6-Membered unsaturated heterocyclic compounds useful for selective inhibition of the coagulation cascade

A compound having the structure:

• 655
• wherein
• X5 is CH, C(Br), C(Cl), or C(F)
• L1 is a linker, linking Z1 to the heterocyclic ring and optionally containing a bond to the carbon of the heterocyclic ring that is gamma to the substituted nitrogen of the heterocyclic ring to form a fused ring with the heterocyclic ring;
• Z1 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with fluorine, hydroxy, carboxy or alkoxycarbonyl;
• Z3 comprises a substituted phenyl, thienyl, or furanyl ring, the phenyl, thienyl or furanyl ring being substituted with an amidine or a derivatized amidine group, and optionally further substituted at any substitutable position with fluorine, hydroxy, carboxy, alkoxycarbonyl, or hydrocarbyloxy;
• Z4 comprises a 5- or 6-membered heteroaryl or aryl ring, the ring atoms of Z4 being Z40, Z41, Z42, Z44 and Z45 when Z4 is a 5-membered ring and Z40, Z41, Z42, Z43, Z44 and Z45 when Z4 is a 6-membered ring, Z40, Z41, Z42, Z43, Z44 and Z45, being carbon, nitrogen, oxygen or sulfur, Z40 being the ring atom through which Z4 is attached to the heterocyclic core ring, Z41 and Z45 each being in an alpha position relative to Z40, Z42 and Z44 each being in a beta position relative to Z40, Z43 being in the gamma position relative to Z40 when Z4 is a 6-membered ring, Z4 having a substituent R42 covalently attached to Z42, and a second substituent bonded to one of Z41, Z43, Z44, or Z45, the substituent being R41 when bonded to Z41, the substituent being R43 when bonded to Z43, the substituent being R44 when bonded to Z44, and the substituent being R45 when bonded to Z45;
• R42 is amino;
• and
• R41, R43, R44 and R45 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or a substituted or unsubstituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus, provided at least one of R411 R43, R44 or R45 is other than hydrogen;
• provided, however, one of the following conditions exist:
• (a) Z3 is other than 4-amidinobenzyl, 4-amidino-2-fluorobenzyl, and 4-amidino-3-fluorobenzyl;
• or (b) (i) Z1 is other than unsubstituted cyclobutyl and unsubstituted isopropyl when X5 is CH or C(Cl) and (ii) neither Z41 nor Z45 is sulfur when Z4 is thienyl;

A compound having the structure:

• 661
• wherein
• X6 is CH, C(Br), C(Cl), or C(F);
• L1 is a linker, linking Z1 to the heterocyclic ring and optionally containing a bond to the carbon of the heterocyclic ring that is gamma to the substituted nitrogen of the heterocyclic ring to form a fused ring with the heterocyclic ring;
• Z1 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl provided that Z1 is other than unsubstituted cyclobutyl or unsubstituted isopropyl.
• Z3 comprises a substituted phenyl, thienyl, or furanyl ring, the phenyl, thienyl or furanyl ring being substituted with an amidine or a derivatized amidine group, and optionally further substituted at any substitutable position with fluorine, hydroxy, carboxy, alkoxycarbonyl, or hydrocarbyloxy;
• Z4 comprises a 5- or 6-membered heteroaryl or aryl ring, the ring atoms of Z4 being Z40, Z41, Z42, Z44 and Z45 when Z4 is a 5-membered ring and Z40, Z41, Z42, Z43, Z44 and Z45 when Z4 is a 6-membered ring, Z40, Z41, Z42, Z43, Z44 and Z45, being carbon, nitrogen, oxygen or sulfur, Z40 being the ring atom through which Z4 is attached to the heterocyclic core ring, Z41 and Z45 each being in an alpha position relative to Z40, Z42 and Z44 each being in a beta position relative to Z40, Z43 being in the gamma position relative to Z40 when Z4 is a 6-membered ring, Z4 having a substituent R42 covalently attached to Z42, and a second substituent bonded to one of Z41, Z43, Z44, or Z45, the substituent being R41 when bonded to Z41, the substituent being R43 when bonded to Z43, the substituent being R44 when bonded to Z44, and the substituent being R45 when bonded to Z45, provided neither Z41 nor Z45 is sulfur when Z4 is thienyl;
• R42 is amino;
• and
• R41, R43, R44 and R45 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or a substituted or unsubstituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus, provided at least one of R41, R43, R44 or R45 is other than hydrogen.

A compound having the structure:

• 667
• wherein
• L1 is a linker, linking Z1 to the heterocyclic ring and optionally containing a bond to the carbon of the heterocyclic ring that is gamma to the substituted nitrogen of the heterocyclic ring to form a fused ring with the heterocyclic ring;
• Z1 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl provided that Z1 is other than unsubstituted cyclobutyl or unsubstituted isopropyl.
• Z3 comprises a substituted phenyl, thienyl, or furanyl ring, the phenyl, thienyl or furanyl ring being substituted with an amidine or a derivatized amidine group, and optionally further substituted at any substitutable position with fluorine, hydroxy, carboxy, alkoxycarbonyl, or hydrocarbyloxy;
• Z4 comprises a 5- or 6-membered heteroaryl or aryl ring, the ring atoms of Z4 being Z40, Z41, Z42, Z44 and Z45 when Z4 is a 5-membered ring and Z401 Z41, Z42, Z43, Z44 and Z45 when Z4 is a 6-membered ring, Z40, Z41, Z42, Z43, Z44 and Z45, being carbon, nitrogen, oxygen or sulfur, Z40 being the ring atom through which Z4 is attached to the heterocyclic core ring, Z41 and Z45 each being in an alpha position relative to Z40, Z42 and Z44 each being in a beta position relative to Z40, Z43 being in the gamma position relative to Z40 when Z4 is a 6-membered ring, Z4 having a substituent R42 covalently attached to Z42, and a second substituent bonded to one of Z41, Z43, Z44, or Z45, the substituent being R41 when bonded to Z41, the substituent being R43 when bonded to Z43, the substituent being R44 when bonded to Z44, and the substituent being R45 when bonded to Z45, provided neither Z41 nor Z45 is sulfur when Z4 is thienyl;
• R42 is amino;
• and
• R41, R43, R44 and R45 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or a substituted or unsubstituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus, provided at least one of R41, R43, R44 or R45 is other than hydrogen.

A compound having the structure:

• 673
• wherein
• X5 and X6 are independently nitrogen, CH, C(F), C(Cl), or C(Br);
• L1 is a linker, linking Z1 to the heterocyclic core ring;
• Z1 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl;
• Z3 comprises a substituted phenyl, thienyl, or furanyl ring, the phenyl, thienyl or furanyl ring being substituted with an amidine or a derivatized amidine group, and optionally substituted with fluorine, provided, however, when Z3 is phenyl or thienyl, the phenyl or thienyl ring is further substituted by at least one of hydroxy, carboxy, alkoxycarbonyl, or hydrocarbyloxy;
• Z4 comprises a 5- or 6-membered heteroaryl or aryl ring, the ring atoms of Z4 being Z40, Z41, Z42, Z44 and Z45 when Z4 is a 5-membered ring and Z40, Z41, Z42, Z43, Z44 and Z45 when Z4 is a 6-membered ring, Z401 Z41, Z42, Z43, Z44 and Z45, being carbon, nitrogen, oxygen or sulfur, Z40 being the ring atom through which Z4 is attached to the heterocyclic core ring, Z41 and Z45 each being in an alpha position relative to Z40, Z42 and Z44 each being in a beta position relative to Z40, Z43 being in the gamma position relative to Z40 when Z4 is a 6-membered ring, Z4 having a substituent R42 covalently attached to Z42, and a second substituent bonded to one of Z41, Z43, Z44, or Z45, the substituent being R41 when bonded to Z411 the substituent being R43 when bonded to Z43, the substituent being R44 when bonded to Z44, and the substituent being R45 when bonded to Z45;
• R42 is amino;
• and
• R41, R43, R44 and R45 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or a substituted or unsubstituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus, provided at least one of R41, R43, R44 or R45 is other than hydrogen.

A compound having the structure:

• 674
• wherein
• X5 and X6 are independently nitrogen, CH, C(F), C(Cl), or C(Br);
• L1 is a linker, linking Z1 to the heterocyclic core ring;
• Z1 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl;
• Z3 comprises a substituted phenyl, thienyl, or furanyl ring, the phenyl, thienyl or furanyl ring being substituted with an amidine or a derivatized amidine group and optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, alkoxycarbonyl, or hydrocarbyloxy;
• Z4 comprises a 5- or 6-membered heteroaryl or aryl ring, the ring atoms of Z4 being Z40, Z41, Z42, Z44 and Z45 when Z4 is a 5-membered ring and Z40, Z41, Z42, Z43, Z44 and Z45 when Z4 is a 6-membered ring, Z40, Z41, Z42, Z43, Z44 and Z45, being carbon, nitrogen, oxygen or sulfur, Z40 being the ring atom through which Z4 is attached to the heterocyclic core ring, Z41 and Z45 each being in an alpha position relative to Z40, Z42 and Z44 each being in a beta position relative to Z40, Z43 being in the gamma position relative to Z40 when Z4 is a 6-membered ring, Z4 having a substituent R42 covalently attached to Z42, and a second substituent bonded to one of Z41, Z43, Z44, or Z45, the substituent being R41 when bonded to Z41, the substituent being R43 when bonded to Z43, the substituent being R44 when bonded to Z44, and the substituent being R41 when bonded to Z45;
• R42 is amino;
• and
• R41, R43, R44 and R45 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or a substituted or unsubstituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus, provided at least one of R41, R43, R44 or R41 is other than hydrogen;
• provided, however, (a) one of Z1, Z3 and Z4 is hydroxy substituted or (b) one of Z1 and Z3 is carboxy substituted.

A compound having the structure:

• 682
• wherein
• X5 is nitrogen, CH, C(F), C(Cl), or C(Br);
• X6 is carbon or nitrogen, provided the dashed line represents a double bond when X6 is carbon and the dashed line represents a single bond when X6 is nitrogen;
• X7 and X8 are independently carbon, nitrogen, oxygen or sulfur;
• Z1 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl;
• Z2 is a hydrogen bond acceptor covalently or datively bonded to the carbon gamma to X5.
• Z3 comprises a substituted phenyl, thienyl, or furanyl ring, the phenyl, thienyl or furanyl ring being substituted with an amidine or a derivatized amidine group and optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, alkoxycarbonyl, or hydrocarbyloxy;
• Z4 comprises a 5- or 6-membered heteroaryl or aryl ring, the ring atoms of Z4 being Z40, Z41, Z42, Z44 and Z45 when Z4 is a 5-membered ring and Z40, Z41, Z42, Z43, Z44 and Z45 when Z4 is a 6-membered ring, Z40, Z41, Z42, Z43, Z44 and Z45, being carbon, nitrogen, oxygen or sulfur, Z40 being the ring atom through which Z4 is attached to the heterocyclic core ring, Z41 and Z45 each being in an alpha position relative to Z40, Z42 and Z44 each being in a beta position relative to Z40, Z43 being in the gamma position relative to Z40 when Z4 is a 6-membered ring, Z4 having a substituent R42 covalently attached to Z42, and a second substituent bonded to one of Z41, Z43, Z44, or Z45, the substituent being R41 when bonded to Z41, the substituent being R43 when bonded to Z43, the substituent being R44 when bonded to Z44, and the substituent being R45 when bonded to Z45;
• R42 is amino;
• R41, R43, R44 and R45 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or a substituted or unsubstituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus, provided at least one of R41, R43, R44 or R45 is other than hydrogen;
• R70 and R80 are independently selected from the group consisting of hydrogen, halogen, amino, hydrocarbyl, substituted hydrocarbyl, aryl, wherein aryl is phenyl optionally substituted by hydroxy, amino, C1-C8 alkyl, or halogen provided that R70 is not present when X7 is a bond and R80 is not present when X8 is a bond;
• or R70 and R80, along with the ring atoms to which each is attached, form a 5- or 6-membered saturated ring;
• and
• n is 0 to 2.

A compound having the structure:

• 686
• wherein
• X5 and X6 are independently nitrogen, CH, C(F) or C(Br);
• T3 is hydroxy, alkoxy, substituted alkoxy, or substituted amino;
• T4 is Cl, Br, I, S(CH3), or OSO2 (CF3);
• Z1 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted with fluorine, hydroxy, carboxy, or alkoxycarbonyl;
• and
• Z2 is a hydrogen bond acceptor covalently bonded to the carbon gamma to X5.

A compound having the structure:

• 687
• wherein
• X5 and X6 are independently nitrogen, CH, C(F) or C(Br);
• Z1 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted with fluorine, hydroxy, carboxy, or alkoxycarbonyl;
• Z2 is a hydrogen bond acceptor covalently bonded to the carbon gamma to X5;
• and
• Z4 is hydrocarbyl, substituted hydrocarbyl, or a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of the 5- or 6-membered heterocyclic or carboxylic ring of Z4 being carbon, nitrogen, oxygen, or sulfur.