Methods and compositions of small molecule modulators of hepatocyte growth factor (scatter factor) activity

A method of administering a therapeutically effective amount of a compound of Formula (A):

• or a tautomer thereof,
• or a pharmaceutically acceptable salt thereof,
• wherein:
• C═C is cis or trans;
• A represents an optionally substituted aromatic or non-aromatic 5-6 membered monocyclic ring, optionally containing 1-4 heteroatoms selected from N, O or S;
• or an optionally substituted aromatic or non-aromatic 8-12 membered bicyclic ring, optionally containing 1-6 heteroatoms selected from N, O or S;
• q is 1 or 2;
• each R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, —NO2, —CN, an optionally substituted aliphatic, heteroaliphatic, aromatic, or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, and —C(═O)Ra;
• n is 0, 1, or 2;
• each RR is independently an optionally substituted aliphatic, heteroaliphatic, aromatic, or heteroaromatic moiety;
• Ra, at each occurrence, is independently selected from the group consisting of hydrogen, hydroxy, and an optionally substituted aliphatic, heteroaliphatic, aryl, or heteroaryl;
• Rb and Rc, at each occurrence, are independently selected from the group consisting of hydrogen, hydroxyl, SO2Rd, and optionally substituted aliphatic, heteroaliphatic, aryl, or heteroaryl;
• Rd, at each occurrence, is independently selected from the group consisting of hydrogen, —N(Re)2, and optionally substituted aliphatic, aryl, or heteroaryl;
• and
• Re, at each occurrence, is independently hydrogen or optionally substituted aliphatic,
• the method comprising administering a pharmaceutical composition comprising the compound of Formula (A) in aqueous buffered saline containing about 40% to about 60% (v/v) polyethylene glycol 300 and about 5% to about 15% polysorbate 80.

A method of treating or lessening the severity of a disease, disorder, or condition selected from ischemic heart disease, damaged and/or ischemic organs, transplants or grafts, ischemia/reperfusion injury, myocardial ischemia, renal failure, renal fibrosis, idiopathic pulmonary fibrosis, vascularization of a damaged and/or ischemic organ, transplant or graft, amelioration of ischemia/reperfusion injury in the kidney, normalization of myocardial perfusion as a consequence of myocardial infarction, fibrosis secondary to renal obstruction, renal trauma and transplantation, and renal failure secondary to chronic diabetes or hypertension,

• comprising administering a pharmaceutical composition comprising a compound of Formula (A):
• or a tautomer thereof,
• or a pharmaceutically acceptable salt thereof,
• wherein:
• C═C is cis or trans;
• A represents an optionally substituted aromatic or non-aromatic 5-6 membered monocyclic ring, optionally containing 1-4 heteroatoms selected from N, O or S;
• or an optionally substituted aromatic or non-aromatic 8-12 membered bicyclic ring, optionally containing 1-6 heteroatoms selected from N, O or S;
• q is 1 or 2;
• each R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, —NO2, —CN, an optionally substituted aliphatic, heteroaliphatic, aromatic, or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, and —C(═O)Ra;
• n is 0, 1, or 2;
• each RR is independently an optionally substituted aliphatic, heteroaliphatic, aromatic, or heteroaromatic moiety;
• Ra, at each occurrence, is independently selected from the group consisting of hydrogen, hydroxy, and an optionally substituted aliphatic, heteroaliphatic, aryl, or heteroaryl;
• Rb and Rc, at each occurrence, are independently selected from the group consisting of hydrogen, hydroxyl, SO2Rd, and optionally substituted aliphatic, heteroaliphatic, aryl, or heteroaryl;
• Rd, at each occurrence, is independently selected from the group consisting of hydrogen, —N(Re)2, and optionally substituted aliphatic, aryl, or heteroaryl;
• and
• Re, at each occurrence, is independently hydrogen or optionally substituted aliphatic,
• in aqueous buffered saline containing about 40% to about 60% (v/v) polyethylene glycol 300 and about 5% to about 15% polysorbate 80.

A method of preparing a pharmaceutical composition comprising a compound of Formula (A):

• or a tautomer thereof,
• or a pharmaceutically acceptable salt thereof,
• wherein:
• C═C is cis or trans;
• A represents an optionally substituted aromatic or non-aromatic 5-6 membered monocyclic ring, optionally containing 1-4 heteroatoms selected from N, O or S;
• or an optionally substituted aromatic or non-aromatic 8-12 membered bicyclic ring, optionally containing 1-6 heteroatoms selected from N, O or S;
• q is 1 or 2;
• each R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, —NO2, —CN, an optionally substituted aliphatic, heteroaliphatic, aromatic, or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRb, and —C(═O)Ra;
• n is 0, 1, or 2;
• each RR is independently an optionally substituted aliphatic, heteroaliphatic, aromatic, or heteroaromatic moiety;
• Ra, at each occurrence, is independently selected from the group consisting of hydrogen, hydroxy, and an optionally substituted aliphatic, heteroaliphatic, aryl, or heteroaryl;
• Rb and Rc, at each occurrence, are independently selected from the group consisting of hydrogen, hydroxyl, SO2Rd, and optionally substituted aliphatic, heteroaliphatic, aryl, or heteroaryl;
• Rd, at each occurrence, is independently selected from the group consisting of hydrogen, —N(Re)2, and optionally substituted aliphatic, aryl, or heteroaryl;
• and
• Re, at each occurrence, is independently hydrogen or optionally substituted aliphatic,
• the method comprising (i) providing a composition of the compound of Formula (A);
• and (ii) formulating the composition in aqueous buffered saline containing about 40% to about 60% (v/v) polyethylene glycol 300 and about 5% to about 15% polysorbate 80.