US2004102448A1PendingUtilityA1
Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade
Est. expiryMay 19, 2019(expired)· nominal 20-yr term from priority
Inventors:Michael S. SouthJohn J. ParlowDarin E. JonesBrenda CaseTom DiceRichard LindmarkMichael HayesMelvin L. RueppelHorng-Chih HuangWei HuangScott LongMatthew MahoneyWilliam L. NeumannDavid B. ReitzJohn I. TrujilloChing-Cheng WangRhonda WoodQingping ZengRick FentonGary W. FranklinCarrie Kusturin
A61P 9/04C07K 5/06139C07D 241/20C07D 409/04C07D 417/12C07D 409/12A61P 43/00C07K 5/06191C07D 403/12A61K 38/00A61P 9/10C07D 401/12C07D 413/12C07D 405/04A61P 7/02A61P 9/00A61P 35/00
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Claims
Abstract
The invention relates to substituted polycyclic aryl and heteroaryl pyrazinone compounds useful as inhibitors of serine proteases of the coagulation cascade and compounds, compositions and methods for anticoagulant therapy for the treatment and prevention of a variety of dirombotic conditions including coronary artery and cerebrovascular diseases.
Claims
exact text as granted — not AI-modifiedWhat we claim is:
1 . A compound having the Formula:
or a pharmaceutically acceptable salt thereof, wherein:
B is formula (V):
wherein D 1 , D 2 , J 1 , J 2 and K 1 independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D 1 , D 2 , J 1 , J 2 and K 1 is O, no more than one of D 1 , D 2 , J 1 , J 2 and K 1 is S, one of D 1 , D 2 , J 1 , J 2 and K 1 must be a covalent bond when two of D 1 , D 2 , J 1 , J 2 and K 1 are O and S, and no more than four of D 1 , D 2 , J 1 , J 2 and K 1 are N;
R 9 , R 10 , R 11 , R 12 , R 13 , R 32 , R 33 , R 34 , R 35 , and R 36 , are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, hydroxy, amino, alkoxyamino, nitro, lower alkylamino, akylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy, carboxy, carboxamido, carboxamidoalkyl, and cyano;
R 16 , R 19 , R 32 , R 33 , R 34 , R 35 , and R 36 are independently optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 32 , R 33 , R 34 , R 35 , and R 36 ;
B is optionally selected from the group consisting of C3-C12 cycloalkyl and C4-C9 saturated heterocyclyl, wherein each ring carbon is optionally substituted with R 33 , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R 9 or R 13 , a ring carbon or nitrogen atom adjacent to the R 9 position and two atoms from the point of attachment is optionally substituted with R 10 , a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of attachment is optionally substituted with R 12 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 10 position is optionally substituted with R 11 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 12 position is optionally substituted with R 33 , and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the R 11 and R 33 positions is optionally substituted with R 34 ;
A is selected from the group consisting of single covalent bond, (W 7 ) rr —(CH(R 15 )) pa and (CH(R 15 )) pa —(W 7 ) rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 6, and W 7 is selected from the group consisting of O, S, C(O), (R 7 )NC(O), (R 7 )NC(S), and N(R 7 ) with the proviso that no more than one of the group consisting of rr and pa is 0 at the same time;
R 7 is selected from the group consisting of hydrido, hydroxy, and alkyl;
R 15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl;
Ψ is selected from the group consisting of NH and NOH;
R 1 is selected from the group consisting of hydrido, alkyl, alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of covalent single bond, (CR 41 R 42 ) q wherein q is an integer selected from 1 through 3, (CH(R 41 )) g —W 0 —(CH(R 42 )) p wherein g and p are integers independently selected from 0 through 3 and W 0 is selected from the group consisting of O, S, C(O), S(O), N(R 41 ), and ON(R 41 ), and (CH(R 41 )) e —W 22 —(CH(R 42 )) h wherein e and h are integers independently selected from 0 through 1 and W 22 is selected from the group consisting of CR 41 ═CR 42 , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso that Z 0 is directly bonded to the pyrazinone ring;
R 41 and R 42 are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl;
Q is selected from the group consisting of hydrido, with the proviso that Z 0 is other than a covalent single bond, and the formula (II):
wherein D 1 , D 2 , J 1 , J 2 and K 1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D 1 , D 2 , J 1 , J 2 and K 1 is O, no more than one of D 1 , D 2 , J 1 , J 2 and K 1 is S, one of D 1 , D 2 , J 1 , J 2 and K 1 must be a covalent bond when two of D 1 , D 2 , J 1 , J 2 and K 1 are O and S, and no more than four of D 1 , D 2 , J 1 , J 2 and K 1 are N, with the proviso that R 9 , R 10 , R 11 , R 12 , and R 13 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
K is (CR 4a R 4b ) n wherein n is an integer selected from 1 through 2;
R 4a and R 4b are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl;
E 0 is E 1 when K is (CR 4a R 4b ) n , wherein E 1 is selected from the group consisting of a covalent single bond, C(O), C(S), C(O)N(R 7 ), (R 7 )NC(O), S(O) 2 , (R 7 )NS(O) 2 , and S(O) 2 N(R 7 );
Y 0 is formula (IV):
wherein D 5 , D 6 , J 5 , and J 6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2 is C, no more than one of D 5 , D 6 , J 5 , and J 6 is O, no more than one of D 5 , D 6 , J 5 , and J 6 is S, one of D 5 , D 6 , J 5 , and J 6 must be a covalent bond when two of D 5 , D 6 , J 5 , and J 6 are O and S, and no more than four of D 5 , D 6 , J 5 , and J 6 are N;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylamino, haloalkoxyalkyl, carboalkoxy, and cyano;
Q b is selected from the group consisting of NR 20 R 21 aminoalkylenyl, Q be wherein Q be is hydrido, N(R 26 )C(NR 25 )N(R 23 )(R 24 ), and C(NR 25 )NR 23 R 24 , with the provisos that no more than one of R 20 and R 21 is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no more than one of R 23 and R 24 is hydroxy, amino, alkylamino, or dialkylamino at the same time;
R 20 , R 21 , R 23 , R 24 , R 25 , and R 26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, aminoalkylenyl, amino, dialkyl amino, alkylamino, and hydroxyalkyl;
Q s is selected from the group consisting of a single covalent bond, (CR 37 R 38 ) b wherein b is an integer selected from 1 through 4, and (CH(R 14 )) c —W 1 —(CH(R 15 )) d wherein c and d are integers independently selected from 1 through 3 and W 1 is selected from the group consisting of C(O)N(R 14 ), (R 14 )NC(O), S(O), S(O) 2 , S(O) 2 N(R 14 ), N(R 14 )S(O) 2 , and N(R 14 ), with the provisos that R 14 is selected from other than halo when directly bonded to N and that (CR 37 R 38 ) b , and (CH(R 14 )) c are bonded to E 0 ;
R 14 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
R 37 and R 38 are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
R 38 is optionally selected from the group consisting of aroyl and heteroaroyl;
Y 0 is optionally Q b —Q ss wherein Q ss is (CH(R 14 )) e —W 2 —(CH(R 15 )) h wherein e and h are integers independently selected from 1 through 2 and W 2 is CR 4a ═CR 4b with the proviso that (CH(R 14 )) e is bonded to E 0 ;
Y 0 is optionally selected from the group consisting of Q b —Q ssss and Q b —Q ssssr wherein Q ssss is (CH(R 38 )) r —W 5 and Q ssssr is (CH(R 38 )) r —W 6 , r is an integer selected from 1 through 2, and W 5 and W 6 are independently selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo(1,2-a)pyridinyl, 3,4-imidazo(1,2-a)pyridinyl, 3,5-imidazo(1,2-a)pyridinyl, 3,6-imidazo(1,2-a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,5-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hyrido containing nitrogen member of the ring of the W 5 and of the ring of the W 6 , other than the points of attachment of W 5 and W 6 , is optionally substituted with one or more of the group consisting of R 9 , R 10 , R 11 , and R 12 , with the provisos that Q is bonded to lowest number substituent position of each W 5 , Q b is bonded to highest number substituent position of each W 6 , and (CH(R 38 )) r is bonded to E 0 .
2 . The compound as recited in claim 1 having the Formula:
or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 32 the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 36 , a carbon adjacent to R 32 and two atoms from the carbon at the point of attachment is optionally substituted by R 33 , a carbon adjacent to R 36 and two atoms from the carbon at the point of attachment is optionally substituted by R 35 , and any carbon adjacent to both R 33 and R 35 is substituted by R 34 ;
R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylamino, carboalkoxy, carboxy, carboxamido, cyano, and Q b ;
B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 32 , R 33 , R 34 , R 35 ,and R 36 ;
B is optionally selected from the group consisting of C3-C12 cycloalkyl and C4-C9 saturated heterocyclyl, wherein each ring carbon is optionally substituted with R 33 , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R 9 or R 13 , a ring carbon or nitrogen atom adjacent to the R 9 position and two atoms from the point of attachment is optionally substituted with R 10 , a ring carbon or nitrogen atom adjacent to the R 13 position and two atoms from the point of attachment is optionally substituted with R 12 , a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R 10 position is optionally substituted with R 11 , a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R 12 position is optionally substituted with R 33 , and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R 11 and R 33 positions is optionally substituted with R 34 ;
R 9 , R 10 , R 11 , R 12 , and R 13 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfamido, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and cyano;
A is selected from the group consisting of single covalent bond and (CH(R 15 )) pa —(W 7 ) rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is selected from the group consisting of O, S, C(O), (R 7 )NC(O), (R 7 )NC(S), and N(R 7 );
R 7 is selected from the group consisting of hydrido, hydroxy and alkyl;
R 15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl;
R 1 is selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of covalent single bond and (CR 41 R 42 ) q wherein q is an integer selected from 1 through 2, (CH(R 41 )) g —W 0 —(CH(R 42 )) p wherein g and p are integers independently selected from 0 through 3 and W 0 is selected from the group consisting of O, S, and N(R 41 ), and (CH(R 41 )) e —W 22 (CH(R 42 )) h wherein e and h are integers independently selected from 0 through 1 and W 22 is selected from the group consisting of CR 41 ═CR 42 , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso that Z 0 is directly bonded to the pyrazinone ring;
R 41 and R 42 are independently selected from the group consisting of hydrido, hydroxy, and amino;
Q is selected from the group consisting of hydrido, with the proviso that Z 0 is other than a covalent single bond, aryl, and heteroaryl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
K is CHR 4a wherein R 4a is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl;
E 0 is selected from the group consisting of a covalent single bond, C(O)N(H), (H)NC(O), (R 7 )NS(O) 2 , and S(O) 2 N(R 7 );
Y 0 is formula (IV):
wherein D 5 , D 6 , J 5 and J 6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one can be a covalent bond, K 2 is C, no more than one of D 5 , D 6 , J 5 , and J 6 can be O, no more than one of D 5 , D 6 , J 5 , and J 6 can be S, one of D 5 , D 6 , J 5 , and J 6 must be a covalent bond when two of D 5 , D 6 , J 5 , and J 6 are O and S, and no more than four of D 5 , D 6 , J 5 and J 6 can be N, with the provisos that R 16 , R 17 , R 18 , and R 19 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
Q b is selected from the group consisting of NR 20 , R 21 , Q be wherein Q be is hydrido, N(R 26 )C(NR 25 )N(R 23 )(R 24 ), and C(NR 25 )NR 23 R 24 , with the provisos that no more than one of R 20 and R 21 is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no more than one of R 23 and R 24 is hydroxy, amino, alkylamino, or dialkylamino at the same time;
R 20 , R 21 , R 23 , R 24 , R 25 , and R 26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino;
Q s is selected from the group consisting of a single covalent bond, (CR 37 R 38 ) b wherein b is an integer selected from 1 through 4, and (CH(R 14 )) c —W 1 —(CH(R 15 )) d wherein c and d are integers independently selected from 1 through 3 and W 1 is selected from the group consisting of C(O)N(R 14 ), (R 14 )NC(O), S(O), S(O) 2 , S(O) 2 N(R 14 ), N(R 14 )S(O) 2 , and N(R 14 ), with the provisos that R 14 is selected from other than halo when directly bonded to N and that (CR 37 R 38 ) b , and (CH(R 14 )) c are bonded to E 0 ;
R 14 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
R 37 and R 38 are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
R 38 is optionally selected from the group consisting of aroyl and heteroaroyl;
Y 0 is optionally Q b —Q ss wherein Q ss is (CH(R 14 )) e —W 2 —(CH(R 15 )) h , wherein e and h are integers independently selected from 1 through 2 and W 2 is CR 4a ═CH with the proviso that (CH(R 14 )) e is bonded to E 0 .
3 . The compound as recited in claim 2 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 32 , R 33 , R 34 , R 35 , and R 36 ;
R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q b ;
A is (CH(R 15 )) pa —W 7 wherein pa is an integer selected from 1 through 3 and W 7 is selected from the group consisting of O, S, and N(R 7 ) wherein R 7 is selected from the group consisting of hydrido and alkyl;
R 15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl with the proviso that R 15 is other than hydroxy and halo when R 15 is on the carbon bonded directly to W 7 ;
R 1 is selected from the group consisting of hydrido, alkyl, cyano, halo, and haloalkyl;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of covalent single bond and (CR 41 R 42 ) q wherein q is an integer selected from 1 through 2;
R 41 and R 42 are independently selected from the group consisting of hydrido, hydroxy, and amino;
Q is selected from the group consisting of aryl and heteroaryl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
R 9 , R 10 , R 11 , R 12 , and R 13 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfamido, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and cyano;
K is CHR 4a wherein R 4a is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl;
E 0 is selected from the group consisting of a covalent single bond, C(O)N(H), (H)NC(O), (R 7 )NS(O) 2 , and S(O) 2 N(R 7 );
Y 0 is formula (IV);
wherein D 5 , D 6 , J 5 , and J 6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2 is C, no more than one of D 5 , D 6 , J 5 , and J 6 is O, no more than one of D 5 , D 6 , J 5 and J 6 is S, one of D 5 , D 6 , J 5 and J 6 must be a covalent bond when two of D 5 , D 6 , J 5 , and J 6 are O and S, and no more than four of D 5 , D 6 , J 5 , and J 6 are N;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylamino, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
Q b is selected from the group consisting of NR 20 R 21 , Q be wherein Q be is hydrido, N(R 26 )C(NR 25 )N(R 23 )(R 24 ), and C(NR 25 )NR 23 R 24 , with the provisos that no more than one of R 20 and R 21 is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no more than one of R 23 and R 24 is hydroxy, amino, alkylamino, or dialkylamino at the same time;
R 20 , R 21 , R 23 , R 24 , R 25 , and R 26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino;
Q s is selected from the group consisting of a single covalent bond, (CR 37 R 38 ) b wherein b is an integer selected from 1 through 3, and (CH(R 14 )) c —W 1 —(CH(R 15 ) wherein c and d are integers independently selected from 1 through 2 and W 1 is selected from the group consisting of C(O)N(R 14 ), (R 14 )NC(O), S(O), S(O) 2 , S(O) 2 N(R 14 ), N(R 14 )S(O) 2 , and N(R 14 ), with the provisos that R 14 is selected from other than halo when directly bonded to N and that (CR 37 R 38 ) b , and (CH(R 14 )) c are bonded to E 0 ;
R 14 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
R 37 and R 38 are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
R 38 is optionally selected from the group consisting of aroyl and heteroaroyl;
Y 0 is optionally Q b —Q ss wherein Q ss is (CH(R 14 )) e —W 2 —(CH(R 15 )) h , wherein e and h are integers independently selected from 1 through 2 and W 2 is CR 4a ═CH with the proviso that (CH(R 14 )) e is bonded to E 0 .
4 . The compound as recited in claim 3 having the Formula;
or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of hydrido, trialkylsilyl, C2-C4 alkyl, C3-C5 alkylenyl, C3-C4 alkenyl, C3-C4 alkynyl, and C2-C4 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 3 atoms from the point of attachment of B to A with one or more of the group consisting of R 32 , R 33 , and R 34 ;
R 32 , R 33 , and R 34 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, and cyano;
A is (CH(R 15 )) pa —N(R 7 ) wherein pa is an integer selected from 1 through 2 and R 7 is selected from the group consisting of hydrido and alkyl;
R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
R 1 is selected from the group consisting of hydrido, alkyl, cyano, halo, and haloalkyl;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of covalent single bond and CH 2 ;
Q is selected from the group consisting of aryl and heteroaryl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano;
Y 0 is formula (IV):
wherein D 5 , D 6 , J 5 , and J 6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2 is C, no more than one of D 5 , D 6 , J 5 , and J 6 is O, no more than one of D 5, D 6 , J 5 , and J 6 is S, one of D 5 , D 6 , J 5 , and J 6 must be a covalent bond when two of D 5 , D 6 , J 5 , and J 6 are O and S, and no more than four of D 5 , D 6 , J 5 , and J 6 are N, with the provisos that R 16 , R 17 , R 18 , and R 19 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
Q b is selected from the group consisting of NR 20 R 21 , Q be wherein Q be is hydrido, C(NR 25 )NR 23 R 24 , and N(R 26 )C(NR 25 )N(R 23 )(R 24 ), with the provisos that no more than one of R 20 and R 21 is hydroxy at the same time and that no more than one of R 23 and R 24 is hydroxy at the same time;
R 20 , R 21 , R 23 , R 24 , R 25 , and R 26 are independently selected from the group consisting of hydrido, alkyl, and hydroxy;
Q s is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .
5 . The compound as recited in claim 4 having the Formula or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, trimethylene, tetramethylene, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and 2,2-difluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 3 atoms from the point of attachment of B to A with one or more of the group consisting of R 32 , R 33 , and R 34 ;
R 32 , R 33 , and R 34 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
A is selected from the group consisting of single covalent bond, NH, and N(CH 3 );
R 1 is selected from the group consisting of hydrido, methyl, ethyl, propyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, fluoro, chloro, and bromo;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of a covalent single bond and CH 2 ;
Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4imidazolyl, 3-pyrazolyl, 4pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano;
Y 0 is selected from the group consisting of:
1-Q b -4-Q s -2-R 16 -3-R 17 -5-R 18 -6-R 19 benzene, 2-Q b -5-Q s -6-R 17 -4-R 18 -2-R 19 pyridine, 3-Q b -6-Q s -2-R 16 -5-R 18 -4-R 19 pyridine, 2-Q b -4-Q s -3-R 16 -6-R 18 pyrazine, 3-Q b -2-Q s -2-R 18 -5-R 18- 4-R 19 pridazine, 2-Q b -5-Q s -6-R 17 -4-R 18 pyrimidine, 5-Q b -2-Q s -3-R 16 -6-R 19 pyrimidine, 3-Q b -5-Q s -4-R 16 -2-R 19 thiophene, 2-Q b -5-Q s -3-R 16 -4-R 17 thiophene, 3-Q b -5-Q s -4-R 16 -2-R 19 furan, 2-Q b -5-Q s -4-R 16 -2-R 19 furan, 3-Q b -5-Q s -4-R 16 -2-R 19 pyrrole, 2-Q b -5-Q s -3-R 16 -4-R 16 -4-R 17 pyrrole, 4-Q b -2-Q s -5-R 19 imidazole, 2-Q b -4-Q s -5-R 17 imidazole, 3-Q b -5-Q s -4-R 16 isoxazole, 5-Q b -3-Q s -4-R 16 isoxazole, 2-Q b -5-Q s -4-R 16 pyrazole, 4-Q b -2-Q s -5-R 19 thiazole, and 2-Q b -5-Q s -4-R 17 thiazole;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1hydroxyethyl, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
Q b is selected from the group consisting of NR 20 R 21 , Q be wherein Q be is hydrido, C(NR 25 )NR 23 R 24 , and N(R 26 )C(NR 25 )N(R 23 )(R 24 ), with the provisos that no more than one of R 20 , R 21 , R 23 , and R 24 can be hydroxy, when any two of the group consisting of R 20 , R 21 , R 23 , and R 24 are bonded to the same atom and that said Q b group is bonded directly to a carbon atom;
R 20 , R 21 , R 23 , R 24 , R 25 , and R 26 are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy;
Q s is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .
6 . The compound as recited in claim 4 having the Formula:
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from the group consisting of CH 2 N(CH 3 ), CH 2 N(CH 2 CH 3 ), CH 2 CH 2 N(CH 3 ), and CH 2 CH 2 N(CH 2 CH 3 );
R 1 is selected from the group consisting of hydrido, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, and bromo;
R 2 is Z 0—Q;
Z 0 is selected from the group consisting of covalent single bond and CH 2 ;
Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano;
Y 0 is selected from the group consisting of:
1-Q b -4-Q s -2-R 16 -3-R 17 -5-R 18 -6-R 19 benzene, 2-Q b -5-Q s -6-R 17 -4-R 18 -2-R 19 pyridine, 3-Q b -6-Q s -2-R 16 -5-R 18 -4-R 19 pyridine, 2-Q b -4-Q s -3-R 16 -6-R 18 pyrazine, 3-Q b -6-Q s -2-R 18 -5-R 18 -4-R 19 pyridazine, 2-Q b -5-Q s -6-R 17 -4-R 18 pyrimidine, 5-Q b -2-Q s -3-R 16 -6-R 19 pyrimidine, 3-Q b -5-Q s -4-R 16 -2-R 19 thiophene, 2-Q b -5-Q s -3-R 16 -4-R 17 thiophene, 3-Q b -5-Q s -4-R 16 -2-R 19 furan, 2-Q b -5-Q s -3-R 16 -4-R 17 furan, 3-Q b -5-Q s -4-R 16 -2-R 19 pyrrole, 2-Q b -5-Q s -3-R 16 -4-R 17 pyrrole, 4-Q b -2-Q s -5-R 19 imidazole, 2-Q b -4-Q s -5-R 17 imidazole, 3-Q b -5-Q s -4-R 16 isoxazole, 5-Q b -3-Q s -4-R 16 isoxazole, 2-Q b -5-Q s -4-R 16 pyrazole, 4-Q b -2-Q s -5-R 19 thiazole, and 2-Q b -5-Q s -4-R 17 thiazole;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, and cyano;
Q b is selected from the group consisting of NR 20 R 21 , C(NR 25 )NR 23 R 24 , and N(R 26 )C(NR 25 )N(R 23 )(R 24 ), with the provisos that no more than one of R 20 , R 21 , R 23 , and R 24 can be hydroxy, when any two of the group consisting of R 20 , R 21 , R 23 , and R 24 are bonded to the same atom and that said Q b group is bonded directly to a carbon atom;
R 20 , R 21 , R 23 , R 24 , R 25 , and R 26 are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy;
Q s is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .
7 . The compound as recited in claim 6 or a pharmaceutically acceptable salt thereof, wherein;
A is selected from the group consisting of CH 2 N(CH 3 ), CH 2 N(CH 2 CH 3 ), CH 2 CH 2 N(CH 3 ), and CH 2 CH 2 N(CH 2 CH 3 );
R 1 is selected from the group consisting of hydrido, methyl, ethyl, propyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, and bromo;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of covalent single bond and CH 2 ;
Q is selected from the group consisting of 5amino-3-amidocarbonylphenyl, 5amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxy-5-aminophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-hydroxyphenyl, 3hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4pyridyl, 2-thienyl, and 3-thienyl;
Y 0 is selected from the group consisting of:
1-Q b -4-Q s -2-R 16 -3-R 17 -5-R 18 -6-R 19 benzene, 2-Q b -5-Q s -6-R 17 -4-R 18 -2-R 19 pyridine, 3-Q b -6-Q s -2-R 16 -5-R 18 -4-R 19 pyridine, 3-Q b -5-Q s -4-R 16 -2-R 19 thiophene, and 2-Q b -5-Q s -3-R 16 -4-R 17 thiophene;
R 16 and R 19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
Q b is selected from the group consisting of Q be wherein Q be is hydrido and C(NR 25 )NR 23 R 24 ;
R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido and methyl;
Q s is CH 2 .
8 . A compound as recited in claim 7 or a pharmaceutically acceptable salt thereof where said compound is selected from the group consisting of:
6-[3-aminophenyl]-chloro-N-[[4-iminomethylphenyl]methyl]-3-[N,N-dimethylhydrazino]-2-oxo-1(2H)-pyrazineacetamide;
6-[3-aminophenyl]-5chloro-3-[N-ethyl-N-methylhydrazino]-N-[[4-iminomethylphenyl]methyl]-2-oxo-1(2H)-pyrazineacetamide;
6-[3-aminophenyl]-chloro-3-[N,N-diethylhydrazino]-N-[[4-iminomethylphenyl]methyl]-2-oxo-1(2H)-pyrazineacetamide;
6-[3-aminophenyl]-3-[N-(azetidin-1-yl)amino]-chloro-N-[[4-iminomethylphenyl]methyl]-2-oxo-1(2H)-pyrazineacetamide.
9 . The compound as recited in claim 2 having the Formula:
or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 32 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 36 , a carbon adjacent to R 32 and two atoms from the carbon at the point of attachment is optionally substituted by R 33 , a carbon adjacent to R 36 and two atoms from the carbon at the point of attachment is optionally substituted by R 35 and any carbon adjacent to both R 33 and R 35 is optionally substituted by R 34 ;
R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q b ;
A is selected from the group consisting of single covalent bond and (CH(R 15 )) pa —(W 7 ) rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is selected from the group consisting of (R 7 )NC(O) and N(R 7 );
R 7 is selected from the group consisting of hydrido, hydroxy and alkyl;
R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
R 1 is selected from the group consisting of hydrido, alkyl, cyano, haloalkyl, and halo;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of covalent single bond and CH 2 ;
Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano;
Y 0 is formula (IV):
wherein D 5 , D 6 , J 5 , and J 6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2 is C, no more than one of D 5 , D 6 , J 5 , and J 6 is O, no more than one of D 5 , D 6 , J 5 , and J 6 is S, one of D 5 , D 6 , J 5 , and J 6 must be a covalent bond when two of D 5 , D 6 , J 5 , and J 6 are O and S, and no more than four of D 5 , D 6 , J 5 , and J 6 are N;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
Q b is selected from the group consisting of NR 20 R 21 , Q be wherein Q be is hydrido, and C(NR 25 )NR 23 R 24 , with the provisos that no more than one of R 20 and R 21 is hydroxy at the same time and that no more than one of R 23 and R 24 is hydroxy at the same time;
R 20 , R 21 , R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido, alkyl, and hydroxy;
Q s is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .
10 . The compound as recited in claim 9 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4imidazolyl, 3-pyrazolyl, 4pyrazolyl, 2-thiazolyl, 3-isoxazoly, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl 2-pyrimidinyl, 4pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 32 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 36 , a carbon adjacent to R 32 and two atoms from the carbon at the point of attachment is optionally substituted by R 33 , a carbon adjacent to R 36 and two atoms from the carbon at the point of attachment is optionally substituted by R 35 , and any carbon adjacent to both R 33 and R 35 is optionally substituted by R 34 ;
R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Q b ;
A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), N(OH), CH 2 , CH 3 CH, CF 3 CH, NHC(O), N(CH 3 )C(O), C(O)NH, C(O)N(CH 3 ), CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 3 CHCH 2 , and CF 3 CHCH 2 ;
R 1 is selected from the group consisting of hydrido, methyl, ethyl, propyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, fluoro, chloro, and bromo;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of covalent single bond and CH 2 ;
Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4imidazolyl, 3-pyrazolyl, 4pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano;
Y 0 is selected from the group consisting of:
1-Q b -4-Q s -2-R 16 -3-R 17 -5-R 18 -6-R 19 benzene, 2-Q b -5-Q s -6-R 17 -4-R 18 -2-R 19 pyridine, 3-Q b -6-Q s -2-R 16 -5-R 18 -4-R 19 pyridine, 2-Q b -4-Q s -3-R 16 -6-R 18 pyrazine, 3-Q b -6-Q s -2-R 18 -5-R 18 -4-R 19 pyridazine, 2-Q b -5-Q s -6-R 17 -4-R 18 pyrimidine, 5-Q b -2-Q s -3-R 16 -6-R 19 pyrimidine, 3-Q b -5-Q s -4-R 16 -2-R 19 thiophene, 2-Q b -5-Q s -4-R 16 -4-R 17 thiophene, 3-Q b -5-Q s -4-R 16 -2-R 19 furan, 2-Q b -5-Q s -3-R 16 -4-R 17 furan, 3-Q b -5-Q s -4-R 16 -2-R 19 pyrrole, 2-Q b -5-Q s -3-R 16 -4-R 17 pyrrole, 4-Q b -2-Q s -5-R 19 imidazole, 2-Q b -4-Q s -5-R 17 imidazole, 3-Q b -5-Q s -4-R 16 isoxazole, 5-Q b -3-Q s -3-R 16 isoxazole, 2-Q b -5-Q s -4-R 16 pyrazole, 4-Q b -2-Q s -5-R 19 thiazole, and 2-Q b -5-Q s -4-R 17 thiazole;
R 16 , R 17 , R 18 and R 19 are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminomethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
Q b is selected from the group consisting of Q be wherein Q be is hydrido and C(NR 25 )NR 23 R 24 , with the proviso that no more than one of R 23 and R 24 is hydroxy at the same time;
R 23 , R 24 ,and R 25 are independently selected from the group consisting of hydrido, methyl, ethyl, and hydroxy;
Q s is selected from the group consisting of a single covalent bond, CH 2 and CH 2 CH 2 .
11 . The compound as recited in claim 10 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of 2-aminophenyl, 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3carboxy-5-hydroxyphenyl, 3-chlorophenyl, 4chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl, 3-pyridyl, 5-chloro-3-trifluoromethyl-2-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, and 3-trifluoromethyl-2-pyridyl;
A is selected from the group consisting of CH 2 , CH 3 CH, CF 3 CH, NHC(O), CH 2 CH 2 , and CH 2 CH 2 CH 2 ;
R 1 is selected from the group consisting of hydrido, methyl, ethyl, propyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, and bromo;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of covalent single bond and CH 2 ;
Q is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; p 1 Y 0 is selected from the group consisting of:
1-Q b -4-Q s -2-R 16 -3-R 17 -5-R 18 -6-R 19 benzene, 2-Q b -5-Q s -6-R 17 -4-R 18 -2-R 19 pyridine, 3-Q b -6-Q s -2-R 16 -5-R 18 -4-R 19 pyridine, 3-Q b -5-Q s -4-R 16 -2-R 19 thiophene, and 2-Q b -5-Q s -3-R 16 -4-R 17 thiophene;
R 16 and R 19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
Q b is selected from the group consisting of Q be wherein Q be is hydrido and C(NR 25 )NR 23 R 24 ;
R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido and methyl;
Q s is CH 2 .
12 . The compound as recited in claim 9 having the Formula:
or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 32 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 36 , a carbon adjacent to R 32 and two atoms from the carbon at the point of attachment is optionally substituted by R 23 , a carbon adjacent to R 36 and two atoms from the carbon at the point of attachment is optionally substituted by R 35 , and any carbon adjacent to both R 33 and R 35 is optionally substituted by R 34 ;
R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q b ;
A is selected from the group consisting of single covalent bond and (CH(R 15 )) pa —(W 7 ) rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is N(R 7 );
R 7 is selected from the group consisting of hydrido and alkyl;
R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
R 1 is selected from the group consisting of hydrido, cyano, haloalkyl, and halo;
R 2 is Z 0 —Q;
Z 0 is a covalent single bond;
Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano;
Y 0 is formula (IV):
wherein D 5 , D 6 , J 5 , and J 6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2 is C, no more than one of D 5 , D 6 , J 5 , and J 6 is O, Do more than one of D 5 , D 6 , J 5 , and J 6 is S, one of D 5 , D 6 , J 5 , and J 6 must be a covalent bond when two of D 5 , D 6 , J 5 , and J 6 are O and S, and no more than four of D 5 , D 6 , J 5 , and J 6 are N;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
Q b is selected from the group consisting of NR 20 R 21 , Q be wherein Q be is hydrido, and C(NR 25 )NR 23 R 24 ;
R 20 , R 21 , R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido and alkyl;
Q s is CH 2 .
13 . The compound as recited in claim 12 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, and 5-isoxazolyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 32 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 36 , a carbon adjacent to R 32 and two atoms from the carbon at the point of attachment is optionally substituted by R 33 , a carbon adjacent to R 36 and two atoms from the carbon at the point of attachment is optionally substituted by R 35 , and any carbon adjacent to both R 33 and R 35 is optionally substituted by R 34 ;
R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q b ;
A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), CH 2 , CH 3 CH, and CH 2 CH 2 ;
R 1 is selected from the group consisting of hydrido, trifluoromethyl, pentafluoroethyl, fluoro, and chloro;
R 2 is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano;
Y 0 is selected from the group consisting of:
1-Q b -4-Q s -2-R 16 -3-R 17 -5-R 18 -6-R 19 benzene, 2-Q b -5-Q s -6-R 17 -4-R 18 -2-R 19 pyridine, 2-Q b -5-Q s -3-R 16 -4-R 17 thiophene, 3-Q b -6-Q s -2-R 16 -5-R 18 -4-R 19 pyridine, 3-Q b -5-Q s -4-R 16 -2-R 19 thiophene, 3-Q b -5-Q s -4-R 16 -2-R 19 furan, 2-Q b -5-Q s -3-R 16 -4-R 17 furan, 3-Q b -5-Q s -R 18 -4-R 16 -2-R 19 pyrrole, 2-Q b -5-Q s -3-R 16 -4-R 17 pyrrole, 4-Q b -2-Q s -5-R 19 thiazole, and 2-Q b -5-Q s -4-R 17 thiazole;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano,
Q b is selected from the group consisting of NR 20 R 21 and
C(NR 25 )NR 23 R 24 , with the proviso that said Q b group is bonded directly to a carbon atom;
R 20 , R 21 , R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido, methyl, and ethyl;
Q s is CH 2 .
14 . The compound as recited in claim 13 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of 2-aminophenyl, 3aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3carboxy-5-hydroxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl, 5-chloro-3-trifluoromethyl-2-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, and 3-trifluoromethyl-2-pyridyl;
A is selected from the group consisting of CH 2 , CH 3 CH, CF 3 CH, NHC(O), CH 2 CH 2 , and CH 2 CH 2 CH 2 ;
R 1 is selected from the croup consisting of hydrido, trifluoromethyl, pentafluoroethyl, fluoro, and chloro;
R 2 is selected from the group consisting of 5amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5hydroxymethylphenyl, 5-amino3-methoxycarbonylphenyl, 3-aminophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
Y 0 is selected from the group consisting of:
1-Q b -4-Q s -2-R 16 -3-R 17 -5-R 18 -6-R 19 benzene, 2-Q b -5-Q s -6-R 17 -4-R 18 -2-R 19 pyridine, 3-Q b -6-Q s -2-R 16 -5-R 18 -1-R 19 pyridine, 3-Q b -5-Q s -4-R 16 -2-R 19 thiophene, and 2-Q b -5-Q s -3-R 16 -4-R 17 thiophene;
R 16 and R 19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
Q b is selected from the group consisting of Q be wherein Q be is hydrido and C(NR 25 )NR 23 R 24 ;
R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido and methyl;
Q s is CH 2 .
15 . The compound as recited in claim 14 or a pharmaceutically acceptable salt thereof, wherein:
B is selected from the group consisting of 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 4-methylphenyl, phenyl, 2-imidazoyl, 3-pyridyl, 4-pyridyl, and 3-trifluoromethyl-2-pyridyl;
A is selected from the group consisting of CH 2 , NHC(O), CH 2 CH 2 , and CH 2 CH 2 CH 2 ;
R 1 is selected from the group consisting of hydrido and chloro;
R 2 is selected from the group consisting of 3-aminophenyl, benzyl, 3-chlorophenyl, 3-dimethylaminophenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 3-methylaminophenyl, 2-methyl phenyl, 3-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-bromo-2-thienyl, 2-thienyl, and 3-thienyl;
Y 0 is selected from the group consisting of 5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amdinobenzyl.
16 . A compound as recited in claim 9 where said compound is selected from the group having the Formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is 3-aminophenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is phenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is phenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 2-imidazoyl, A is CH 2 CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-dimethylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 2-methylphenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is phenyl, B is 3-aminophenyl, A is C(O)NH, Y 0 is 4-amidinobenzyl, and R 1 is hydrido;
R 2 is phenyl, B is 3-amidinophenyl, A is CH 2 , Y 0 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-(N-methylamino)phenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-thienyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-methylsulfonamidophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is phenyl, B is 4-amidinophenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-methylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is hydrido;
R 2 is phenyl, B is phenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is phenyl, B is 4-pyridyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is phenyl, B is 3-pyridyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-chlorophenyl, B is 4-pyridyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-methylphenyl, B is 4-phenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is hydrido;
R 2 is 3-thienyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro.
17 . The compound as recited in claim 2 having the Formula:
or a pharmaceutically acceptable salt thereof, wherein:
B is selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 32 , R 33 , R 34 , R 35 , and R 36 ;
R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q b ;
A is selected from the group consisting of single covalent bond and (CH(R 15 )) pa —(W 7 ) rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is selected from the group consisting of (R 7 )NC(O) and N(R 7 );
R 7 is selected from the group consisting of hydrido, hydroxy and alkyl;
R 15 is selected from the croup consisting of hydrido, halo, alkyl, and haloalkyl;
R 1 is selected from the group consisting of hydrido, alkyl, cyano, haloalkyl, and halo;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of covalent single bond and CH 2 ;
Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano;
Y 0 is formula (IV):
wherein D 5 , D 6 , J 5 , and J 6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2 is C, no more than one of D 5 , D 6 , J 5 , and J 6 is O, no more than one of D 5 , D 6 , J 5 , and J 6 is S, one of D 5 , D 6 , J 5 , and J 6 must be a covalent bond when two of D 5 , D 6 , J 5 , and J 6 are O and S, and no more than four of D 5 , D 6 , J 5 , and J 6 are N;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
Q b is selected from the group consisting of NR 20 R 21 , Q be wherein Q be is hydrido, C(NR 25 )NR 23 R 24 and N(R 26 )C(NR 25 )N(R 23 )(R 24 ), with the provisos that DO more than one of R 20 and R 21 is hydroxy at the same time and that no more than none of R 23 and R 24 is hydroxy at the same time;
R 20 , R 21 , R 23 , R 24 , R 25 , and R 26 are independently selected from the group consisting of hydrido, alkyl, and hydroxy;
Q s is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .
18 . The compound as recited in claim 17 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of hydrido, ethyl, 2-propynyl, 2-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butenyl, 3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methyl butyl, 3methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexenyl, 3-hexenyl, 4hexenyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more of the group consisting of R 32 , R 33 , R 34 , R 35 , and R 36 ;
R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of hydrido, amidino, guanidino , carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Q b ;
A is selected from the croup consisting of single covalent bond, NH, N(CH 3 ), N(OH), CH 2 , CH 3 CH, CF 3 CH, NHC(O), N(CH 3 )C(O), C(O)NH, C(O)N(CH 3 ) CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 3 CHCH 2 , and CF 3 CHCH 2 ;
R 1 is selected from the group consisting of hydrido, methyl, ethyl, propyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, fluoro, chloro, and bromo;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of covalent single bond and CH 2 ;
Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano;
Y 0 is selected from the group consisting of:
1-Q b -4-Q s -2-R 16 -3-R 17 -5-R 18 -6-R 19 benzene, 2-Q b -5-Q s -6-R 17 -4-R 18 -2-R 19 pyridine, 3-Q b -6-Q s -2-R 16 -5-R 18 -4-R 19 pyridine, 2-Q b -4-Q s -3-R 16 -6-R 18 pyrazine, 3-Q b -6-Q s -2-R 18 -5-R 18 -4-R 19 pyridazine, 2-Q b -5-Q s -6-R 17 -4-R 18 pyrimidine, 5-Q b -2-Q s -3-R 16 -6-R 19 pyrimidine, 3-Q b -5-Q s -4-R 16 -2-R 19 thiophene, 2-Q b -5-Q s -3-R 16 -4-R 17 thiophene, 3-Q b -5-4-Q s -4-R 16 -2-R 19 furan, 2-Q b -5-Q s -3-R 16 -4-R 17 furan, 3-Q b -5-Q s -4-R 16 -2-R 19 pyrrole, 2-Q b -5-Q s -3-R 16 -4-R 17 pyrrole, 4-Q b -2-Q s -5-R 19 imidazole, 2-Q b -4-Q s -5-R 17 imidazole, 3-Q b -5-Q s -4-R 16 isoxazole, 5-Q b -3-Q s -4-R 16 isoxazole, 2-Q b -5-Q s -4-R 16 pyazole, 4-Q b -2-Q s -5-R 19 thiazole, and 2-Q b -5-Q s -4-R 17 thiazole;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
Q b is selected from the group consisting of NR 20 R 21 , Q be , wherein Q be is hydrido, C(NR 25 )NR 23 R 24 , and N(R 26 )C(NR 25 )N(R 23 )(R 24 ), with the provisos that no more than one of R 20 and R 21 is hydroxy at the same time and that no more than one of R 23 and R 24 is hydroxy at the same time;
R 20 , R 21 , R 23 , R 24 , R 25 , and R 26 are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy;
Q s is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .
19 . The compound as recited in claim 18 or a pharmaceutically acceptable salt thereof, wherein:
B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl, (S)-2-butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2-dimethylaminophenyl, 2-cyanoethyl, 6hydroxyhexyl, 2-hydroxyethyl, 2-amidinophenyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl, 4hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-animobutyl;
A is selected from the group consisting of single covalent bond, CH 2 , NHC(O), CH 2 CH 2 , CH 2 CH 2 CH 2 , and CH 3 CHCH 2 ;
R 1 is selected from the group consisting of hydrido, methyl, ethyl, propyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, and bromo;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of covalent single bond and CH 2 ;
Q is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylyaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
Y 0 is selected from the group consisting of:
1-Q b -4-Q s -2-R 16 -3-R 17 -5-R 18 -6-R 19 benzene, 2-Q b -5-Q s -6-R 17 -1-R 18 -2-R 19 pyridine, 3-Q b -6-Q s -2-R 16 -5-R 18 -4-R 19 pyridine, 3-Q b -5-Q s -4-R 16 -2-R 19 thiophene, and 2-Q b -5-Q s -3-R 16 -4-R 17 thiophene;
R 16 and R 19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
Q b is selected from the group consisting of Q be wherein Q be is hydrido and C(NR 25 )NR 23 R 24 ;
R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido and methyl;
Q s is CH 2 .
20 . The compound as recited in claim 17 having the Formula:
or a pharmaceutically acceptable salt thereof, wherein:
B is selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 32 , R 33 , R 34 , R 35 , and R 36 ;
R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q b ;
A is selected from the group consisting of single covalent bond and (CH(R 15 )) pa —(W 7 ) rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is N(R 7 );
R 7 is selected from the group consisting of hydrido and alkyl;
R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalky;
R 1 is selected from the group consisting of hydrido, cyano, haloalkyl, and halo;
R 2 is Z 0 —Q;
Z 0 is a covalent single bond;
Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano;
Y 0 is formula (IV):
wherein D 5 , D 6 , J 5 and J 6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2 is C, no more than one of D 5 , D 6 , J 5 , and J 6 is O, no more than one of D 5 , D 6 , J 5 , and J 6 is S, one of D 5 , D 6 , J 5 , and J 6 must be a covalent bond when two of D 5 , D 6 , J 5 , and J 6 are O and S, and no more than four of D 5 , D 6 , J 5 , and J 6 are N;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
Q b is selected from the group consisting of NR 20 R 21 , Q be wherein Q be is hydrido, N(R 26 )C(NR 25 )N(R 23 )(R 24 ), and C(NR 25 )NR 23 R 24 ;
R 20 , R 21 , R 23 , R 24 , R 25 , and R 26 are independently selected from the group consisting of hydrido and alkyl;
Q s is CH 2 .
21 . The compound as recited in claim 17 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 2-methyl-2-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-3-hexenyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more of the group consisting of R 32 , R 33 , R 34 , R 35 , and R 36 ;
R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q b ;
A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), CH 2 , CH 3 CH, and CH 2 CH 2 ;
A is optionally selected from the group consisting of CH 2 N(CH 3 ), CH 2 N(CH 2 CH 3 ), CH 2 CH 2 N(CH 3 ), and CH 2 CH 2 N(CH 2 CH 3 ) with the proviso that B is hydrido;
R 1 is selected from the group consisting of hydrido, trifluoromethyl, pentafluoroethyl, fluoro, and chloro,
R 2 is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano;
Y 0 is selected from the group consisting of:
1-Q b -4-Q s -2-R 16 -3-R 17 -5-R 18 -6-R 19 benzene, 2-Q b -5-Q s -6-R 17 -4-R 18 -2-R 19 pyridine, 2-Q b -5-Q s -3-R 16 -4-R 17 thiophene, 3-Q b -6-Q s -2-R 16 -5-R 18 -4-R 19 pyridine, 3-Q b -5-Q s -4-R 16 -2-R 19 thiophene, 3-Q b -5-Q s -4-R 16 -2-R 19 furan, 2-Q b -5-Q s -3-R 16 -4-R 17 furan, 3-Q b -5-Q s -4-R 16 -2-R 19 pyrrole, 2-Q b -5-Q s -3-R 16 -4-R 17 pyrrole, 4-Q b -2-Q s -5-R 19 thiazole, and 2-Q b -5-Q s -4-R 17 thiazole;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano;
Q b is selected from the group consisting of NR 20 R 21 , C(NR 25 )NR 23 R 24 , and N(R 26 )C(NR 25 )N(R 23 )(R 24 ), with the proviso that said Q b group is bonded directly to a carbon atom;
R 20 , R 21 , R 23 , R 24 , R 25 , and R 26 are independently selected from the group consisting of hydrido, methyl, and ethyl;
Q s is CH 2 .
22 . The compound as recited in claim 21 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of hydrido,ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl, (S)-2-butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinophenyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4aminobutyl;
A is selected from the group consisting of single covalent bond, CH 2 , CH 3 CH, and CH 2 CH 2 ;
R 1 is selected from the group consisting of hydrido, trifluoromethyl, fluoro, and chloro;
R 2 is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methyl phenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylyaminophenyl, 2-methoxy,phenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
Y 0 is selected from the group consisting of:
1-Q b -4-Q s -2-R 16 -3-R 17 -5-R 18 -6-R 19 benzene, 2-Q b -5-Q s -6-R 17 -4-R 18 -2-R 19 pyridine, 3-Q b -6-Q s -2-R 16 -5-R 18 -4-R 19 pyridine, 3-Q b -5-Q s -4-R 16 -2-R 19 thiophene, and 2-Q b -5-Q s -3-R 16 -4-R 17 thiophene;
R 16 and R 19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
Q b is selected from the group consisting of Q be wherein Q be is hydrido and C(NR 25 )NR 23 R 24 ;
R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido and methyl;
Q s is CH 2 .
23 . The compound as recited in claim 22 or a pharmaceutically acceptable salt thereof, wherein:
B is selected from the group consisting of hydrido,ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl, (S)-2-butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinophenyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl;
A is selected from the group consisting of single covalent bond, CH 2 , CH 3 CH, and CH 2 CH 2 ;
R 1 is selected from the group consisting of hydrido and chloro;
R 2 is selected from the group consisting of 5-amino-2-fluorophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, 3-carboxyphenyl, 3-cyanophenyl, 3-methoxycarbonylphenyl, phenyl, and 3-pyridyl;
Y 0 is selected from the group consisting of 5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro4-amidinobenzyl, and 3-fluoro-4-amidinobenzyl.
24 . A compound as recited in claim 17 where said compound is selected from the group having the Formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is (S)-2-butyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 5-amino-2-fluorophenyl, B is isopropyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 2-methyl-3-aminophenyl, B is isopropyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is ethyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is ethyl, A is single bond, Y 0 is 4-amidino-2-fluorobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 2-propenyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is isopropyl, A is single bond, Y 0 is 4-amidino-2-fluorobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is isopropyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 2-butyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is (R)-2-butyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 2-propynyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 3-pentyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is hydrido;
R 2 is 3-aminophenyl, B is hydrido, A is CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is ethyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 2-methypropyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 2-propyl, A is CH 3 CH, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is propyl, A is single bond, Y 0 is 4-amidino-2-fluorobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 6-amidocarbonylhexyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is hydrido;
R 2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 3-hydroxypropyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 2-methylpropyl, A is single bond, Y 0 is 4-amidino-2-fluorobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is butyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 2-methoxy-2-ethyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 5-amidino-2-thienylmethyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 4-amidino-3-2-fluorobenzyl, and R 1 is hydrido;
R 2 is 3-carboxyphenyl, B is 2-propyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is hydrido;
R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 4-amidino-3-fluorobenzyl, and R 1 is chloro.
25 . The compound as recited in claim 2 having the Formula:
or a pharmaceutically acceptable salt thereof, wherein:
B is selected from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally substituted with R 33 , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R 9 or R 13 , a ring carbon or nitrogen adjacent to the R 9 position and two atoms from the point of attachment is optionally substituted with R 10 , a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of attachment is optionally substituted with R 12 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 10 position is optionally substituted with R 11 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 12 position is optionally substituted with R 33 , and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the R 11 and R 33 positions is optionally substituted with R 34 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano;
R 33 and R 34 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q b ;
A is selected from the group consisting of single covalent bond and (CH(R 15 )) pa —(W 7 ) rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is selected from the group consisting of (R 7 )NC(O) and N(R 7 );
R 7 is selected from the group consisting of hydrido, hydroxy and alkyl;
R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
R 1 is selected from the group consisting of hydrido, alkyl, cyano, haloalkyl, and halo;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of covalent single bond and CH 2 ;
Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
Y 0 is formula (IV):
wherein D 5 , D 6 , J 5 , and J 6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2 is C, no more than one of D 5 , D 6 , J 5 , and J 6 is O, no more than one of D 5 , D 6 , J 5 , and J 6 is S, one of D 5 , D 6 , J 5 , and J 6 must be a covalent bond when two of D 5 , D 6 , J 5 , and J 6 are O and S, and no more than four of D 5 , D 6 , J 5 , and J 6 are N;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
Q b is selected from the group consisting of NR 20 R 21 , Q be wherein Q be is hydrido, and C(NR 25 )NR 23 R 24 , with the provisos that no more than one of R 20 and R 21 is hydroxy at the same time and that no more than one of R 23 and R 24 is hydroxy at the same time;
R 20 , R 21 , R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido, alkyl, and hydroxy;
Q s is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .
26 . The compound as recited in claim 25 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, norbornyl, 7-oxabicyclo[2,2,1]heptan-2-yl, bicyclo[3,1,0]hexan-6-yl, cycloheptyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon is optionally substituted with R 33 , ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R 9 or R 13 , a ring carbon or nitrogen adjacent to the R 9 position and two atoms from the point of attachment is optionally substituted with R 10 , and a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of attachment is optionally substituted with R 12 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthlio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano;
R 33 is selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Q b ;
A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), N(OH), CH 2 , CH 3 CH, CF 3 CH, NHC(O), N(CH 3 )C(O), C(O)NH, C(O)N(CH 3 ), CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 3 CHCH 2 , and CF 3 CHCH 2 ;
R 1 is selected from the group consisting of hydrido, methyl, ethyl, propyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, fluoro, chloro, and bromo;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of covalent single bond and CH 2 :
Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
Y 0 is selected from the group consisting of:
1-Q b -4-Q s -2-R 16 -3-R 17 -5-R 18 -6-R 19 benzene, 2-Q b -5-Q s -6-R 17 -4-R 18 -2-R 19 pyridine, 3-Q b -6-Q s -2-R 16 -5-R 18 -4-R 19 pyridine, 2-Q b -4-Q s -3-R 16 -6-R 18 pyrazine, 3-Q b -6-Q s -2-R 18 -5-R 18 -4-R 19 pyridazine, 2-Q b -5-Q s -6-R 17 -4-R 18 pyrimidine, 5-Q b -2-Q s -3-R 16 -6-R 19 pyrimidine, 3-Q b -5-Q s -4-R 16 -2-R 19 thiophene, 2-Q b -5-Q s -3-R 16 -4-R 17 thiophene, 3-Q b -5-Q s -4-R 16 -2-R 19 furan, 2-Q b -5-Q s -3-R 16 -4-R 17 furan, 3-Q b -5-Q s -4-R 16 -2-R 19 pyrrole, 2-Q b -5-Q s -3-R 16 -4-R 17 pyrrole, 4-Q b -2-Q s -5-R 19 imidazole, 2-Q b -4-Q s -5-R 17 imidazole, 3-Q b -5-Q s -4-R 16 isoxazole, 5-Q b -3-Q s -4-R 16 isoxazole, 2-Q b -5-Q s -4-R 16 pyrazole, 4-Q b -2-Q s -5-R 19 thiazole, and 2-Q b -5-Q s -4-R 17 thiazole;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl , 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
Q b is selected from the croup consisting of Q be wherein Q be is hydrido and C(NR 25 )NR 23 R 24 , with the proviso that no more than one of R 23 and R 24 is hydroxy at the same time;
R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido, methyl, ethyl, and hydroxy;
Q s is selected from the group consisting of a single covalent bond, CH 2 and CH 2 CH 2 .
27 . The compound as recited in claim 26 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxalan-2-yl, 2-(2R)-bicyclo[2,2,1]-heptyl, 1-pyrrolidinyl, 1-piperidinyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 7-oxabicyclo[2,2,1]heptan-2-yl, bicyclo[3,1,0]hexan-6-yl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl;
A is selected from the group consisting of single covalent bond, CH 2 , NHC(O), CH 2 CH 2 , and CH 2 CH 2 CH 2 ;
R 1 is selected from the group consisting of hydrido, methyl, ethyl, propyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, and bromo;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of covalent single bond and CH 2 ;
Q is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifuoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
Y 0 is selected from the group consisting of:
1-Q b -4-Q s -2-R 16 -3-R 17 -5-R 18 -6-R 19 benzene, 2-Q b -5-Q s -6-R 17 -4-R 18 -2-R 19 pyridine, 3-Q b -6-Q s -2-R 16 -5-R 18 -4-R 19 pyridine, 3-Q b -5-Q s -4-R 16 -2-R 19 thiophene, and 2-Q b -5-Q s -3-R 16 -4-R 17 thiophene;
R 16 and R 19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
Q b is selected from the group consisting of Q be wherein Q be is hydrido and C(NR 25 )NR 23 R 24 ;
R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido and methyl;
Q s is CH 2 .
28 . The compound as recited in claim 25 having the Formula:
or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting, of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally substituted with R 33 , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R 9 or R 13 , a ring carbon or nitrogen adjacent to the R 9 position and two atoms from the point of attachment is optionally substituted with R 10 , a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of attachment is optionally substituted with R 12 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 10 position is optionally substituted with R 11 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 12 position is optionally substituted with R 33 , and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the R 11 and R 33 positions is optionally substituted with R 34 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano;
R 33 and R 34 are independently selected from the group consisting of hydrido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, and cyano;
R 33 is optionally Q b ;
A is selected from the group consisting of single covalent bond and (CH(R 15 )) pa —(W 7 ) rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is N(R 7 );
R 7 is selected from the group consisting of hydrido and alkyl;
R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
R 1 is selected from the group consisting of hydrido, cyano, haloalkyl, and halo;
R 2 is Z 0 —Q;
Z 0 is a covalent single bond:
Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano;
Y 0 is formula (IV):
wherein D 5 , D 6 , J 5 , and J 6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2 is C, no more than one of D 5 , D 6 , J 5 , and J 6 is O, no more than one of D 5 , D 6 , J 5 , and J 6 is S, one of D 5 , D 6 , J 5 , and J 6 must be a covalent bond when two of D 5 , D 6 , J 5 , and J 6 are O and S, and no more than four of D 5 , D 6 , J 5 , and J 6 are N;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
Q b is selected from the group consisting of NR 20 R 21 , Q be wherein Q be is hydrido, and C(NR 25 )NR 23 R 24 ;
R 20 , R 21 , R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido and alkyl;
Q s is CH 2 .
29 . The compound as recited in claim 28 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxalan-2-yl, 2-(2R)-bicyclo[2,2,1]-heptyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, bicyclo[3,1,0]hexan-6-yl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon is optionally substituted with R 33 , ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R 9 or R 13 , a ring carbon or nitrogen adjacent to the R 9 position and two atoms from the point of attachment are optionally substituted with R 10 , and a ring carbon or nitrogen atom adjacent to the R 13 position and two atoms from the point of attachment is optionally substituted with R 12 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano;
R 33 is selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, carboxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, cyano, and Q b ;
A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), CH 2 , CH 3 CH, CH 2 CH 2 , and CH 2 CH 2 CH 2 ;
R 1 is selected from the group consisting of hydrido, trifluoromethyl, pentafluoroethyl, fluoro, and chloro;
R 2 is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
Y 0 is selected from the group consisting of:
1-Q b -4-Q s -2-R 16 -3-R 17 -5-R 18 -6-R 19 benzene, 2-Q b -5-Q s -6-R 17 -4-R 18 -2-R 19 pyridine, 2-Q b -5-Q s -3-R 16 -4-R 17 thiophene, 3-Q b -6-Q s -2-R 16 -5-R 18- 4-R 19 pyridine, 3-Q b -5-Q s -4-R 16 -2-R 19 thiophene, 3-Q b -5-Q s -4-R 16 -2-R 19 furan, 2-Q b -5-Q s -3-R 16 -4-R 17 furan, 3-Q b -5-Q s -4-R 16 -2-R9pyrrole, 2-Q b -5-Q s -3-R 16 -4-R 17 pyrrole, 4-Q b -2-Q s -5-R 19 thiazole, and 2-Q b -5-Q s -4-R 17 thiazole;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano,
Q b is selected from the group consisting of NR 20 R 21 and C(NR 25 )NR 23 R 24 , with the proviso that said Q b group is bonded directly to a carbon atom;
R 20 , R 21 , R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido, methyl, and ethyl;
Q s is CH 2 .
30 . The compound as recited in claim 29 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl, 2-(2R)-bicyclo[2,2,1]-heptyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 1-pyrrolidinyl and 1-piperidinyl;
A is selected from the group consisting of a single covalent bond, CH 2 , NHC(O), CH 2 CH 2 and CH 2 CH 2 CH 2 ;
R 1 is selected from the group consisting of hydrido, trifluoromethyl, fluoro, and chloro:
R 2 is selected from the group consisting of 3-aminophenyl, 2,6-dichlorophenyl, 2-hydroxyphenyl, 5-amino-2-thienyl, and 3-thienyl;
Y 0 is selected from the group consisting of:
1-Q b -4-Q s -2-R 16 -3-R 17 -5-R 18 -6-R 19 benzene, 3-Q b -5-Q s -4-R 16- 2-R 19 thiophene, and 2-Q b -5-Q s -3-R 16 -4-R 17 thiophene;
R 16 and R 19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
Q b is selected from the group consisting of Q be wherein Q be is hydrido and C(NR 25 )NR 23 R 24 ;
R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido and methyl;
Q s is CH 2 .
31 . The compound as recited in claim 30 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl, 2-(2R)-bicyclo[2,2,1]-heptyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, and 1-piperidinyl;
A is selected from the group consisting of a single covalent bond, CH 2 , CH 2 CH 2 and CH 2 CH 2 CH 2 ;
R 1 is selected from the group consisting of hydrido and chloro;
R 2 is selected from the group consisting of 3-aminophenyl, 2,6-dichlorophenyl, 2-hydroxyphenyl, phenyl, 5-amino-2-thienyl, and 3-thienyl;
Y 0 is selected from the group consisting of 5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amdinobenzyl.
32 . A compound as recited in claim 25 where said compound is selected from the group having the Formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is 3-aminophenyl, B is cycylopropyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidino-2-fluorobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is cyclopropyl, A is single bond, Y 0 is 4-amidino-2-fluorobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is hydrido;
R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidino-3-fluorobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is cyclopropyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 2-(2R)-bicyclo[2,2,1]-heptyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y 0 is 4-amidino-2-fluorobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is cyclohexyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is hydrido;
R 2 is 3-aminophenyl, B is oxalan-2-yl, A is CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is phenyl, B is 1-pyrrolidinyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 1-piperidinyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 1,1-dioxothiolan-3-yl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-aminophenyl, B is 1-pyrrolidinyl, A is CH 2 CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is phenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro;
R 2 is 3-thienyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is hydrido;
R 2 is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidinobenzyl, and R 1 is chloro.
33 . The compound having the Formula:
or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 32 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 36 , a carbon adjacent to R 32 and two atoms from the carbon at the point of attachment is optionally substituted by R 33 , a carbon adjacent to R 36 and two atoms from the carbon at the point of attachment is optionally substituted by R 35 , and any carbon adjacent to both R 33 and R 35 is substituted by R 34 ;
R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylamino, carboalkoxy, carboxy, carboxamido, cyano, and Q b ;
B is optionally selected from the croup consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the croup consisting of R 32 , R 33 , R 34 , R 35 , and R 36 ;
B is optionally selected from the group consisting of C3-C12 cycloalkyl and C4-C9 saturated heterocyclyl, wherein each ring carbon is optionally substituted with R 33 , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R 9 or R 13 , a ring carbon or nitrogen adjacent to the R 9 position and two atoms from the point of attachment is optionally substituted with R 10 , a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of attachment is optionally substituted with R 12 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 10 position is optionally substituted with R 11 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 12 position is optionally substituted with R 33 , and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the R 11 and R 33 positions is optionally substituted with R 34 ;
R 9 , R 10 , R 11 , R 12 , and R 13 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfamido, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and cyano;
A is selected from the group consisting of single covalent bond and (CH(R 15 )) pa —(W 7 ) rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is selected from the group consisting of O, S, C(O), (R 7 )NC(O), (R 7 )NC(S), and N(R 7 );
R 7 is selected from the group consisting of hydrido, hydroxy and alkyl;
R 15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl;
R 1 is selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;
R 2 is Z 0 —Q;
Z 0 is selected from the group consisting of covalent single bond and (CR 41 R 42 ) q wherein q is an integer selected from 1 through 2, (CH(R 41 )) g —W 0 —(CH(R 42 )) p wherein g and p are integers independently selected from 0 through 3 and W 0 is selected from the group consisting of O, S, and N(R 41 ), and (CH(R 41 )) e —W 22 —(CH(R 42 )) h wherein e and h are integers independently selected from 0 through 1 and W 22 is selected from the group consisting of CR 41 ═CR 42 , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso that Z 0 is directly bonded to the pyrazinone ring;
R 41 and R 42 are independently selected from the group consisting of hydrido, hydroxy, and amino;
Q is selected from the group consisting of hydrido with the proviso that Z 0 is other than a covalent single bond, aryl and heteroaryl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
K is CHR 4a wherein R 4a is selected from the group consisting of hydrido, hydroxyalkyl, alkyl alkoxyalkyl, alkylthioalkyl, and haloalkyl;
E 0 is selected from the group consisting of a covalent single bond, C(O)N(H), (H)NC(O), (R 7 )NS(O) 2 , and S(O) 2 N(R 7 );
Y AT is Q b —Q s ;
Q s is (CR 37 R 38 ) b wherein b is an integer selected from 1 through 4, R 37 is selected from the group consisting of hydrido, alkyl, and haloalkyl, and R 38 is selected from the group consisting of hydrido, alkyl, haloalkyl, aroyl, and heteroaroyl with the provisos that there is at least one aroyl or heteroaroyl substituent, that no more than one aroyl or heteroaroyl is bonded to (CR 37 R 38 ) b at the same time, that said aroyl and said heteroaroyl are optionally substituted at from one through three of the ring carbons with a substituent selected from the group consisting of R 16 , R 17 , R 18 , and R 19 , that said aroyl and said heteroaroyl are bonded to the CR 37 R 38 that is directly bonded to E 0 , that is no more than one alkyl or one haloalkyl is bonded to a CR 37 R 38 at the same time, and that said alkyl and haloalkyl are bonded to a carbon other than the one bonding the aroyl or heteroaroyl;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R 16 and R 19 are optionally Q b with the proviso that no more than one of R 16 and R 19 is Q b at the same time and that Q b is Q be ;
Q b is selected from the group consisting of NR 20 R 21 , Q be wherein Q be is hydrido, N(R 26 )C(NR 25 )N(R 23 )(R 24 ), and C(NR 25 )NR 23 R 24 , with the provisos that no more than one of R 20 and R 21 is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no more than one of R 23 and R 24 is hydroxy, amino, alkylamino, or dialkylamino at the same time;
R 20 , R 21 , R 23 , R 24 , R 25 , and R 26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino.
34 . The compound as recited in claim 33 having the Formula:
or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, and 5-isoxazolyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 32 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 36 , a carbon adjacent to R 32 and two atoms from the carbon at the point of attachment is optionally substituted by R 33 , a carbon adjacent to R 36 and two atoms from the carbon at the point of attachment is optionally substituted by R 35 , and any carbon adjacent to both R 33 and R 35 is optionally substituted by R 34 ;
R 32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q b ;
B is optionally selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 2-methy-2-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3,3,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more of the group consisting of R 32 , R 33 , R 34 , R 35 , and R 36 ;
B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxalan-2-yl, 2-(2R)-bicyclo[2,2,1]-heptyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, bicyclo[3,1,0]hexanyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon is optionally substituted with R 33 , ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R 9 or R 13 , a ring carbon or nitrogen adjacent to the R 9 position and two atoms from the point of attachment is optionally substituted with R 10 , and a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of attachment is optionally substituted with R 12 ;
R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano;
R 10 and R 12 are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano;
A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), CH 2 , CH 3 CH, CH 2 CH 2 , and CH 2 CH 2 CH 2 ;
R 1 is selected from the group consisting of hydrido, trifluoromethyl, pentafluoroethyl, fluoro, and chloro;
R 2 is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R 9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 ;
Y 0 is Q b —Q s ;
Q s is selected from the group consisting of:
C[R 37 (benzoyl)](CR 37 R 38 ) b ], C[R 37 (2-pyridylcarbonyl])](CR 37 R 38 ) b ], C[R 37 (3-pyridylcarbonyl])](CR 37 R 38 ) b ], C[R 37 (4-pyridylcarbonyl])](CR 37 R 38 ) b ], C[R 37 (2-thienylcarbonyl])](CR 37 R 38 ) b ], C[R 37 (3-thienylcarbonyl])](CR 37 R 38 ) b ], C[R 37 (2-thiazolylcarbonyl])](CR 37 R 38 ) b ], C[R 37 (4-thiazolylcarbonyl])](CR 37 R 38 ) b ], and C[R 37 (5-thiazolylcarbonyl])](CR 37 R 38 ) b ], wherein b is an integer selected from 1 through 3, R 37 and R 38 are independently selected from the group consisting of hydrido, alkyl, and haloalkyl, with the provisos that said aroyl and said heteroaroyl are optionally substituted at from one through three of the ring carbons with a substituent selected from the group consisting of R 16 , R 17 , R 18 , and R 19 with the proviso that R 17 and R 18 are optionally substituted at a carbon selected from other than the meta and para carbons relative to the carbonyl of the benzoyl substituent and the heteroaroyl substituent, that said benzoyl and said heteroaroyl are bonded to the carbon directly bonded to amide nitrogen of the 1-(amidocarbonymethylene) group, and that is no more than one alkyl or one haloalkyl is bonded to a CR 37 R 38 at the same time;
R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano;
Q b is selected from the group consisting of NR 20 R 21 and C(NR 25 )NR 23 R 24 , with the proviso that said Q b group is bonded directly to a carbon atom;
R 20 , R 21 , R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido, methyl, and ethyl.
35 . The compound as recited in claim 34 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of 2-aminophenyl, 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichloropbenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl, 5-chloro-3-trifluoromethyl-2-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, and 3-trifluoromethyl-2-pyridyl;
B is optionally selected from the group consisting of hydrido,ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl, (S)-2-butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl;
B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl, 2-(2R)-bicyclo[2,2,1]-heptyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 1-pyrrolidinyl and 1-piperidinyl;
A is selected from the group consisting of single covalent bond, CH 2 , CH 3 CH, CH 2 CH 2 , and CH 2 CH 2 CH 2 ;
R 1 is selected from the group consisting of hydrido, methyl, ethyl, propyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, and bromo;
R 2 is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
Y AT is Q b —Q s ;
Q s is selected from the group consisting of:
[CH(benzoyl)](CH 2 ) b , [CH(2-pyridylcarbonyl)](CH 2 ) b , [CH(3-pyridylcarbonyl)](CH 2 ) b , [CH(4-pyridylcarbonyl)](CH 2 ) b , [CH(2-thienylcarbonyl)](CH 2 ) b , [CH(3-thienylcarbonyl)](CH 2 ) b , [CH(2-thiazolylcarbonyl)](CH 2 ) b , [CH(4-thiazolylcarbonyl)](CH 2 ) b , and [CH(5-thiazolylcarbonyl)](CH 2 ) b , wherein b is an integer selected from 1 through 3, with the provisos that said aroyl and said heteroaroyl are optionally substituted at from one through three of the ring carbons with a substituent selected from the group consisting of R 16 , R 17 , R 18 , and R 19 with the proviso that R 17 and R 18 are optionally substituted at a carbon selected from other than the meta and para carbons relative to the carbonyl of the benzoyl substituent and the heteroaroyl substituent, and that said benzoyl and said heteroaroyl substituent are bonded to the carbon directly bonded to amide nitrogen of the 1-(amidocarbonymethylene) group;
R 16 and R 19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
Q b is C(NR 25 )NR 23 R 24 ;
R 23 , R 24 , and R 25 are independently selected from the group consisting of hydrido and methyl.
36 . The compound as recited in claim 35 or a pharmaceutically acceptable salt thereof, wherein;
B is selected from the group consisting of 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 4-methylphenyl, phenyl, 2-imidazoyl, 3-pyridyl, 4-pyridyl, and 3-trifluoromethyl-2-pyridyl;
B is optionally selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl, (S)-2-butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl;
B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl, 2-(2R)-bicyclo[2,2,1]-heptyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, and 1-piperidinyl;
A is selected from the group consisting of a single covalent bond, CH 2 , CH 2 CH 2 and CH 2 CH 2 CH 2 ;
R 1 is selected from the group consisting of hydrido and chloro;
R 2 is selected from the group consisting of 3-aminophenyl, benzyl, 2,6-dichlorophenyl, 5-amino-2-thienyl, 5-amino-2-fluorophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-carboxyphenyl, 3-cyanophenyl, 3-chlorophenyl, 2-hydroxyhenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 3-methoxycarbonylphenyl, 3-dimethylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, phenyl, 3-pyridyl, 3-trifluoroacetamidophenyl, 3-bromo-2-thienyl, 2-thienyl, and 3-thienyl;
Y AT is selected from the group consisting of 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, 5-guanidino-1-oxo-1-(4-thiazolyl)-2-pentyl, 5-guanidino-1-oxo-1-(5-thiazolyl)-2-pentyl, 5-guanidino-1-oxo-1-(4-amino-2-thiazolyl)-2-pentyl, and 5-guanidino-1-oxo-1-phenyl-2-pentyl.
37 . A compound as recited in claim 33 where said compound is selected from the group having the Formula:
or a pharmaceutically acceptable salt thereof, wherein;
R 2 is 3-aminophenyl, B is phenyl, A is CH 2 , Y AT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and R 1 is chloro;
R 2 is phenyl, B is phenyl, A is CH 2 CH 2 , Y AT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and R 1 is hydrido;
R 2 is benzyl, B is phenyl, A is CH 2 CH 2 , Y AT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and R 1 is hydrido;
R 2 is phenyl, B is phenyl, A is CH 2 CH 2 , Y AT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and R 1 is chloro;
R 2 is benzyl, B is phenyl, A is CH 2 CH 2 , Y AT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and R 1 is chloro;
R 2 is phenyl, B is phenyl, A is CH 2 CH 2 , T AT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and R 1 is hydrido.
38 . A composition for inhibiting thrombotic conditions in blood comprising a compound of any one of claims 8 , 16 , 24 , 32 , and 37 and a pharmaceutically acceptable carrier.
39 . A composition for inhibiting thrombotic conditions in blood comprising a compound of any one of claims 1 through 7 , claims 9 through 15 , claims 17 through 23 , claims 25 through 31 , and claims 33 through 36 and a pharmaceutically acceptable carrier.
40 . A method for inhibiting thrombotic conditions in blood comprising adding to blood a therapeutically effective amount of a composition of any one of claims 38 and 39 .
41 . A method for inhibiting formation of blood platelet aggregates in blood comprising adding to blood a therapeutically effective amount of a composition of any one of claims 38 and 39 .
42 . A method for inhibiting thrombus formation in blood comprising adding to blood a therapeutically effective amount of a composition of any one of claims 38 and 39 .
43 . A method for treating or preventing venuous thromboembolism and pulmonary embolism in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of any one of claims 38 and 39 .
44 . A method for treating or preventing deep vein thrombosis in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of of any one of claims 38 and 39 .
45 . A method for treating or preventing cardiogenic thromboembolism in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of any one of claims 38 and 39 .
46 . A method for treating or preventing thromboembolic stroke in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a composition of any one of claims 38 and 39 .
47 . A method for treating or preventing thrombosis associated with cancer and cancer chemotherapy in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a composition of any one of claims 38 and 39 .
48 . A method for treating or preventing unstable angina in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a composition of any one of claims 38 and 39 .
49 . A method for inhibiting thrombus formation in blood comprising adding to blood a therapeutically effective amount of a compound of any one of claims 1 through 37 with a therapeutically effective amount of fibrinogen receptor antagonist.
50 . The use of a compound of any one of claims 1 through 37 , or a pharmaceutically acceptable salt thereof, in the manufacture of medicament for inhibiting thrombus formation, treating thrombus formation, or preventing thrombus formation in a mammal.Cited by (0)
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