US 2017/0183333 A1Published application

Derivatives of n-(arylamino) sulfonamides as inhibitors of mek

AssigneeArdea Biosciences, Inc.

InventorsAndreas Maderna, Jean-Michel Vernier, Dinesh Barawkar, Varaprasad Chamakura, Hassan El Abdellaoul, Zhi Hong

Life of this patent

Estimating the term…

Abstract

This invention concerns N-(2-arylamino) aryl sulfonamides, which are inhibitors of MEK and are useful in treatment of cancer and other hyperproliferative diseases.

Claims10

Dependent claims

A compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof

wherein
Z is H or F;
X is F, Cl, CH3, CH2OH, CH2F, CHF2, or CF3;
Y is I, Br, Cl, CF3, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, where Het is a 5- to 10-membered mono- or bicyclic heterocyclic group, which group is saturated, olefinic, or aromatic, containing 1-5 ring heteroatoms selected independently from N, O, and S;
where
all said phenyl or Het groups are optionally substituted with F, Cl, Br, I, acetyl, methyl, CN, NO2, CO2H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkyl-C(═O)—, C1-C3 alkyl-C(═S)—, C1-C3 alkoxy-C(═S)—, C1-C3 alkyl-C(═O)O—, C1-C3 alkyl-O—(C═O)—, C1-C3 alkyl-C(═O)NH—, C1-C3 alkyl-C(═NH)NH—, C1-C3 alkyl-NH—(C═O)—, di-C1-C3 alkyl-N—(C═O)—, C1-C3 alkyl-C(═O)N(C1-C3 alkyl)-, C1-C3 alkyl-S(═O)2NH— or trifluoromethyl;
all said methyl, ethyl, C1-C3 alkyl, and cyclopropyl groups are optionally substituted with OH;
all said methyl groups are optionally substituted with one, two, or three F atoms;
R0 is H, F, Cl, Br, I, CH3NH—, (CH3)2N—, C1-C6 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, monosubstituted phenyl, O(C1-C4 alkyl), O—C(═O)(C1-C4 alkyl) or C(═O)O(C1-C4 alkyl);
where
said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl and phenyl groups are optionally substituted with 1-3 substituents selected independently from F, Cl, Br, I, OH, CN, cyanomethyl, nitro, phenyl and trifluoromethyl;
said C1-C6 alkyl and C1-C4 alkoxy groups also optionally substituted with OCH3 or OCH2CH3;
G is G1, G2, R1a, R1b, R1c, R1d, R1e, Ar1, Ar2 or Ar3;
where
G1 is C1-C6 alkyl optionally substituted with one amino, C1-C3 alkylamino, or dialkylamino group, said dialkylamino group comprising two C1-C4 alkyl groups which may be identical or non-identical;
or
G1 is a C3-C8 diamino alkyl group;
G2 is a 5- or 6-membered ring, which is saturated, unsaturated, or aromatic, containing 1-3 ring heteroatoms selected independently from N, O, and S, optionally substituted with 1-3 substituents selected independently from F, Cl, OH, O(C1-C3 alkyl), OCH3, OCH2CH3, CH3C(═O)NH, CH3C(═O)O, CN, CF3, and a 5-membered aromatic heterocyclic group containing 1-4 ring heteroatoms selected independently from N, O, and S;
R1a is methyl, optionally substituted with 1-3 fluorine atoms or 1-3 chlorine atoms, or with OH, cyclopropoxy, or C1-C3 alkoxy, where said cyclopropoxy group or the C1-C3 alkyl moieties of said C1-C3 alkoxy groups are optionally substituted with one hydroxy or methoxy group, and where all C3-alkyl groups within said C1-C4 alkoxy are optionally further substituted with a second OH group;
R1b is CH(CH3)—C1-3 alkyl or C3-C6 cycloalkyl, said alkyl and cycloalkyl groups optionally substituted with 1-3 substituents selected independently from F, Cl, Br, I, OH, OCH3, and CN;
R1c is (CH2)nOmR′;
where
m is 0 or 1;
and where
when m is 0, n is 1 or 2;
when m is 1, n is 2 or 3;
R′ is C1-C6 alkyl, optionally substituted with 1-3 substituents selected independently from F, Cl, OH, OCH3, OCH2CH3, and C3-C6 cycloalkyl;
R1d is C(A)(A′)(B)—;
where
B is H or C1-4 alkyl, optionally substituted with one or two OH groups;
A and A′ are independently H or C1-4 alkyl, optionally substituted with one or two OH groups;
or
A and A′, together with the carbon atom to which they are attached, form a 3- to 6-member saturated ring;
R1e is
where
q is 1 or 2;
R2 and R3 are each independently, H, F, Cl, Br, CH3, CH2F, CHF2, CF3 OCH3, OCH2F, OCHF2, OCF3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl or methylsulfonyl;
R4 is H, F, Cl, Br, CH3, CH2F, CHF2, CF3 OCH3, OCH2F, OCHF2, OCF3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol, 1,3,4-thiadiazol, 5-methyl-1,3,4-thiadiazol 1H-tetrazolyl, N-morpholyl carbonyl amino, N-morpholylsulfonyl and N-pyrrolidinylcarbonylamino;
R5 is H, F, Cl or methyl;
R6 is H, F, Cl or methyl;
Ar1 is
where
U and V are, independently, N, CR2 or CR3;
R2, R3 and R4 are, independently, H, F, Cl, Br, CH3, CH2F, CHF2, CF3 OCH3, OCH2F, OCHF2, OCF3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl, N-morpholylcarbonylamino, N-morpholylsulfonyl, N-pyrrolidinylcarbonylamino, and methylsulfonyl;
R5 and R6 are, independently, H, F, Cl or methyl;
Ar2 is
where
the dashed line represents alternative formal locations for the second ring double bond;
U is —S—, —O— or —N═, and where
when U is —O— or —S—, V is —CH═, —CCl═ or —N═;
when U is —N═, V is —CH═, —CCl═, or —N═;
R7 is H or methyl;
R8 is H, acetamido, methyl, F or Cl;
Ar3 is
where
U is —NH—, —NCH3— or —O—;
R7 and R8 are, independently, H, F, Cl, or methyl.

54 more elements

A method for inhibiting MEK enzymes comprising contacting said MEK enzyme with a composition comprising a compound of formula I or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, sufficient to inhibit said enzyme, wherein said enzyme is inhibited

wherein
Z is H or F;
X is F, Cl, CH3, CH2OH, CH2F, CHF2, or CF;
Y is I, Br, Cl, CF3, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, where Het is a 5- to 10-membered mono- or bicyclic heterocyclic group, which group is saturated, olefinic, or aromatic, containing 1-5 ring heteroatoms selected independently from N, 0, and S;
where
all said phenyl or Het groups are optionally substituted with F, Cl, Br, I, acetyl, methyl, CN, NO2, CO2H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkyl-C(═O)—, C1-C3 alkyl-C(═S)—, C1-C3 alkoxy-C(═S)—, C1-C3 alkyl-C(═O)O—, C1-C3 alkyl-O—(C═O)—, C1-C3 alkyl-C(═O)NH—, C1-C3 alkyl-C(═NH)NH—, C1-C3 alkyl-NH—(C═O)—, di-C1-C3 alkyl-N—(C═O)—, C1-C3 alkyl-C(═O)N(C1-C3 alkyl)-, C1-C3 alkyl-S(═O)2NH— or trifluoromethyl;
all said methyl, ethyl, C1-C3 alkyl, and cyclopropyl groups are optionally substituted with OH,
all said methyl groups are optionally substituted with one, two, or three F atoms;
R0 is H, F, Cl, Br, I, CH3NH—, (CH3)2N—, C1-C6 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, monosubstituted phenyl, O(C1-C4 alkyl), O—C(═O)(C1-C4 alkyl) or C(═O)O(C1-C4 alkyl);
where
said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl and phenyl groups are optionally substituted with 1-3 substituents selected independently from F, Cl, Br, I, OH, CN, cyanomethyl, nitro, phenyl and trifluoromethyl;
said C1-C6 alkyl and C1-C4 alkoxy groups also optionally substituted with OCH3 or OCH2CH3;
G is G1, G2, R1a, R1b, R1c, R1d, R1e, Ar1, Ar2 or Ar3;
where
G1 is C1-C6 alkyl optionally substituted with one amino, C1-C3 alkylamino, or dialkylamino group, said dialkylamino group comprising two C1-C4 alkyl groups which may be identical or non-identical;
or
G1 is a C3-C8 diamino alkyl group;
G2 is a 5- or 6-membered ring, which is saturated, unsaturated, or aromatic, containing 1-3 ring heteroatoms selected independently from N, O, and S, optionally substituted with 1-3 substituents selected independently from F, Cl, OH, O(C1-C3 alkyl), OCH3, OCH2CH3, CH3C(═O)NH, CH3C(═O)O, CN, CF3, and a 5-membered aromatic heterocyclic group containing 1-4 ring heteroatoms selected independently from N, O, and S;
R1a is methyl, optionally substituted with 1-3 fluorine atoms or 1-3 chlorine atoms, or with OH, cyclopropoxy, or C1-C3 alkoxy, where said cyclopropoxy group or the C1-C3 alkyl moieties of said C1-C3 alkoxy groups are optionally substituted with one hydroxy or methoxy group, and where all C3-alkyl groups within said C1-C4 alkoxy are optionally further substituted with a second OH group;
R1b is CH(CH3)—C1-3 alkyl or C3-C6 cycloalkyl, said alkyl and cycloalkyl groups optionally substituted with 1-3 substituents selected independently from F, Cl, Br, I, OH, OCH3, and CN;
R1c is (CH2)nOmR′;
where
m is 0 or 1;
and where
when m is 0, n is 1 or 2:
when m is 1, n is 2 or 3:
R′ is C1-C6 alkyl, optionally substituted with 1-3 substituents selected independently from F, Cl, OH, OCH3, OCH2CH3, and C3-C6 cycloalkyl;
R1d is C(A)(A′)(B)—;
where
B is H or C1-4 alkyl, optionally substituted with one or two OH groups;
A and A′ are independently H or C1-4 alkyl, optionally substituted with one or two OH groups;
or
A and A′, together with the carbon atom to which they are attached, form a 3- to 6-member saturated ring;
R1e is
where
q is 1 or 2;
R2 and R3 are each independently, H, F, Cl, Br, CH3, CH2F, CHF2, CF3 OCH3, OCH2F, OCHF2, OCF3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl or methylsulfonyl;
R4 is H, F, Cl, Br, CH3, CH2F, CHF2, CF3 OCH3, OCH2F, OCHF2, OCF3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol, 1,3,4-thiadiazol, 5-methyl-1,3,4-thiadiazol 1H-tetrazolyl, N-morpholyl carbonyl amino, N-morpholylsulfonyl and N-pyrrolidinylcarbonylamino;
R5 is H, F, Cl or methyl:
R6 is H, F, Cl or methyl;
A1 is
where
U and V are, independently, N, CR2 or CR3;
R2, R3 and R4 are, independently, H, F, Cl, Br, CH3, CH2F, CHF2, CF3 OCH3, OCH2F, OCHF2, OCF3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl, N-morpholylcarbonylamino, N-morpholylsulfonyl, N-pyrrolidinylcarbonylamino, and methylsulfonyl;
R5 and R6 are, independently, H, F, Cl or methyl;
Ar2 is
where
the dashed line represents alternative formal locations for the second ring double bond;
U is —S—, —O— or —N═, and where
when U is —O— or —S—, V is —CH═, —CCl═ or —N═;
when U is —N═, V is —CH═, —CCl═, or —N═;
R7 is H or methyl:
R8 is H, acetamido, methyl, F or Cl;
Ar3 is
where
U is —NH—, —NCH3— or —O—;
R7 and R8 are, independently, H, F, Cl, or methyl.

54 more elements

A method for the treatment of an oncologic disease, a proliferative disease or an inflammatory disease in an individual or a method for inhibiting tumor size increase, reducing the size of a tumor, or reducing tumor proliferation in an individual,

comprising administering to said individual an effective amount of a compound of formula I or a pharmaceutically acceptable salt, ester, or tautomer thereof:
wherein
Z is H or F;
X is F, Cl, CH3, CH2OH, CH2F, CHF2, or CF3;
Y is I, Br, Cl, CF3, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, O-Methyl, O-Ethyl, S-Methyl or phenyl;
where
said phenyl group is optionally substituted with F, Cl, Br, I, acetyl, methyl, CN, NO2, CO2H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkyl-C(═O)—, C1-C3 alkyl-C(═S)—, C1-C3 alkoxy-C(═S)—, C1-C3 alkyl-C(═O)O—, C1-C3 alkyl-O—(C═O)—, C1-C3 alkyl-C(═O)NH—, C1-C3 alkyl-C(═NH)NH—, C1-C3 alkyl-NH—(C═O)—, di-C1-C3 alkyl-N—(C═O)—, C1-C3 alkyl-C(═O)N(C1-C3 alkyl)-, C1-C3 alkyl-S(═O)2NH— or trifluoromethyl;
all said methyl, ethyl, C1-C3 alkyl, and cyclopropyl groups are optionally substituted with OH;
all said methyl groups are optionally substituted with one, two, or three F atoms;
R0 is H, F, Cl, Br, I, CH3NH—, (CH3)2N—, C1-C6 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, monosubstituted phenyl, O(C1-C4 alkyl), O—C(═O)(C1-C4 alkyl) or C(═O)O(C1-C4 alkyl);
where
said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl and phenyl groups are optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, CN, cyanomethyl, nitro, phenyl and trifluoromethyl;
said C1-C6 alkyl and C1-C4 alkoxy groups are also optionally substituted with OCH3 or OCH2CH3;
G is G1, G2, R1a, R1b, R1c, R1d, R1e, Ar1, Ar2 or Ar3;
where
G1 is C1-C6 alkyl optionally substituted with one amino, or is a C3-C8 diamino alkyl group;
G2 is a 5- or 6-membered ring, which is saturated, unsaturated, or aromatic, containing 1-3 ring heteroatoms independently selected from the group consisting of O, and S, optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, OH, O(C1-C3 alkyl), OCH3, OCH2CH3, CH3C(═O)NH, CH3C(═O)O, CN, CF3, and a 5-membered aromatic heterocyclic group containing 1-4 ring heteroatoms independently selected from the group consisting of N, O, and S;
R1a is methyl, optionally substituted with 1-3 fluorine atoms or 1-3 chlorine atoms, or with OH, cyclopropoxy, or C1-C3 alkoxy, where said cyclopropoxy group or the C1-C3 alkyl moieties of said C1-C3 alkoxy groups are optionally substituted with one hydroxy or methoxy group, and where all C3-alkyl groups within said C1-C3 alkoxy are optionally further substituted with a second OH group;
R1b is CH(CH3)—C1-3 alkyl or C3-C6 cycloalkyl, said alkyl and cycloalkyl groups optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, OCH3, and CN;
R1c is (CH2)nOmR′;
where
m is 0 or 1;
and where
when m is 0, n is 1 or 2;
when m is 1, n is 2 or 3;
R′ is C1-C6 alkyl, optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, OH, OCH3, OCH2CH3, and C3-C6 cycloalkyl;
R1d is C(A)(A′)(B)—;
where
B is H or C1-4 alkyl, optionally substituted with one or two OH groups;
A and A′ are independently H or C1-4 alkyl, optionally substituted with one or two OH groups;
or
A and A′, together with the carbon atom to which they are attached, form a 3- to 6-member saturated ring;
R1e is
where
q is 1 or 2;
R2 and R3 are each independently, H, F, Cl, Br, CH3, CH2F, CHF2, CF3 OCH3, OCH2F, OCHF2, OCF3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl or methylsulfonyl;
R4 is H, F, Cl, Br, CH3, CH2F, CHF2, CF3 OCH3, OCH2F, OCHF2, OCF3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol, 1,3,4-thiadiazol, 5-methyl-1,3,4-thiadiazol 1H-tetrazolyl, N-morpholyl carbonyl amino, N-morpholylsulfonyl or N-pyrrolidinylcarbonylamino;
R5 is H, F, Cl or methyl;
R6 is H, F, Cl or methyl;
Ar1 is
where
U and V are, independently, N, CR2 or CR3;
R2, R3 and R4 are, independently, H, F, Cl, Br, CH3, CH2F, CHF2, CF3 OCH3, OCH2F, OCHF2, OCF3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl, N-morpholylcarbonylamino, N-morpholylsulfonyl, N-pyrrolidinylcarbonylamino, or methylsulfonyl;
R5 and R6 are, independently, H, F, Cl or methyl;
Ar2 is
where
the dashed line represents alternative formal locations for the second ring double bond;
U is —S—, —O— or —N═, and where
when U is —O— or —S—, V is —CH═, —CCl═ or —N═;
when U is —N═, V is —CH═, —CCl═, or —N═;
R7 is H or methyl;
R8 is H, acetamido, methyl, F or Cl;
Ar3 is
where
U is —NH—, —NCH3— or —O—;
and
R7 and R8 are, independently, H, F, Cl, or methyl.

54 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/227,395Filed 3 Aug 2016
Priority: 21 Jul 2005
Published: 29 Jun 2017
Term ends: Not estimatedThe source records don’t support an estimate.

Classification59 codes

C07D 417/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61K 31/18
Amides, e.g. hydroxamic acids: sulfonamides
A61K 31/34
Having oxygen as the only ring hetero atom, e.g. fungichromin: having five-membered rings with one oxygen as the only ring hetero atom, e.g.…
A61K 31/381
Having sulfur as a ring hetero atom: having five-membered rings

Family

Application60/701,814Us provisional application · filed 21 Jul 2005
Application60/706,719Us provisional application · filed 8 Aug 2005
Application60/731,633Us provisional application · filed 28 Oct 2005
Application60/833,886Us provisional application · filed 28 Jul 2006
Application11/830,733Division · filed 30 Jul 2007
Application13/243,368Division · filed 23 Sep 2011
Application14/478,467Continuation · filed 5 Sep 2014
Application15/227,395Continuation
Application14/478,467Division
Application11/830,733Continuation in part
US 2008/0058340 A1Published application
US 2012/0022076 A1Published application
US 2014/0378466 A1Published application
US 8,101,799 B2Related patent
US 8,829,052 B2Related patent
US 2017/0183333 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

This invention concerns N-(2-arylamino) aryl sulfonamides, which are inhibitors of MEK and are useful in treatment of cancer and other hyperproliferative diseases.

A compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof

wherein
Z is H or F;
X is F, Cl, CH3, CH2OH, CH2F, CHF2, or CF3;
Y is I, Br, Cl, CF3, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, where Het is a 5- to 10-membered mono- or bicyclic heterocyclic group, which group is saturated, olefinic, or aromatic, containing 1-5 ring heteroatoms selected independently from N, O, and S;
where
all said phenyl or Het groups are optionally substituted with F, Cl, Br, I, acetyl, methyl, CN, NO2, CO2H, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkyl-C(═O)—, C1-C3 alkyl-C(═S)—, C1-C3 alkoxy-C(═S)—, C1-C3 alkyl-C(═O)O—, C1-C3 alkyl-O—(C═O)—, C1-C3 alkyl-C(═O)NH—, C1-C3 alkyl-C(═NH)NH—, C1-C3 alkyl-NH—(C═O)—, di-C1-C3 alkyl-N—(C═O)—, C1-C3 alkyl-C(═O)N(C1-C3 alkyl)-, C1-C3 alkyl-S(═O)2NH— or trifluoromethyl;
all said methyl, ethyl, C1-C3 alkyl, and cyclopropyl groups are optionally substituted with OH;
all said methyl groups are optionally substituted with one, two, or three F atoms;
R0 is H, F, Cl, Br, I, CH3NH—, (CH3)2N—, C1-C6 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, monosubstituted phenyl, O(C1-C4 alkyl), O—C(═O)(C1-C4 alkyl) or C(═O)O(C1-C4 alkyl);
where
said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl and phenyl groups are optionally substituted with 1-3 substituents selected independently from F, Cl, Br, I, OH, CN, cyanomethyl, nitro, phenyl and trifluoromethyl;
said C1-C6 alkyl and C1-C4 alkoxy groups also optionally substituted with OCH3 or OCH2CH3;
G is G1, G2, R1a, R1b, R1c, R1d, R1e, Ar1, Ar2 or Ar3;
where
G1 is C1-C6 alkyl optionally substituted with one amino, C1-C3 alkylamino, or dialkylamino group, said dialkylamino group comprising two C1-C4 alkyl groups which may be identical or non-identical;
or
G1 is a C3-C8 diamino alkyl group;
G2 is a 5- or 6-membered ring, which is saturated, unsaturated, or aromatic, containing 1-3 ring heteroatoms selected independently from N, O, and S, optionally substituted with 1-3 substituents selected independently from F, Cl, OH, O(C1-C3 alkyl), OCH3, OCH2CH3, CH3C(═O)NH, CH3C(═O)O, CN, CF3, and a 5-membered aromatic heterocyclic group containing 1-4 ring heteroatoms selected independently from N, O, and S;
R1a is methyl, optionally substituted with 1-3 fluorine atoms or 1-3 chlorine atoms, or with OH, cyclopropoxy, or C1-C3 alkoxy, where said cyclopropoxy group or the C1-C3 alkyl moieties of said C1-C3 alkoxy groups are optionally substituted with one hydroxy or methoxy group, and where all C3-alkyl groups within said C1-C4 alkoxy are optionally further substituted with a second OH group;
R1b is CH(CH3)—C1-3 alkyl or C3-C6 cycloalkyl, said alkyl and cycloalkyl groups optionally substituted with 1-3 substituents selected independently from F, Cl, Br, I, OH, OCH3, and CN;
R1c is (CH2)nOmR′;
where
m is 0 or 1;
and where
when m is 0, n is 1 or 2;
when m is 1, n is 2 or 3;
R′ is C1-C6 alkyl, optionally substituted with 1-3 substituents selected independently from F, Cl, OH, OCH3, OCH2CH3, and C3-C6 cycloalkyl;
R1d is C(A)(A′)(B)—;
where
B is H or C1-4 alkyl, optionally substituted with one or two OH groups;
A and A′ are independently H or C1-4 alkyl, optionally substituted with one or two OH groups;
or
A and A′, together with the carbon atom to which they are attached, form a 3- to 6-member saturated ring;
R1e is
where
q is 1 or 2;
R2 and R3 are each independently, H, F, Cl, Br, CH3, CH2F, CHF2, CF3 OCH3, OCH2F, OCHF2, OCF3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl or methylsulfonyl;
R4 is H, F, Cl, Br, CH3, CH2F, CHF2, CF3 OCH3, OCH2F, OCHF2, OCF3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol, 1,3,4-thiadiazol, 5-methyl-1,3,4-thiadiazol 1H-tetrazolyl, N-morpholyl carbonyl amino, N-morpholylsulfonyl and N-pyrrolidinylcarbonylamino;
R5 is H, F, Cl or methyl;
R6 is H, F, Cl or methyl;
Ar1 is
where
U and V are, independently, N, CR2 or CR3;
R2, R3 and R4 are, independently, H, F, Cl, Br, CH3, CH2F, CHF2, CF3 OCH3, OCH2F, OCHF2, OCF3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl, N-morpholylcarbonylamino, N-morpholylsulfonyl, N-pyrrolidinylcarbonylamino, and methylsulfonyl;
R5 and R6 are, independently, H, F, Cl or methyl;
Ar2 is
where
the dashed line represents alternative formal locations for the second ring double bond;
U is —S—, —O— or —N═, and where
when U is —O— or —S—, V is —CH═, —CCl═ or —N═;
when U is —N═, V is —CH═, —CCl═, or —N═;
R7 is H or methyl;
R8 is H, acetamido, methyl, F or Cl;
Ar3 is
where
U is —NH—, —NCH3— or —O—;
R7 and R8 are, independently, H, F, Cl, or methyl.

54 more elements

Facts

Application

15/227,395Filed 3 Aug 2016

Priority

21 Jul 2005

Published

29 Jun 2017

Term ends

Not estimatedThe source records don’t support an estimate.

Classification59 codes

C07D 417/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61K 31/18
Amides, e.g. hydroxamic acids: sulfonamides
A61K 31/34
Having oxygen as the only ring hetero atom, e.g. fungichromin: having five-membered rings with one oxygen as the only ring hetero atom, e.g.…
A61K 31/381
Having sulfur as a ring hetero atom: having five-membered rings

Family

Application60/701,814Us provisional application · filed 21 Jul 2005

Application60/706,719Us provisional application · filed 8 Aug 2005

Application60/731,633Us provisional application · filed 28 Oct 2005

Application60/833,886Us provisional application · filed 28 Jul 2006

Application11/830,733Division · filed 30 Jul 2007

Application13/243,368Division · filed 23 Sep 2011

Application14/478,467Continuation · filed 5 Sep 2014

Application15/227,395Continuation

Application14/478,467Division

Application11/830,733Continuation in part

US 2008/0058340 A1Published application

US 2012/0022076 A1Published application

US 2014/0378466 A1Published application

US 8,101,799 B2Related patent

US 8,829,052 B2Related patent

US 2017/0183333 A1This patent

From the US filing history. Foreign family members aren’t listed.