;
or
a pharmaceutically acceptable salt, ester or prodrug thereof.

21 more elements

A compound of Formula IIc:

wherein R26, R27 and R29 are each independently H, halo, —OH, —NO2, —CN, —CF3, —CHF2, —CH2CH3, —CH2CF3, —CF2CF3, —CH2Cl, —CH2OH, —CH2CH2OH, —CH2NH2, —CH2CH2NH2, —CH2SO2CH3, —OR23, —C(O)R23, —C(O)OR23, —C(O)N(R23)(R24), —OC(O)R23, —OC(O)OR23, —OC(O)N(R23)(R24), —N(R23)(R24), —S(O)2R23, —S(O)R23, —SR23, —S(O)2N(R23)(R24);
—NR23C(O)R24, —NR23C(O)OR24, —NR23SOOR24, —NR23 C(O)N(R24)(R25), —NR23SO2R24, —NR23SO2N(R24)(R25) or optionally substituted C1-6 alkyl, C1-6 alkoxy, or aryl;
where R23, R24 and R25 are each independently H, C1-4 alkyl or C3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
R31 and R32 are each independently H, alkyl or C5-6 aryl;
R40 is H, alkyl, alkylene, —C(O)OR39, —C(O)N(R37)(R38) or —N(NH2)C(O)NH(CH2)nPh;
R41 is —N(R37)(R38);
R37 and R38 are each independently H, —C(O)OR39, —C(O)cycloalkyl-Ph, —S(O)2R39, —C(O)R39, —OC(O)R39, —C(O)(CH2)qR39, —S(O)2NHR39, —S(O)2N(R44)(R39), —C(O)N(R44)(R39) or —NHC(O)N(R44)(R39);
or optionally substituted C1-6 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocycloalkyl, C5-8 aryl or 5 to 8 membered heteroaryl;
and
R39 and R44 are independently H or optionally substituted C1-6 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocyloalkyl, C5-8 aryl or 5 to 8 membered heteroaryl;
wherein n is an integer from 0 to 4;
and q is an integer from 0 to 6;
wherein each of the phenyl ring A carbon atoms 3, 5 or 6 including its respective substituents is optionally replaced by N;
or phenyl ring A carbons atoms 5 and 6 together and their respective substituents are optionally replaced by S, N or O;
or
a pharmaceutically acceptable salt, ester or prodrug thereof.

13 more elements

A compound of Formula IId:

R26, R27 and R29 are each independently H, halo, —OH, —NO2, —CN, —CF3, —CHF2, —CH2CH3, —CH2CF3, —CF2CF3, —CH2Cl, —CH2OH, —CH2CH2OH, —CH2NH2, —CH2CH2NH2, —CH2SO2CH3, —OR23, —C(O)R23, —C(O)OR23, —C(O)N(R23)(R24), —OC(O)R23, —OC(O)OR23, —OC(O)N(R23)(R24), —N(R23)(R24), —S(O)2R23, —S(O)R23, —SR23, —S(O)2N(R23)(R24);
—NR23C(O)R24, —NR23C(O)OR24, —NR23SOOR24, —NR23C(O)N(R24)(R25), —NR SO2R24, —NR23SO2N(R24)(R25) or optionally substituted C1-6 alkyl, C1-6 alkoxy, or aryl;
where R23, R24 and R25 are each independently H, C1-4 alkyl or C3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
R31 and R32 are each independently H, alkyl or C5-6 aryl;
R40 is H, C1-6 alkyl, alkylene, —C(O)OR37, —C(O)N(R37)(R38) or —N(NH2)C(O)NH(CH2)nPh, wherein R37 and R38 are each independently H, —C(O)OR39, —C(O)cycloalkyl-Ph, —S(O)2R39, —OC(O)R39, —C(O)(CH2)qR39, —S(O)2N(R44)(R39), —C(O)N(R44)(R39) or —NHC(O)N(R44)(R39);
or optionally substituted C1-6 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocycloalkyl, C5-8 aryl or 5 to 8 membered heteroaryl;
R42 is H, optionally substituted C1-3 alkyl, —C(O)OH, —C(O)CH3, —C(O)cyclopropyl-Ph, —S(O)2R39, —S(O)2NHR39 or —C(O)(CH2)qR39;
wherein each of the phenyl ring A carbon atoms 3, 5 or 6 including its respective substituents is optionally replaced by N;
or phenyl ring A carbons atoms 5 and 6 together and their respective substituents are optionally replaced by S, N or O;
R39 is H, optionally substituted C1-6 alkyl, C3-8 cycloalkyl, 3 to 8 membered heterocycloalkyl, C5-8 aryl or 5 to 8 membered heteroaryl;
or
a pharmaceutically acceptable salt, ester or prodrug thereof.

9 more elements

A compound of Formula IIe:

wherein R26, R27 and R29 are each independently H, halo, —OH, —NO2, —CN, —CF3, —CHF2, —CH2CH3, —CH2CF3, —CF2CF3, —CH2Cl, —CH2OH, —CH2CH2OH, —CH2NH2, —CH2CH2NH2, —CH2SO2CH3, —OR23, —C(O)R23, —C(O)OR23, —C(O)N(R23)(R24), —OC(O)R23, —OC(O)OR23, —OC(O)N(R23)(R24), —N(R23)(R24), —S(O)2R23, —S(O)R23, —SR23, —S(O)2N(R23)(R24);
—NR C(O)R24, —NR23C(O)OR24, —NR23SOOR24, —NR23 C(O)N(R24)(R25), —NR23 SO2R24, —NR23SO2N(R24)(R25) or optionally substituted C1-6 alkyl, C1-6 alkoxy, or aryl;
where R23, R24 and R25 are each independently H, C1-4 alkyl or C3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
R31 and R32 are each independently H, alkyl or C5-6 aryl;
R40 is H, alkyl, alkylene, —C(O)OR39, —C(O)N(R37)(R38) or —N(NH2)C(O)NH(CH2)nPh;
R37 and R38 are each independently H, —C(O)OR39, —C(O)cycloalkyl-Ph, —S(O)2R39, —C(O)R39, —OC(O)R39, —C(O)(CH2)qR39, —S(O)2, —S(O)2NHR39, —S(O)2N(R44)(R39), —N(R44)(R39), —C(O)N(R44)(R39) or —NHC(O)N(R44)(R39);
or optionally substituted C1-6 alkyl, C3-8 cycloalkyl, C5-8 aryl, 3 to 8 membered heterocycloalkyl or 5 to 8 membered heteroaryl;
R39 is H or optionally substituted C1-6 alkyl, aryl or heteroaryl;
R43 is H, —NHR39 or R39;
wherein n is an integer from 0 to 4;
and
wherein each of the phenyl ring A carbon atoms 3, 5 or 6 including its respective substituents are optionally replaced by N;
or phenyl ring A carbons atoms 5 and 6 and their respective substituents are optionally replaced by S, N or O;
or
a pharmaceutically acceptable salt, ester or prodrug thereof.

12 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/280,724Filed 15 Nov 2005
Priority: 15 Nov 2004
Published: 29 Jun 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07F 9/6541
Five-membered rings: condensed with carbocyclic rings or carbocyclic ring systems
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 1/18
Drugs for disorders of the alimentary tract or the digestive system: for pancreatic disorders, e.g. pancreatic enzymes
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents