THERAPEUTIC COMPOUNDS AND METHODS OF USE THEREOF

The invention provides a compound of formula (I):   or a salt thereof, wherein R1, R2, R3, R4 and R6 have any of the values described in the specification, as well as compositions comprising a compound of formula (I). The compounds are agonists of the TGR5 receptor.

BACKGROUND

Bile acids are known for their role in aiding in the digestion and absorption of fats and fat-soluble vitamins and nutrients. The acids and their derivatives have been investigated as potential therapeutics for a surprisingly diverse set of clinical indications. Ursodeoxycholic acid (UDCA) and obeticholic acid, the 6α-ethyl derivative of chenodeoxycholic acid (CDCA), are both US-FDA approved drugs for the treatment of primary biliary cholangitis (Hirschfield, G. M. et al.Gastroenterology2015, 148, 751-761). Obeticholic acid, an agonist of the farnesoid X nuclear receptor (FXR), also improved liver histology in clinical trials for non-alcoholic steatohepatitis (NASH) (Neuschwander-Tetri, B. A. et al.Gastroenterology2015, 148, 704-706) and reduced portal hypertension in animal models (Len, V. et al.Hepatology2014, 59, 2286-2298). UDCA derivatives, including the taurine conjugate TUDCA, have been extensively studied as anti-apoptotic agents, demonstrating beneficial effects in animal models of acute kidney injury, myocardial infarction, and stroke (Amaral, J. D. et al.J. Lipid Res.2009, 50, 1721-1734). Other bile acid derivatives have been found to serve as glucocorticoid modulators (Sharma, R. et al.J. Med. Chem.2011, 54, 122-130) or to inhibit the growth of human cancer cell lines (Ren, J. et al.Steroids2013, 78, 53-58). Bile acids have also been used as carriers to improve the oral absorption of drugs, as bile acid-drug conjugates can potentially be actively absorbed from the gut by the same transporters that absorb endogenous bile acids, including the apical sodium-dependent bile acid transporter (ASBT) (Kramer, W. et al.Biol. Chem.2011, 392, 77-94).

Importantly, bile acids are also endogenous agonists of the TGR5 receptor, alternatively referred to as GPBAR1 or M-BAR. The TGR5 receptor is widely expressed in human tissues, including the pancreas, liver, spleen, brain, skin, and the gastrointestinal tract (Duboc, H. et al.Dig. Liver Dis.2014, 46, 302-312 van Nierop, F. S. et al.Lancet Diabetes Endocrinol.2017, 5, 224-233 and Xu, Y. et al.J. Med. Chem.2016, 59, 6553-6579). Both steroidal and non-steroidal TGR5 agonists have been studied extensively as possible therapeutics for type 2 diabetes and demonstrated significant improvements in GLP-1 secretion and glucose reduction in animal models of the disease (Xu, Y. et al.J. Med Chem.2016, 59, 6553-6579). TGR5 activation is also believed to have anti-inflammatory effects (van Nierop, F. S. et al.Lancet Diabetes Endocrinol.2017, 5, 224-233 and Baars. A. et al.Microorganisms2015, 3, 641). However, TGR5 agonists are not without their potential drawbacks, leading to reports in animal models of problems with increased gallbladder filling (Li. T. et al.Mol. Endocrinol.2011, 25, 1066-1071 and Briere, D. A. et al.PLoS ONE2015, 10, e0136873), pruritus (Alemi, F. et al.J Clin. Invest.2013, 123, 1513-1530), and significant reductions in vascular tone and blood pressure (Fryer, R. M. et al.J. Pharmacol. Exp. Ther.2014, 348, 421-431).

Recent studies have investigated the interaction of bile acids and the TGR5 receptor as part of the ongoing research into finding improved methods for controllingClostridium difficileinfection (CDI) (Weingarden, A. R. et al.PLoS ONE2016, 11, e0147210; Weingarden, A. R. et al.J. Clin. Gastroenterol.2016, 50, 624-30 and Stoltz, K. L. et al.J. Med. Chem.2017, 60, 3451-3471).C. difficile(recently reclassified asClostridioides difficile) is an anaerobic, Gram-positive spore-forming bacterium. Spores of this bacterium use the presence of specific bile acids as an indicator of a favorable environment for germination. Current research has shown a number of synthetic UDCA and CDCA analogs capable of inhibiting the germination ofC. difficilespores more potently than naturally occurring derivatives (Stoltz, K. L. et al.J. Med. Chem.2017, 60, 3451-3471). In addition, a present chemical library contained a number of analogs in which the carboxylic acid of the parent bile acid was modified by conjugation. The availability of these analogs, along with several new derivatives that have been synthesized, provided an excellent opportunity to expand current knowledge of the structure-activity relationship (SAR) of bile acid derivatives at the TGR5 receptor. Interests in methods to increase the TGR5 potency of current derivatives, as TGR5 agonists could potentially reduce the symptoms of inflammatory bowel disease (Yoneno, K. et al.Immunology2013, 139, 19-29), a condition often found alongside CDI that complicates the treatment of CDI by existing therapies including fecal microbiota transplantation (Khoruts, A. et al.Clin. Gastroenterol. Hepatol.2016, 14, 1433-8).

US2014/0206657A1 relates to methods of synthesizing certain specific bile acid analogues and derivatives, their effects on TGR5 activity, and their possible use in treating diabetes and liver diseases.

WO2017/142895A1 relates to certain specific bile acid analogues and derivatives that are reported to be useful for preventing, treating, and/or reducing the risk of developing aClostridium-associated disease.

Currently there is a need for additional agents that are agonists of the TGR5 receptor. In particular, there is a need for TGR5 agonists with improved properties, such as, for example, improved activity, potency, solubility, selectivity, or toxicity. Such agents would be useful for treating TGR5 mediated conditions, such as diabetes, obesity and/or inflammatory bowel disease.

SUMMARY

In one aspect the present invention provides compounds that are potent agonists of the TGR5 receptor and useful for treating TGR5 mediated conditions (e.g. diabetes, obesity and/or inflammatory bowel disease).

Accordingly, the invention provides a method for treating a TGR5 mediated condition in an animal comprising administering to the animal a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R1is (C1-C6)alkyl that is substituted with one or more R5, wherein R5is independently selected from the group consisting of halo, cyano, heterocycle, heteroaryl, —OH, —C(═O)NH(C1-C6alkyl)(S(O)2Rc), —C(═O)NH(C1-C6alkyl)(C(═O)ORc), —C(═O)NRaRb, —OS(O)3Rc, —C(═O)NH(S(O)2Rc), —C(═O)ORc, and —C(═O)(C1-C6alkyl), wherein any heterocycle and heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, carboxy, —OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of —OH and (C1-C6)alkoxy;

R2is selected from the group consisting of —OH, —OC(═O)Rc, —OS(O)3H and (C1-C6)alkoxy;

R3is selected from the group consisting of —OC(═O)Rd, (C1-C6)alkyl, —OS(O)3Reand (C1-C6)alkoxy;

R4is selected from the group consisting of H and —OH, where;

Raand Rbare independently selected from H and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle;

each Rcis independently selected from H and (C1-C6)alkyl;

Rdis H or (C2-C6)alkyl; or when R2is —OH, Rdis H or (C1-C6)alkyl;

Reis (C1-C6)alkyl; and

R6is selected from the group consisting of H and (C1-C6)alkyl, or R6and R3together with the atom to which they are attached form a carbocycle or heterocycle, wherein the carbocycle or heterocycle is optionally substituted with halo, cyano, heteroaryl, —OH and (C1-C6)alkyl.

The invention also provides a compound of formula (I) as or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of a TGR5 mediated condition.

The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating a TGR5 mediated condition.

The invention also provides a compound of formula (I):

or a salt thereof, wherein:

R1is (C1-C6)alkyl that is substituted with one or more R5wherein R5is independently selected from the group consisting of halo, cyano, heterocycle, heteroaryl, —OH, —C(═O)NH(C1-C6alkyl)(S(O)2Rc), —C(═O)NH(C1-C6alkyl)(C(═O)ORc), —C(═O)NRaRb, —OS(O)3Rc, —C(═O)NH(S(O)2Rc), —C(═O)ORc, and —C(═O)(C1-C6alkyl), wherein any heterocycle and heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, carboxy, —OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of —OH and (C1-C6)alkoxy;

R2is selected from the group consisting of —OH, —OC(═O)Rc, —OS(O)3H and (C1-C6)alkoxy;

R3is selected from the group consisting of —OC(═O)Rd, (C1-C6)alkyl, —OS(O)3Rcand (C1-C6)alkoxy;

R4is selected from the group consisting of H and —OH, where;

Raand Rbare independently selected from H and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle;

each Rcis independently selected from H and (C1-C6)alkyl;

Rdis H or (C2-C6)alkyl; or when R2is —OH, Rdis H or (C1-C6)alkyl;

R6is selected from the group consisting of H and (C1-C6)alkyl, or R6and R3together with the atom to which they are attached form a carbocycle or heterocycle, wherein the carbocycle or heterocycle is optionally substituted with halo, cyano, heteroaryl, —OH and (C1-C6)alkyl;

provided that the compound or salt is not selected from the group consisting of:

and salts thereof.

The invention also provides a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy.

The invention also provides a method for promoting a TGR5 agonist effect comprising contacting TGR5 with an effective TGR5 agonising amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof.

The invention also provides an anti-diabetic, anti-obesity, or anti-inflammatory bowel disease composition comprising a compound of formula (1) as or a pharmaceutically acceptable salt thereof.

The invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of formula (I) or a salt thereof.

Applicant has discovered that C-7 alkoxy substitution in compounds of Formula (1) provides compounds with improved TGR5 agonist potency compared to corresponding compounds with C-7 hydroxy substitution. In one aspect, the invention is directed toward C-7 alkoxy (e.g. methoxy) substituted compounds and to their use in treating TGR5 mediated conditions, such as diabetes, inflammatory bowel disease, obesity, nonalcoholic steatohepatitis, primary bilary cholangitis, primary sclerosing cholangitis, gastric cancer, and/or other inflammatory diseases.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used, unless otherwise described: halo or halogen is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.

The term “alkyl”, by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., C1-8means one to eight carbons). Examples include (C1-C8)alkyl, (C2-C8)alkyl, C1-C6)alkyl, (C2-C6)alkyl and (C3-C6)alkyl. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and and higher homologs and isomers.

The term “alkenyl” refers to an unsaturated alkyl radical having one or more double bonds. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl) and the higher homologs and isomers.

The term “alkynyl” refers to an unsaturated alkyl radical having one or more triple bonds. Examples of such unsaturated alkyl groups ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers.

The term “alkoxy” refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”).

The term “alkylthio” refers to an alkyl groups attached to the remainder of the molecule via a thio group.

The term “cycloalkyl” refers to a saturated or partially unsaturated (non-aromatic) all carbon ring having 3 to 8 carbon atoms (i.e., (C1-C8)carbocycle). The term also includes multiple condensed, saturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, carbocycle includes multicyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 3 to 15 carbon atoms, about 6 to 15 carbon atoms, or 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycles with up to about 20 carbon atoms). The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. For example, multicyclic carbocyles can be connected to each other via a single carbon atom to form a spiro connection (e.g., spiropentane, spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fused connection (e.g., carbocycles such as decahydronaphthalene, norsabinane, norcarane) or via two non-adjacent carbon atoms to form a bridged connection (e.g., norbornane, bicyclo[2.2.2]octane, etc). Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, pinane, and adamantane.

The term “aryl” as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed carbon ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., cycloalkyl. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, indanyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.

The term “heterocycle” refers to a single saturated or partially unsaturated ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that have at least one such saturated or partially unsaturated ring, which multiple condensed ring systems are further described below. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The term “heterocycle” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a single heterocycle ring (as defined above) can be condensed with one or more groups selected from cycloalkyl, aryl, and heterocycle to form the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heterocycle) can be at any position of the multiple condensed ring system including a heterocycle, aryl and carbocycle portion of the ring. In one embodiment the term heterocycle includes a 3-15 membered heterocycle. In one embodiment the term heterocycle includes a 3-10 membered heterocycle. In one embodiment the term heterocycle includes a 3-8 membered heterocycle. In one embodiment the term heterocycle includes a 3-7 membered heterocycle. In one embodiment the term heterocycle includes a 3-6 membered heterocycle. In one embodiment the term heterocycle includes a 4-6 membered heterocycle. In one embodiment the term heterocycle includes a 3-10 membered monocyclic or bicyclic heterocycle comprising 1 to 4 heteroatoms. In one embodiment the term heterocycle includes a 3-8 membered monocyclic or bicyclic heterocycle comprising 1 to 3 heteroatoms. In one embodiment the term heterocycle includes a 3-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. In one embodiment the term heterocycle includes a 4-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1-isoindolinyl]-3′-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, and 1,4-dioxane.

The term “heteroaryl” as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; “heteroaryl” also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, “heteroaryl” includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl oxazolyl or furyl. “Heteroaryl” also includes multiple condensed ring systems (e.g. ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from cycloalkyl, aryl, heterocycle, and heteroaryl. It is to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, and quinazolyl.

The term “alkoxycarbonyl” as used herein refers to a group (alkyl)-O—C(═O)—, wherein the term alkyl has the meaning defined herein.

The term “alkanoyloxy” as used herein refers to a group (alkyl)-C(═O)—O—, wherein the term alkyl has the meaning defined herein.

As used herein, the term “protecting group” refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl 2-(trimethylsilyl)ethoxymethyl, 2-4p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P. G. M. Wuts and T. W. Greene, Greene'sProtective Groups in Organic Synthesis4thedition, Wiley-Interscience, New York, 2006.

As used herein a wavy line “” that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule.

The terms “treat” “treatment”, or “treating” to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition. The terms “treat”, “treatment”, or “treating” also refer to both therapeutic treatment and/or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For example, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. “Treat”, “treatment”, or “treating,” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented. In one embodiment “treat”, “treatment”, or “treating” does not include preventing or prevention,

The phrase “therapeutically effective amount” or “effective amount” includes but is not limited to an amount of a compound of the that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein, or (iv) produces the described biological effect (e.g. produces a TGR5 agonist effect).

The term “mammal” as used herein refers to humans, higher non-human primates, rodents, domestic, cows, horses, pigs, sheep, dogs and cats. In one embodiment, the mammal is a human. The term “patient” as used herein refers to any animal including mammals. In one embodiment, the patient is a mammalian patient. In one embodiment, the patient is a human patient.

The compounds disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention

It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (2H or D). As a non-limiting example, a —CH3group may be substituted with —CD3.

The pharmaceutical compositions of the invention can comprise one or more excipients. When used in combination with the pharmaceutical compositions of the invention the term “excipients” refers generally to an additional ingredient that is combined with the compound of formula (I) or the pharmaceutically acceptable salt thereof to provide a corresponding composition. For example, when used in combination with the pharmaceutical compositions of the invention the term “excipients” includes, but is not limited to: carriers, binders, disintegrating agents, lubricants, sweetening agents, flavoring agents, coatings, preservatives, and dyes.

When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95 the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted.

The term “residue” as it applies to the residue of a compound refers to a compound that has been modified in any manner which results in the creation of an open valence wherein the site of the open valence. The open valence can be created by the removal of 1 or more atoms from the compound (e.g., removal of a single atom such as hydrogen or removal of more than one atom such as a group of atoms including but not limited to an amine, hydroxyl, methyl, amide (e.g., —C(═O)NH2) or acetyl group). The open valence can also be created by the chemical conversion of a first function group of the compound to a second functional group of the compound (e.g., reduction of a carbonyl group, replacement of a carbonyl group with an amine) followed by the removal of 1 or more atoms from the second functional group to create the open valence.

Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. It is to be understood that two or more values may be combined. It is also to be understood that the values listed herein below (or subsets thereof) can be excluded.

In one embodiment, the compound of formula (1) is a compound of formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:

R1is (C1-C6)alkyl that is substituted with one or more R5, wherein R5is independently selected from the group consisting of halo, cyano, heterocycle, heteroaryl, —OH, —C(═O)NH(C1-C6alkyl)(S(O)2Rc), —C(═O)NH(C1-C6alkyl)(C(═O)ORc), —C(═O)NRaRb, —OS(O))3Rc, —C(═O)NH(S(O)2Rc), —C(═O)ORc, and —C(═O)(C1-C6alkyl), wherein any heterocycle and heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, carboxy, —OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of —OH and (C1-C6)alkoxy;

R2is selected from the group consisting of —OH, —OC(═O)Rc, —OS(O)3H and (C1-C6)alkoxy;

R3is selected from the group consisting of —OC(═O)Rd, (C1-C6)alkyl, —OS(O)3Rcand (C1-C6)alkoxy;

R4is selected from the group consisting of H and —OH, where;

Raand Rbare independently selected from H and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle;

each Rcis independently selected from H and (C1-C6)alkyl;

Rdis H or (C2-C6)alkyl; or when R2is —OH, Rdis H or (C1-C6)alkyl;

Reis (C1-C6)alkyl and

R6is selected from the group consisting of H and (C1-C6)alkyl.

In one embodiment, the compound of formula (1) is a compound of formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein:

R1is (C1-C6)alkyl that is substituted with one or more R5, wherein R5is independently selected from the group consisting of halo, cyano, heterocycle, heteroaryl, —OH, —C(═O)NH(C1-C6alkyl)(S(O)2Rc), —C(═O)NH(C1-C6alkyl)(C(═O)OR), —C(═O)NRaRb, —OS(O)3Rc, —C(═O)NH(S(O)2Rc), —C(═O)ORc, and —C(═)(C1-C6alkyl), wherein any heterocycle and heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, carboxy, —OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxy carbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of —OH and (C1-C6)alkoxy;

R2is selected from the group consisting of —OH, —OC(═O)Rc, —OS(O)3H and (C1-C6)alkoxy;

R3is selected from the group consisting of —OC(═O)Rd, (C1-C6)alkyl, —OS(O)3Reand (C1-C6)alkoxy;

R4is selected from the group consisting of H and —OH, where;

Raand Rbare independently selected from H and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle;

each Rcis independently selected from H and (C1-C6)alkyl;

Rdis H or (C2-C6)alkyl; or when R2is —OH, Rdis H or (C1-C6)alkyl;

Reis (C1-C6)alkyl; and

R6is selected from the group consisting of H and (C1-C6)alkyl.

or a pharmaceutically acceptable salt thereof, wherein:

R1is (C1-C6)alkyl that is substituted with one or more R5, wherein R5is independently selected from the group consisting of halo, cyano, heterocycle, heteroaryl, —OH, —C(═O)NH(C1-C6alkyl)(S(O)2Rc), —C(═O)NH(C1-C6alkyl)(C(═O)OR), —C(═O)NRaRb, —OS(O)3Rc, —C(═O)NH(S(O)2Rc), —C(═O)ORc, and —C(═)(C1-C6alkyl), wherein any heterocycle and heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, carboxy, —OH, cyano, (C1-C6)alkyl, (C1-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of —OH and (C1-C6)alkoxy;

R2is selected from the group consisting of —OH, —OC(═O)Rc, —OS(O)3H and (C1-C6)alkoxy;

R4is selected from the group consisting of H and —OH, where;

Raand Rbare independently selected from H and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle;

each Rcis independently selected from H and (C1-C6)alkyl;

Reis (C1-C6)alkyl; and

n is 1, 2, or 3.

In one embodiment, R1is (C3-C6)alkyl that is substituted with one or more R5, wherein R5is independently selected from the group consisting of halo, cyano, heterocycle, heteroaryl, —OH, —C(═O)NH(C1-C6alkyl)(S(O)2Rc), —C(═O)NH(C1-C6alkyl)(C(═O)ORc), —C(═O)NRaRb, —OS(O)3Rc, —C(═O)NH(S(O)2Rc), —C(═O)ORc, and —C(═O)(C1-C6alkyl), wherein any heterocycle and heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, carboxy, —OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of —OH and (C1-C6)alkoxy.

In one embodiment, R1is (C1-C6)alkyl that is substituted with one or more R5, wherein R5is independently selected from the group consisting of halo, cyano, heterocycle, heteroaryl, —OH, —C(═)NH(C1-C6alkyl)(S(O)2Rc), —C(═O)NH(C1-C6alkyl)(C(═O)ORc), —C(═O)NRaRb, —OS(O)3Rc, —C(═O)NH(S(O)2Rc), —C(═O)ORc, and —C(═O)(C1-C6alkyl), wherein any heterocycle and heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, carboxy, —OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of —OH and (C1-C6)alkoxy.

In one embodiment, R1is

In one embodiment, R1is

In one embodiment, R1is

In one embodiment, R5is heteroaryl optionally substituted with (C1-C6)alkyl.

In one embodiment, R5is heteroaryl substituted with methyl.

In one embodiment, the invention provides a compound of formula (I):

or a salt thereof, wherein:

R1is (C1-C6)alkyl that is substituted with one or more R5, wherein R5is independently selected from the group consisting of halo, cyano, heterocycle, heteroaryl, —OH, —C(═O)NH(C1-C6alkyl)(S(O)2Rc), —C(═O)NH(C1-C6alkyl)(C(═O)ORc), —C(═O)NRaRb, —OS(O)3Rc, —C(═O)NH(S(O)2Rc), —C(═O)ORc, and —C(═O)(C1-C6alkyl), wherein any heterocycle and heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, carboxy, —OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of —OH and (C1-C6)alkoxy;

R2is selected from the group consisting of —OH, —OC(═O)Rc, —OS(O)3H and (C1-C6)alkoxy;

R4is selected from the group consisting of H and —OH, where;

Raand Rbare independently selected from H and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle;

each Rc, is independently selected from H and (C1-C6)alkyl;

Reis (C1-C6)alkyl; and

R6is selected from the group consisting of H and (C1-C6)alkyl, or R6and R3together with the atom to which they are attached form a carbocycle or heterocycle, wherein the carbocycle or heterocycle is optionally substituted with halo, cyano, heteroaryl, —OH and (C1-C6)alkyl.

In one embodiment, the invention provides a compound of formula (I):

or a salt thereof, wherein:

R1is (C1-C6)alkyl that is substituted with one or more R5, wherein R5is independently selected from the group consisting of halo, cyano, heterocycle, heteroaryl, —OH, —C(═O)NH(C1-C6alkyl)(S(O)2Rc), —C(═O)NH(C1-C6alkyl)(C(═O)ORc), —C(═)NRaRb, —OS(O)3Rc, —C(═O)NH(S(O)2Rc), —C(═O)ORc, and —C(═O)(C1-C6alkyl), wherein any heterocycle and heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, carboxy, —OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of —OH and (C1-C6)alkoxy;

R2is selected from the group consisting of —OH, —OC(═O)Rc, —OS(O)3H and (C1-C6)alkoxy;

R4is selected from the group consisting of H and —OH, where;

Raand Rbare independently selected from H and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle;

each Rcis independently selected from H and (C1-C6)alkyl;

R6is selected from the group consisting of H and (C1-C6)alkyl, or R6and R3together with the atom to which they are attached form a carbocycle or heterocycle, wherein the carbocycle or heterocycle is optionally substituted with halo, cyano, heteroaryl, —OH and (C1-C6)alkyl;provided that the compound or salt is not selected from the group consisting of:

and salts thereof.

In one embodiment, the invention provides a compound of formula (1):

or a salt thereof, wherein:

R1is (C1-C6)alkyl that is substituted with one or more R5, wherein R5is independently selected from the group consisting of halo, cyano, heterocycle, heteroaryl, —OH, —C(═O)NH(C1-C6alkyl)(S(O)2Rc), —C(═O)NH(C1-C6alkyl)(C(═O)Oc), —C(═O)NRaRb, —OS(O)3Rc, —C(═O)NH(S(O)2Rc), —C(═O)ORc, and —C(═O)(C1-C6alkyl), wherein any heterocycle and heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, carboxy, —OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of —OH and (C1-C6)alkoxy;

R2is selected from the group consisting of —OH, —OC(═O)Rc, —OS(O)3H and (C1-C6)alkoxy;

R4is selected from the group consisting of H and —OH, where;

Raand Rbare independently selected from H and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle;

each R is independently selected from H and (C1-C6)alkyl;

Rdis H or (C2-C6)alkyl; or when R2is —OH, Rdis H or (C1-C6)alkyl;

Reis (C1-C6)alkyl; and

R6is selected from the group consisting of H and (C1-C6)alkyl, or R6and R3together with the atom to which they are attached form a carbocycle or heterocycle, wherein the carbocycle or heterocycle is optionally substituted with halo, cyano, heteroaryl, —OH and (C1-C6)alkyl;provided that the compound or salt is not selected from the group consisting of:

and salts thereof.

In one embodiment, the invention provides a compound of formula (I):

or a salt thereof, wherein:

R1is (C1-C6)alkyl that is substituted with one or more R5, wherein R5is independently selected from the group consisting of halo, cyano, heterocycle, heteroaryl, —OH, —C(═O)NH(C1-C6alkyl)(S(O)2Rc), —C(═O)NH(C1-C6alkyl)(C(═)ORc), —C(O)NRaRb, —OS(O)3Rc, —C(═O)NH(S(O)2Rc), —C(═O)ORc, and —C(═O)(C1-C6alkyl), wherein any heterocycle and heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, carboxy, —OH, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy, wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio and (C2-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of —OH and (C1-C6)alkoxy;

R2is selected from the group consisting of —OH, —OC(═O)Rc, —OS(O)3H and (C1-C6)alkoxy;

R4is selected from the group consisting of H and —OH, where;

Raand Rbare independently selected from 1- and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and (C1-C6)alkoxy; or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered ring heterocycle;

each Rcis independently selected from H and (C1-C6)alkyl;

R6is selected from the group consisting of H and (C1-C6)alkyl, or R6and R3together with the atom to which they are attached form a carbocycle or heterocycle, wherein the carbocycle or heterocycle is optionally Substituted with halo, cyano, heteroaryl, —OH and (C1-C6)alkyl.

In one embodiment. R2is not —OC(═O)H.

In one embodiment, R3is not —OC(═O)H.

In one embodiment, both R2and R3are not —OC(═O)H.

In one embodiment, the compounds of formula (I) exclude compounds wherein R2is —OH; R3is —OC(═O)CH3; R4is H; and R1is (C1-C6)alkyl that is substituted with one or more groups independently selected from the group consisting of —OH, heteroaryl, and —C(═O)ORc.

In one embodiment, the invention provides a method for treating a TGR5 mediated condition in an animal (e.g. a human) in need of such treatment comprising administering to the animal a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a method for treating a TGR5 mediated condition in an animal (e.g. a human) comprising administering to the animal an effective TGR5 agonist amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a method for treating a TGR5 mediated condition in an animal (e.g. a human) in need of such treatment comprising administering to the animal an effective TGR5 agonist amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a TGR5 agonizing composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides an anti-obesity composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides an anti-inflammatory bowel disease composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides an anti-diabetic composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In cases where compounds are sufficiently basic or acidic, a salt of a compound of formula (I) can be useful as an intermediate for isolating or purifying a compound of formula (I). Additionally, administration of a compound of formula (I) as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

EXAMPLES

Example 3. Synthesis of (R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-hydroxy-7-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid

Example 4. Synthesis of (R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-hydroxy-7-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-N-(2-(2-methoxyethoxy)ethyl)pentanamide

a. Preparation of (R)-4-((3R,5R,7R,8R,9S,10S,13R,14S,17R)-3-((tert-butyldimethyl-silyl)oxy)-7-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-N-(2-(2-methoxyethoxy)ethyl)pentanamide.

To a solution of (R)-4-((3R,5R,7R,8R,9S,10S,13R,4S,17R)-3-((tert-butyldimethyl-silyl)oxy)-7-methoxy-10,13-dimethylhexadecahydro-H-cyclopenta[a]phenanthren-17-yl)pentanoic acid (114.5 mg, 0.220 mmol) in DCM (4 mL) was added DIEA (0.075 mL) and HATU (87.5 mg, 0.230 mmol). After stirring for 12 minutes, 2-(2-methoxyethoxy)ethanamine (0.030 mL, 0.241 mmol) was added by syringe. The next day, the crude material was purified by flash column chromatography on silica gel (35-100% EtOAc in hexanes as eluent). The resulting material was dissolved in EtOAc (75 mL) and extracted with water (4×75 mL) to obtain the title compound (131.7 mg, 96% yield) as a colorless oil.

b. Preparation of (R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-hydroxy-7-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-N-(2-(2-methoxyethoxy)ethyl)pentanamide.

Example 5. Synthesis of (3R,5S,7R,8R,9S,10S,13R,14S,17R)-7-methoxy-17-((R)-4-(5-(methoxymethyl)-1,3,4-oxadiazol-2-yl)butan-2-yl)-10,13-dimethylhexadecahydro-1-cyclopenta[a]phenanthren-3-ol

To a solution of (R)-4-((3R,5R,7R,8R,9S,10S,13R,14S,17R)-3-((tert-butyldimethyl-silyl)oxy)-7-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid (163.3 mg, 0.314 mmol) in DCM (6 mL) was added DIEA (0.100 mL) and HATU (128 mg, 0.337 mmol). After stirring for 10 minutes, 2-methoxyacetohydrazide (37.2 mg, 0.357 mmol) was added. After stirring for three days, the crude material was purified by flash column chromatography on silica gel (40-100% EtOAc in hexanes as eluent). The resulting material was dissolved in EtOAc (75 mL) and extracted with water (3×75 mL) to obtain the title compound (177 mg, 93% yield) as a white solid.

b. Preparation of 2-((R)-3-((3R,5R,7R,8R,9S,10S,13R,14S,17R)-3-((tert-butyl-dimethylsilyl)oxy)-7-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butyl)-5-(methoxymethyl)-1,3,4-oxadiazole.

To a solution of (R)-4-((3R,5R,7R,8R,9S,10S,13R,14S,17R)-3-((tert-butyl-dimethylsilyl)oxy)-7-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-N′-(2-methoxyacetyl)pentanehydrazide (168.8 mg, 0.278 mmol) in DCM (3 mL) and triethylamine (0.2 mL) was added 4-toluenesulfonyl chloride (59 mg, 0.309 mmol). After stirring overnight, the crude material was purified by flash column chromatography on silica gel (20-100% EtOAc in hexanes as eluent) to obtain the title compound (106.7 mg, 65% yield) as a clear, colorless oil.

c. Preparation of (3R,5S,7R,8R,9S,10S,13R,14S,17R)-7-methoxy-17-((R)-4-(5-(methoxymethyl)-1,3,4-oxadiazol-2-yl)butan-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol.

Example 6. Synthesis of (R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-hydroxy-7-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)pentanamide

a. Preparation of (R)-4-((3R,5R,7R,8R,9S,10S,13R,14S,17R)-3-((tert-butyl-dimethylsilyl)oxy)-7-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]-phenanthren-17-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)pentanamide.

To a solution of (R)-4-((3R,5R,7R,8R,9S,10S,13R,14S,17R)-3-((tert-butyl-dimethylsilyl)oxy)-7-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]-phenanthren-17-yl)pentanoic acid (100 mg, 0.192 mmol) in DCM (4 mL) was added DIEA (0.075 mL) and HATU (77 mg, 0.203 mmol). After stirring for 10 minutes, D-glucamine (42 ng, 0.232 mmol) was added. After stirring overnight, the reaction mixture was diluted with water (50 mL) and extracted with DCM (2×50 nL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography on silica gel (0-10% MeOH in EtOAc as eluent) to obtain the title compound (49.7 mg, 38% yield).

(R)-4-((3R,5R,7R,8R,9S,10S,13R,14S,17R)-3-((tert-butyldimethylsilyl)oxy)-7-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)pentanamide (49.5 mg, 0.095 mmol) was dissolved in 1 M TBAF in THF (2.0 mL). After stirring at room temperature for 4 days, the reaction mixture was concentrated and the resulting residue was purified by liquid chromatography (10% CH3CN/water to 100% CH3CN, C18 column) to yield, after lyophilization, the title compound (31.9 mg, 59%) as a white solid. L C/MS (ESI): m/z calcd. C31H56NO8(M+H+) 570.4, found 570.4.

Example 7. Synthesis of (R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3-hydroxy-7-methoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-N-methyl-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)pentanamide

TGR5 agonist activity was evaluated by assaying cAMP production in a recombinant cell line expressing human TGR5 receptor as described in Example 8.

TGR5 agonist activity was evaluated by assaying cAMP production in a recombinant cell line expressing human TGR5 receptor. Data for representative compounds is provided in the following table.

A comparison of this data and the data presented inFIG. 2andFIG. 3demonstrates that potency improved when the 7-hydroxy group was replaced with a 7-methoxy group.

The following illustrate representative pharmaceutical dosage forms, containing a compound of formula (1) (‘Compound X’), for therapeutic or prophylactic use in humans.

(vi) Aerosolmg/canCompound X=20.0Oleic acid10.0Trichloromonofluoromethane5,000.0Dichlorodifluoromethane10,000.0Dichlorotetrafluoroethane5,000.0
The above formulations may be obtained by conventional procedures well known in the pharmaceutical art.

All publications (including A. Nakhi, et al.,J. Med. Chem.2019, 62, 6824-2830), patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.