Substituted imidazole derivatives, compositions, and methods of use as PTPase inhibitors

A compound of Formula I, II, III, or IV:

• wherein
• Ar1, Ar2, Ar4, and Ar5 are independently selected from the group consisting of:
• phenyl, indanyl, tetrahydronaphthyl, pyridazine, pyrimidine, pyrazine, pyridine, piperidine, 4,5-diaza-indanyl, 5,6,7,8-tetrahydro-cinnoline, and 1-H-pyridin-2-one, and
• Ar3 is phenyl, naphthalene, indanyl, tetrahydronaphthyl, pyridazine, pyrimidine, pyrazine, pyridine, piperidine, 4,5-diaza-indanyl, or 5,6,7,8-tetrahydro-cinnoline,
• wherein
• Ar1, Ar2, Ar3, and Ar4 are each optionally substituted 1 to 4 times with a group independently selected from Rb, and
• Ar5 is optionally substituted 1 to 4 times with a group selected from Ra;
• V is C, W is C, X is N, Y is C, Z is N,
• when sides b, c, and e are single bonds, and sides a and d are double bonds;
• or
• V is C, W is N, X is C, Y is N, Z is C,
• when sides a, c, and d are single bonds, and sides b and e are double bonds;
• or
• V is C, W is N, X is C, Y is C, Z is N,
• when sides a, b, and d are single bonds, and sides c and e are double bonds;
• L1 is -T1-L3-T2-,
• wherein
• L3 is a direct bond, —C1-10 alkylene, —C2-10 alkenylene, or —C2-10 alkynylene;
• T1 and T2 are independently selected from the group consisting of a direct bond, —CH2—, —O—, —N(R16)—, —C(O)—, —CON(R16)—, —N(R16)C(O)—, —N(R16)CON(R17)—, —N(R16)C(O)O—, —OC(O)N(R16)—, —N(R16)SO2—, —SO2N(R16)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, —N(R16)SO2N(R17)—, —N═N—, and —N(R16)—N(R17)—;
• wherein
• R16 and R17 are independently selected from the group consisting of:
• -hydrogen, —C1-10 alkyl, -aryl, -arylene-C1-10 alkyl, and —C1-10 alkylene-aryl, wherein alkyl and aryl are optionally substituted with Rc;
• L2 is selected from the group consisting of:
• —CH(R18)—CH(R19)—, —N(R18)C(O)—, —N(R18)—, —N(R18)S(O)2—, —C(O)N(R18)—, —S(O)2N(R18), (trans) —C(R18)═C(R19)—, (cis) —C(R18)═C(R19)—, —C≡C—, —C(O)—, —O—, —C1-5 alkylene-O—, O—C1-5 alkylene, —(CH2)r—, 1,1 cycloalkylmethylene, or a direct bond,
• wherein
• R18 and R19 are independently selected from the group consisting of:
• -hydrogen, —C1-10 alkyl, -aryl, -arylene-C1-10 alkyl, and —C1-10 alkylene-aryl, wherein alkyl and aryl are optionally substituted with Rc;
• L4 is selected from the group consisting of:
• a direct bond and —CH2—,
• R1, R2, R3, R4, and R5 are independently selected from the group consisting of hydrogen and Rb,
• R6 is selected from the group consisting of hydrogen and Rb,
• R11 is selected from the group consisting of Rb,
• G is
• wherein
• a)
• D is C(R7)(R8), and
• E is C(R7) or N,
• when side f is a single bond, or
• b)
• D is C(R7), and
• E is C,
• when side f is a double bond,
• wherein
• R7 and R8 are independently selected from the group consisting of halo, hydroxy, amino, cyano, nitro, carboxy, —SO3H, Rf and Rg;
• or
• wherein
• a)
• D is C(R7), and
• E is C(R7)(R8) or N(R9),
• when side f is a single bond, or
• b)
• D is C, and
• E is C(R7) or N,
• when side f is a double bond,
• wherein
• R7 and R8 are independently selected from the group consisting of:
• halo, hydroxy, amino, cyano, nitro, carboxy, —SO3H, Rf and Rg;
• and
• R9 is Rd,
• M is hydrogen or a counter ion selected from the group consisting of:
• Na+, K+, and other pharmaceutically acceptable counter ions;
• Ra is
• a) -cycloalkyl,
• b) -cyano,
• c) —ORd,
• d) —NO2,
• e) -halogen,
• f) —S(O)mC2-10 alkyl,
• g) —SRd,
• h) —S(O)2ORd,
• i) —S(O)mNRdRe,
• j) —NRdS(O)mRe,
• k) —NRdRe,
• l) —O(CRfRg)nNRdRe,
• m) —C(O)Rd,
• n) —CO2Rd,
• o) —CO2(CRfRg)nCONRdRe,
• p) —OC(O)Rd,
• q) —C(O)NRdRe
• r) —NRdC(O)Re,
• s) —OC(O)NRdRe,
• t) —NRdC(O)ORe,
• u) —NRdC(O)NRdRe,
• v) —CF3,
• w) —OCF3
• x) —C1-10 alkyl,
• y) —C2-10 alkenyl,
• z) —C2-10 alkynyl,
• aa) —C1-10 alkylene-aryl,
• bb) —C1-10 alkylene-heteroaryl,
• cc) -heteroaryl,
• dd) —C(Rf)═C(Rg)—Rf, or
• ee) —C≡C—Rf,
• wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, and cycloalkyl groups are optionally substituted 1-4 times with a group independently selected from Rc;
• Rb is
• a) -cycloalkyl,
• b) -cyano,
• c) —ORd,
• d) —NO2,
• e) -halogen,
• f) —S(O)mRd,
• g) —SRd,
• h) —S(O)2ORd,
• i) —S(O)mNRdRe,
• j) —NRdS(O)mRe,
• k) —NRdRe,
• l) —O(CRfRg)nNRdRe,
• m) —C(O)Rd,
• n) —CO2Rd,
• o) —CO2(CRfRg)nCONRdRe,
• p) —OC(O)Rd,
• q) —C(O)NRdRe,
• r) —NRdC(O)Re,
• s) —OC(O)NRdRe,
• t) —NRdC(O)ORe,
• u) —NRdC(O)NRdRe,
• v) —CF3,
• w) —OCF3
• x) —C1-10 alkyl,
• y) —C2-10 alkenyl,
• z) —C2-10 alkynyl,
• aa) —C1-10 alkylene-aryl,
• bb) —C1-10 alkylene-heteroaryl,
• cc) -heteroaryl,
• dd) —C(Rf)═C(Rg)—Rf, or
• ee) —C≡C—Rf,
• wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, and cycloalkyl groups are optionally substituted 1-4 times with a group independently selected from Rc;
• Rc is
• a) -halogen,
• b) -amino,
• c) -carboxy,
• d) —C1-4 alkyl,
• e) —O—C1-4 alkyl,
• f) -cycloalkyl,
• g) —O-cycloalkyl,
• h) -aryl,
• i) —C1-4 alkylene-aryl,
• j) -hydroxy,
• k) —CF3,
• l) —O-aryl,
• m) -heteroaryl,
• n) -heteroaryl-C1-10 alkyl,
• o) heterocyclyl,
• p) —CO2—C1-10alkyl, or
• q) —CO2—C1-10 alkyl-aryl,
• Rd and Re are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cycloalkyl, —C1-10 alkylene-cycloalkyl, aryl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl groups are optionally substituted with one to four substitutents independently selected from Rc;
• or Rd and Re together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with 1-3 times with Rc, and wherein 1 or 2 carbon atoms in the heterocyclic ring may be oxidized,
• Rf and Rg are independently selected from hydrogen, C1-10 alkyl, cycloalkyl, —C1-10 alkylene-cycloalkyl, and aryl, wherein alkyl, cycloalkyl, and aryl groups are optionally substituted with one to four substitutents independently selected from Rc;
• or Rf and Rg together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen optionally substituted with 1-3 times with Rc, and wherein 1 or 2 carbon atoms in the heterocyclic ring may be oxidized;
• m is an integer from 1 to 2,
• n is an integer from 1 to 10,
• q is an integer from 1 to 2,
• r is an integer from 1 to 5, and
• s is an integer from 0 to 3,
• or a pharmaceutically acceptable salt thereof.