Compounds of formula I are provided: ##STR00001##
R.sub.1 is an alkoxy or O(CH.sub.2).sub.pX, p is an integer from 2 to 3 and X is OH, NH.sub.2, or CO.sub.2H, m is an integer from 0 to 5, n is an integer from 0 to 5, each R.sub.2 is independently selected from hydrogen, alkenyl, hydroxyalkyl, alkoxymethyl, heterocyclyl, hetereocyclylmethyl, amino, amido, hydroxamido, any of which may be optionally substituted with one or more of acyl, alkyl, alkoxy, hydroxyalkyl, or halogen, each R.sub.3 is independently selected from hydrogen, halogen, alkyl, alkenyl, carboxy, hydroxymethyl, amido, and at least one of R.sub.2 and R.sub.3 is not hydrogen.

Compounds of formula I are provided: ##STR00001##
R.sub.1 is an alkoxy or O(CH.sub.2).sub.pX, p is an integer from 2 to 3 and X is OH, NH.sub.2, or CO.sub.2H, m is an integer from 0 to 5, n is an integer from 0 to 5, each R.sub.2 is independently selected from hydrogen, alkenyl, hydroxyalkyl, alkoxymethyl, heterocyclyl, hetereocyclylmethyl, amino, amido, hydroxamido, any of which may be optionally substituted with one or more of acyl, alkyl, alkoxy, hydroxyalkyl, or halogen, each R.sub.3 is independently selected from hydrogen, halogen, alkyl, alkenyl, carboxy, hydroxymethyl, amido, and at least one of R.sub.2 and R.sub.3 is not hydrogen.

The present invention describes a method for the synthesis of enantiomerically pure 3-amidinophenylalanine derivatives, which are used as pharmaceutically effective urokinase inhibitors, by starting from 3-cyanophenylalanine derivatives. The methods of manufacture comprising only one synthesis step lead to new intermediates, namely 3-hydroxyamidino- and 3-amidrazonophenylalanine derivatives. These intermediates or their acetyl derivatives can be reduced into the desired 3-amidino-phenylalanine derivatives under gentle conditions (H.sub.2 or ammonium .[.formiate.]. .Iadd.formate.Iaddend., Pd/C (approx. 10%), ethanol/water, room temperature, normal pressure or also H.sub.2, Pd/C, AcOH or HCl/ethanol, 1-3 bar) in excellent yields and in an enantiomeric excess of up to 99.9%.

The present invention describes a method for the synthesis of enantiomerically pure 3-amidinophenylalanine derivatives, which are used as pharmaceutically effective urokinase inhibitors, by starting from 3-cyanophenylalanine derivatives. The methods of manufacture comprising only one synthesis step lead to new intermediates, namely 3-hydroxyamidino- and 3-amidrazonophenylalanine derivatives. These intermediates or their acetyl derivatives can be reduced into the desired 3-amidino-phenylalanine derivatives under gentle conditions (H.sub.2 or ammonium .[.formiate.]. .Iadd.formate.Iaddend., Pd/C (approx. 10%), ethanol/water, room temperature, normal pressure or also H.sub.2, Pd/C, AcOH or HCl/ethanol, 1-3 bar) in excellent yields and in an enantiomeric excess of up to 99.9%.

Heterobifunctional chemical linkers useful in protein degraders and other medicinal chemistry applications are provided. The heterobifunctional linkers include alky ne-piperidine and alkane-piperidine linkers: alkane-piperazine linkers; alkanamino PEGylated linkers; dipiperazine linkers; piperazine-pyridine/pyrimidine-alkyne linkers; pyridine-PEG-piperazine linkers and pyrimidine-piperazine-PEG linkers. Also provided are combinations of the provided linkers with a ligand that targets a degradation pathway, such as an E3 ubiquitin ligase enzyme.

Heterobifunctional chemical linkers useful in protein degraders and other medicinal chemistry applications are provided. The heterobifunctional linkers include alky ne-piperidine and alkane-piperidine linkers: alkane-piperazine linkers; alkanamino PEGylated linkers; dipiperazine linkers; piperazine-pyridine/pyrimidine-alkyne linkers; pyridine-PEG-piperazine linkers and pyrimidine-piperazine-PEG linkers. Also provided are combinations of the provided linkers with a ligand that targets a degradation pathway, such as an E3 ubiquitin ligase enzyme.

Disclosed are modulators of the human relaxin receptor 1, for example, of formula (I), wherein A, R.sup.1, and R.sup.2 are as defined herein, that are useful in treating mammalian relaxin receptor 1 mediated facets of human health, e.g., cardiovascular disease. Also disclosed is a composition comprising a pharmaceutically suitable carrier and at least one compound of the disclosure, and a method for therapeutic intervention in a facet of mammalian health that is mediated by a human relaxin receptor 1.

##STR00001##

Disclosed are modulators of the human relaxin receptor 1, for example, of formula (I), wherein A, R.sup.1, and R.sup.2 are as defined herein, that are useful in treating mammalian relaxin receptor 1 mediated facets of human health, e.g., cardiovascular disease. Also disclosed is a composition comprising a pharmaceutically suitable carrier and at least one compound of the disclosure, and a method for therapeutic intervention in a facet of mammalian health that is mediated by a human relaxin receptor 1.

##STR00001##

The present disclosure provides processes for the N-dealkylation of tertiary amines and the use of transition metal catalysts to prepare tertiary N-allyl amine derivatives and secondary amine derivatives thereof. The tertiary amines can be alkaloids and, more particularly, the tertiary amines can be opioids. In specific embodiments, the present disclosure provides methods for use in processes for the synthesis of naloxone and naltrexone from oripavine.

The present disclosure provides processes for the N-dealkylation of tertiary amines and the use of transition metal catalysts to prepare tertiary N-allyl amine derivatives and secondary amine derivatives thereof. The tertiary amines can be alkaloids and, more particularly, the tertiary amines can be opioids. In specific embodiments, the present disclosure provides methods for use in processes for the synthesis of naloxone and naltrexone from oripavine.