Non-systemic TGR5 agonists

This application claims the benefit of International Application No. PCT/US2017/039998, filed Jun. 29, 2017, which claims the benefit of U.S. Provisional Application Ser. No. 62/357,427, filed on Jul. 1, 2016. The entire teachings of the referenced applications are herein incorporated by reference in their entirety.

The present invention relates to novel compounds and pharmaceutically acceptable salts thereof that are useful as non-systemic TGR5 agonists. The present invention also relates to compositions containing such compounds, process of preparing and methods of use thereof.

TGR5 (also known as G protein-coupled bile acid receptor 1 (GPBAR1), M-BAR, or BG-371) is a receptor present on L-cells within the gastrointestinal compartment in humans. Upon binding of bile acids, TGR5 causes the release of glucagon-like peptide-1 (GLP-1) which in turn stimulates insulin secretion and suppresses glucagon secretion (Katsuma et al., Biochem. Biophys. Res. Commun., 2005, 329 (1), 386-390). Therapeutic attempts have been made to elevate GLP-1 in the blood to improve glycemic control. One approach involves the use of dipeptidyl peptidase-4 (DPP-4) inhibitors to slow down GLP-1 degradation. Another approach employs GLP-1 analogs that mimic the natural GLP-1. Yet another approach utilizes TGR5 agonists to stimulate the TGR5 receptor and trigger its signal cascades within the L-cells for glucose control.

Multiple TGR5 modulators with diverse structural features have been reported. U.S. Pat. No. 8,114,862 discloses a series of 23-substituted bile acids that mimic natural bile acids as TGR5 modulators. WO2013/164838 discloses TGR5 agonists containing 1, 2, 4-triazole with a linker containing sulfur and their use in treating diabetes, obesity and related disorders. WO2009/026241 discloses TGR5 modulators having a structure of pyrimidin-4-one that is fused with a 5 or 6-membered heterocyclic or heteroaryl group. WO2012/082947 discloses pyrazolyl based TGR5 agonists. WO2011/071565 discloses TGR5 agonists that are imidazole derivatives. WO2012/149236 discloses bicyclic heteroaryl compounds that are TGR5 agonists. WO2013/134527 discloses polycyclic alkaloids as TGR5 agonists. WO2004/067008 discloses TGR5 agonists containing benzodiazepine-2-one. WO2013/096771 discloses TGR5 agonists containing tetrahydroquinoxaline and their use in treating type 2 diabetes mellitus. WO2013/096771 further discloses some TGR5 compounds that are substantially non-bioavailable in the blood stream.

There has been a concern for an increased risk of pancreatitis in type 2 diabetes patients treated with GLP-1-based therapies (Singh et al., JAMA Intern. Med., 2013, 173 (7), 534-539). Subsequent clinical studies, however, do not seem to support this contention (Butler et al., Diabetes, 2013, 62 (7), 2595-2604). It remains to be determined if systemic delivery of a TGR5 agonist may attribute to the pancreatitis.

Phillips et al. disclosed trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as potent, orally bioavailable TGR5 agonists ( J. Med. Chem., 2014, 57(8), 3263-3282). The lead Compound (45h) represents a potent and selective TGR5 agonist that has high plasma exposure (i.e., high C max value). The authors reported glycemic effect of Compound 45h was lost upon chronic dosing. Phillips et al. questioned toxicological and therapeutic issues that may limit the utility of these systemic TGR5 agonists for treatment of metabolic disease.

There is a continuing need in developing a non-systemic TGR5 agonist, one that is restricted in the gastrointestinal compartment and has clinical safety and efficacy profiles suitable for oral administration in treating metabolic disorders.

The present invention provides novel compounds represented by formula (I):

and formula (II):

and pharmaceutically acceptable salts thereof.

The present heterocyclic compounds are useful non-systemic TGR5 agonists to treat metabolic disorders including diabetes and obesity. The present invention provides a pharmaceutical composition containing such compounds as well as a process of making them and a method of administering same to treat patients suffering from metabolic disorders. The present compounds may be used in combination with other anti-diabetic drugs.

FIG. 1 depicts the plasma glucose level in an Oral Glucose Tolerance Test (OGTT) in C57BL/6NT mice treated with vehicle, sitagliptin (3 mg/kg), Compound 56 (30 mg/kg), or Compound 56 (30 mg/kg)+sitagliptin (3 mg/kg).

FIG. 2 depicts the area under the curve (AUC) of plasma glucose level in an Oral Glucose Tolerance Test (OGTT) in C57BL/6NT mice treated with vehicle, sitagliptin (3 mg/kg), Compound 56 (30 mg/kg), or Compound 56 (30 mg/kg)+sitagliptin (3 mg/kg).

FIG. 3 depicts the GLP-1 elevation in C57BL/6NT mice treated with vehicle, sitagliptin (3 mg/kg), Compound 56 (30 mg/kg), or Compound 56 (30 mg/kg)+sitagliptin (3 mg/kg).

FIG. 4 depicts the plasma glucose level in an Oral Glucose Tolerance Test (OGTT) in C57BL/6NT mice treated with Compound 268 (30 mg/kg)+sitagliptin (3 mg/kg) or sitagliptin (3 mg/kg).

FIG. 5 depicts the area under the curve (AUC) of plasma glucose level in an Oral Glucose Tolerance Test (OGTT) in C57BL/6NT mice treated with Compound 268 (30 mg/kg)+sitagliptin (3 mg/kg) or sitagliptin (3 mg/kg).

FIG. 6 depicts the GLP-1 elevation in C57BL/6NT mice treated with treated with Compound 268 (30 mg/kg)+sitagliptin (3 mg/kg) or sitagliptin (3 mg/kg).

FIG. 7 depicts the time course (i.e., 6, 12, 18, and 24 hours) of the changes in bile weights in DIO male mice treated with Compound 268 (30 mg/kg)+sitagliptin (10 mg/kg), or sitagliptin (10 mg/kg).

FIG. 8 depicts the bile weights in C57BL/6N lean mice treated with Compound 268 (30 mg/kg)+sitagliptin (10 mg/kg) or sitagliptin (10 mg/kg).

FIG. 9 depicts the time course (i.e., 6, 12, 18, and 24 hours) increases in GLP-1 in DIO male mice treated with Compound 268 (30 mg/kg)+sitagliptin (10 mg/kg) or sitagliptin (10 mg/kg).

FIG. 10 depicts the time course (i.e., 6, 12, 18, and 24 hours) of plasma concentration of Compound 268 in DIO male mice.

FIG. 11 depicts the plasma concentration of Compound 268 in the Compound 268 (10 mg/kg)+sitagliptin (3 mg/kg) or sitagliptin (3 mg/kg) in C57BL/5N mice after oral dosing. Note that there is a minimal level change in plasma Compound 268 at 6 hour post-dose.

FIG. 12 depicts the sustained GLP-1 increase in plasma following oral administration of Compound 268 (30 mg/kg)+sitagliptin (10 mg/mkg) or sitagliptin (10 mg/kg) in DIO mice at 0, 3, 6, 9, and 12 hours of day 1 (after dose 2) and day 5 (after dose 10).

FIG. 13 depicts the time course of bile weight changes over times in DIO mice receiving Compound 268 (30 mg/kg)+sitagliptin (10 mg/kg) or sitagliptin (10 mg/kg).

FIG. 14 depicts the plasma concentration of Compound 268 at 0, 3, 6, 9, and 12 hours after the 2 nd dose and 3, 6, 9, and 12 hours after the 10 th dose.

FIG. 15 depicts the C max (nM) of Compounds 56, 126, 268, 199, 61, and 249 (10 mg/kg) in ICR mice with and without 1-aminobenzotriazole pretreatment (150 mg/kg). Propranolol serves as a positive control.

FIG. 16 depicts the body weight changes over 42 days in DIO mice receiving twice a day oral administration of vehicle, Compound 268 (30 mg/kg), sitagliptin (10 mg/kg), or Compound 268 (30 mg/kg)+sitagliptin (10 mg/kg). Rimonabant (10 mg/kg once a day) serves at the positive control.

FIG. 17 depicts the food intake over multiple weeks in DIO mice receiving twice a day oral administration of vehicle, Compound 268 (30 mg/kg), sitagliptin (10 mg/kg), or Compound 268 (30 mg/kg)+sitagliptin (10 mg/kg). Rimonabant (10 mg/kg once a day) serves at the positive control.

FIG. 18 depicts the glucose levels in an OGTT experiment in DIO mice conducted after 5 weeks receiving twice a day oral administration of vehicle, Compound 268 (30 mg/kg), sitagliptin (10 mg/kg), or Compound 268 (30 mg/kg)+sitagliptin (10 mg/kg). Rimonabant (10 mg/kg once a day) serves at the positive control.

FIG. 19 depicts the insulin levels in an OGTT experiment in DIO mice conducted after 5 weeks receiving twice a day oral administration of vehicle, Compound 268 (30 mg/kg), sitagliptin (10 mg/kg), or Compound 268 (30 mg/kg)+sitagliptin (10 mg/kg). Rimonabant (10 mg/kg once a day) serves at the positive control.

FIG. 20 depicts the total tissue mass of DIO mice after 6 weeks of receiving twice a day oral administration of vehicle, Compound 268 (30 mg/kg), sitagliptin (10 mg/kg), or Compound 268 (30 mg/kg)+sitagliptin (10 mg/kg). Rimonabant (10 mg/kg once a day) serves at the positive control.

FIG. 21 depicts the fat mass of DIO mice after 6 weeks of receiving twice a day oral administration of vehicle, Compound 268 (30 mg/kg), sitagliptin (10 mg/kg), or Compound 268 (30 mg/kg)+sitagliptin (10 mg/kg). Rimonabant (10 mg/kg once a day) serves at the positive control.

FIG. 22 depicts the lean mass of DIO mice after 6 weeks of receiving twice a day oral administration of vehicle, Compound 268 (30 mg/kg), sitagliptin (10 mg/kg), or Compound 268 (30 mg/kg)+sitagliptin (10 mg/kg). Rimonabant (10 mg/kg once a day) serves at the positive control.

FIG. 23 depicts the GLP-1 elevation in DIO mice after 43 days of receiving twice a day oral administration of vehicle, Compound 268 (30 mg/kg), sitagliptin (10 mg/kg), or Compound 268 (30 mg/kg)+sitagliptin (10 mg/kg). Rimonabant (10 mg/kg once a day) serves at the positive control.

FIG. 24 depicts the plasma concentration of Compound 268 in DIO mice after 43 days of receiving twice a day oral administration of vehicle, Compound 268 (30 mg/kg), sitagliptin (10 mg/kg), or Compound 268 (30 mg/kg)+sitagliptin (10 mg/kg). Rimonabant (10 mg/kg once a day) serves at the positive control.

FIG. 25 depicts the bile weight change in DIO mice after 43 days of receiving twice a day oral administration of vehicle, Compound 268 (30 mg/kg), sitagliptin (10 mg/kg), or Compound 268 (30 mg/kg)+sitagliptin (10 mg/kg). Rimonabant (10 mg/kg once a day) serves at the positive control.

As used herein, number ranges where provided (e.g., 1-6) refer to each and every number in that range as a discrete embodiment.

As used herein, the term “alkyl” refers to a saturated carbon chain up to 10 carbons that may be linear, branched or a combination thereof. Exemplary alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- and tert-butyl, pentyl, hexyl, and the like. C 1-6 alkyl refers to a saturated carbon chain that may be linear, branched or a combination thereof which contains one to six carbon atoms.

As used herein, the term “alkenyl” refers a carbon chain up to 10 carbons that contains at least one carbon-carbon double bond, and that may be linear, branched or a combination thereof. Exemplary alkenyl includes vinyl, allyl, isopropenyl, pentneyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.

As used herein, the term “alkynyl” refers a carbon chain up to 10 carbons that contains at least one carbon-carbon triple bond, and that may be linear, branched or a combination thereof. Exemplary alkynyl includes ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like.

As used herein, the term “alkoxy” refers to an alkyl up to 10 carbons linked to the parent structure through an oxygen. Exemplary alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.

As used herein, the term “cycloalkyl” refers to a monocyclic, bicyclic, tricyclic or bridged saturated hydrocarbon ring system containing 3-14 carbons. Exemplary cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthyl and the like.

As used herein, the term “cycloalkenyl” refers a monocyclic, bicyclic, tricyclic or bridged non-aromatic hydrocarbon ring system containing 3-14 carbons and at least one double bond. Exemplary cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.

As used herein, the term “heterocycloalkyl” refers to a monocyclic, bicyclic, tricyclic, or bridged saturated hydrocarbon ring system containing 2-14 carbons and 1, 2, 3, 4, or 5 heteroatoms selected from oxygen (“0”), sulfur (“S”) and nitrogen (“N”) atoms. Exemplary heterocycloalkyl includes aziridinyl, azetidinyl, tetrahydrofuranyl, dioxanyl, oxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, imidazolidinyl, pyrrolidinyl, pyrazolidinyl, tetrahydropyranyl, and the like.

As used herein, the term “aryl” refers to a monocyclic, bicyclic, or tricyclic hydrocarbon ring system containing 5-14 carbon atoms, wherein at least one of the rings is aromatic. Aryl includes a ring system in which an aromatic ring is fused to a non-aromatic ring, such as a cycloalkyl or a cycloalkenyl ring. Exemplary aryl includes phenyl, naphthyl, indanyl, benzocyclobutanyl, tetrahydronaphthy, and the like.

As used herein, the term “heteroaryl” refers to a monocyclic, bicyclic or tricyclic hydrocarbon ring system containing 5-14 carbon atoms and containing 1, 2, 3, 4, or 5 heteroatoms selected from oxygen (“O”), sulfur (“S”) and nitrogen (“N”) atoms, wherein at least one of the heteroatoms containing rings is aromatic. “Heteroaryl” also refers to a ring system in which an aromatic heteroatom containing ring is fused to a non-aromatic ring such as a cycloalkyl, cycloalkenyl or heterocycloalkyl ring, and refers to a ring system in which an aryl is fused to a non-aromatic heteroatom containing ring, such as a heterocycloalkyl ring. Exemplary heteroaryl includes pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, oxo-dihydroqunoline, indolyl, oxindole, isoquinolyl, dibenzofuranyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydrobenzodioxinyl, dihydroindolyl, isoindolinyl, and the like.

As used herein, the term “halogen” refers to fluorine, chlorine, bromine, and iodine.

As used herein, the term “floating bond”, when used in connection with a substituent depicted in a formula (e.g., —(R)), refers to that substituent (e.g., R) permitted on any available carbon or nitrogen atom in the ring to which the substituent is attached, unless expressly depicted or described.

As used herein, the term that a certain group “is optionally substituted” refers to any group having that particular component thereof can be further substituted. For example, “alkyl group is optionally further substituted with” refers any group possessing an alkyl component can be further substituted thereof. The term includes “mono-”, “di-” or “tri-” substitutions.

As used herein, the term “ortho,” “meta” and “para” (abbreviated as “o-,” “m-,” and “p-”) refers to the position of two identical or different substituents relative to each other in a benzene ring. For example, ortho substitution refers to two substituents that are located in the 1, 2 positions of a benzene ring; meta substitution refers to two substituents that are located in the 1, 3 positions of a benzene ring; para substitution refers to two substituents that are located in the 1, 4 positions of a benzene ring.

When any variable (e.g., R 1 , R 2 ) occurs more than one time in any substituent, its definition on each occurrence is independent of its definition at every other occurrence. Also combinations of substituents and/or variables are permissible only if such combinations result in stable compounds, and conform to well-known principles of chemical structure connectivity and stability. A squiggly line “ ” across a bond in a substituent variable represents the points of attachment.

As used herein, the term “pharmaceutically acceptable” refers to compositions, polymers, solvates, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without causing excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable risk and benefit ratio.

As used herein, the term “pharmaceutically acceptable salt” refers to a derivative of a compound of the present invention wherein the parent compound is modified by making acid or base salts thereof. It includes inorganic or organic acid salts of basic residues such as amines; and inorganic or organic basic salts of acidic residues such as carboxylic acids. Exemplary pharmaceutically acceptable salt includes acetate, bicarbonate, bisulfate, formate, hydrochloride, sulfate, phosphate, and the like.

As used herein, the term “pharmaceutical composition” refers to a composition comprising a compound of the present invention together with a pharmaceutically acceptable carrier.

As used herein, the term “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable excipient that is not injurious to a patient. Exemplary pharmaceutically acceptable carrier includes starch, cellulose, gelatin, talc, glycol, polyol, ester, agar, buffering agents, alginic acid, and the like that are employed in pharmaceutical formulations.

As used herein, the term “administering” or “administration” refers to providing a compound, a pharmaceutically acceptable salt, solvate, or prodrug thereof to a human subject in need of treatment by oral administration.

As used herein, the term “mammal” refers to animal species that has the distinguished features by the presence of sweat glands, including those that are specialized to produce milk to nourish the young. Exemplary mammal includes human, mouse, rat, dog and the like.

As used herein, the term “treating” or “treatment” refers to an intervention (e.g., the administration of an agent to a subject) which cures, ameliorates or lessons the symptoms of a disease or removes (or lessens the impacts of) its cause(s).

As used herein, the term “therapeutically effective amount” refers to an amount of a compound of the present invention which, as compared to a corresponding human subject who has not received such an amount, results in improved treatment, prevention, or amelioration of metabolic disorders. The amount will depend on the particular condition, co-administrated compounds if any, and the characteristics of the human subject, such as general health, other diseases, age, sex, genotype, body weight, and tolerance to drugs. Those skilled in the art will be able to determine appropriate dosages depending on these and other factors.

As used herein, the term “combination” refers to a compound of the present invention and an additional therapeutic agent useful for the treatment of metabolic disorders. Exemplary therapeutic agent includes insulin, GLP-1 mimics, DPP-4 inhibitors, and the like. DPP-4 inhibitors include but not limited to alogliptin, linagliptin, saxagliptin, sitagliptin, anagliptin, teneligliptin, trelagliptin, vildagliptin, gemigliptin, omarigliptin, evogliptin, and dutogliptin.

As used herein, the term “metabolic disorder” refers to a disorder that disrupts the normal process of converting food to energy on a cellular level (i.e., metabolism that involves the processing or transporting proteins (amino acids), carbohydrates (sugars and starches), or lipids (fatty acids). Such disorder is usually due to a hormone or enzyme deficiency.

As used herein, the term “TGR5-related metabolic disorder” refers to a metabolic disorder that is resulted from a deficiency in TGR5 signaling. Exemplary TGR5-related metabolic disorders include, but not limited to pre-diabetes, type-2 diabetes/glucose homeostasis, obesity, fibrosing cholangitis, inflammatory diseases such as colitis, digestive disease such as pancreatitis and cancer. Such metabolic disorders are understood to be treatable with a TGR5 agonist.

As used herein, the term “diabetic,” “diabetes” or “diabetes mellitus” are used interchangeably in this application to refer to a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. The term “type 2 diabetes (formerly adult-onset diabetes)” refers to a condition in which a human is clinically diagnosed with any of the three tests: (i) having a fasting plasma blood glucose level of 126° mg/dL or greater on two separate occasions; (ii) an oral glucose tolerance of 200 mg/dL or greater; or (iii) an A1C (hemoglobin A1c test) of 6.5% or greater.

As used herein, the term “pre-diabetic” or “pre-diabetes” refers to a condition in which blood glucose levels are higher than normal, but not high enough to be classified as diabetes. Pre-diabetes in human is clinically diagnosed with any of the three tests: (i) having a fasting plasma blood glucose level between 100 and 125 mg/dL (“impaired fasting glucose”); (ii) an oral glucose tolerance between 140 and 199 mg/dL (“impaired glucose tolerance”); or (iii) an A1C of 5.7-6.4 percent.

As used herein, the term “obesity” refers to an adult human who has a body mass index (“BMI”) of 30 or higher.

As used herein, the term “non-systemic” refers to minimized systemic exposure of a compound after ingestion. For purposes of this application, “non-systemic” and “low plasma exposure” are used interchangeably and refer to C max of <200 ng/mL.

As used herein, the term “non-absorbed” refers to a compound that is restricted to the gut compartment and acts within the intestinal lumen without reaching the systemic circulation.

As used herein, the term “bioavailability” or “systemic availability” refers to the extent to which a compound that is taken up by a specific tissue or organ after administration; the proportion of the dose of a drug that reaches the systemic circulation intact after administration by a route other than intravenous. Bioavailability is distinct from its chemical potency.

As used herein, the term “EC 50 ” refers to the concentration of a compound which induces a response halfway between the baseline and maximum after a specified exposure time and is used as a measure of compound potency. It represents the concentration of a compound where 50% of its maximal effect is observed.

As used herein, the term “pharmacokinetics” (PK) refers to how the body affects a specific drug after administration through the mechanisms of absorption and distribution, as well as the chemical changes of the substance, and the effects and routes of excretion of the metabolites of the drug. Measured PK metrics include: C max (peak plasma concentration of a drug after administration), t max (time to reach C max ), area under the curve (“AUC” the integral of the concentration-time curve), bioavailability, and the like.

The present invention relates to novel heteroyclic compounds and pharmaceutically acceptable salts thereof that are useful in the treatment of type-2 diabetes and obesity. These compounds are non-systemic TGR5 agonists. The present invention also relates to pharmaceutical compositions containing such compounds, process of making and methods of using such compounds in treating metabolic disorders.

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

or a pharmaceutically acceptable salt thereof, wherein:

each R 1 is independently CN, C 1-6 alkyl, pyridyl, or C 1-6 alkoxy, wherein alkyl group is optionally further substituted with 1-4 halogen; m is 0, 1, 2, or 3; R 2 is C 1-6 alkyl or H, wherein alkyl group is optionally further substituted with 1-4 halogen; X is CH or N; P is CH or N; L 1 , L 2 and L 3 are each independently absent,

As used herein, the symbol when drawn through a bond refers to the point of attachment of a functional group to the parent molecule. When the functional group has two symbols present, it means the functional group has two points of attachment. For purpose of the present application, the left-hand point of attachment of the functional group is attached to the left-hand side of the parent molecule. While the right-hand point of attachment of the functional group is attached to the right-hand side of the parent molecule. For example, the left-hand side of L 1 is attached to (CHR) n2 of the parent molecule, while the right-hand side of the L 1 is attached to (CHR) n1 of the parent molecule.

In one embodiment, L 3 is absent, and L 1 and L 2 are each independently

wherein N is optionally further mono- or di-substituted with C 1-3 alkyl.

In one preferred embodiment, when L 3 is absent, L 1 and L 2 are each independently

wherein N is optionally further substituted with C 1-3 alkyl.

In one preferred embodiment, when L 3 is absent, L 1 and L 2 are each independently

wherein N is optionally further substituted with C 1-3 alkyl.

In one embodiment, L 2 and L 3 are absent, and L 1 is

wherein N is optionally further mono- or di-substituted with C 1-3 alkyl.

In one preferred embodiment, when L 2 and L 3 are absent, L 1 is

wherein N is optionally further substituted with C 1-3 alkyl.

In one preferred embodiment, when L 2 and L 3 are absent, L 1 is

wherein N is optionally further substituted with C 1-3 alkyl.

In one embodiment, n 1 , n 2 , n 3 and n 4 are each independently 0, 1, 2, 3 or 4.

In one preferred embodiment, n 1 , n 2 , n 3 and n 4 are each independently 0, 1, 2 or 3.

In one embodiment, each R is independently H, NH 2 , COOH or C 1-6 alkylNHC(NH)ONH 2 .

In one preferred embodiment, each R is independently H, NH 2 or COOH.

In one embodiment, T is

or NH 2 , wherein N is optionally further mono-, di-, or tri-substituted with C 1-3 alkyl.

In one preferred embodiment, T is

or NH 2 , wherein N is optionally further mono-, di-, or tri-substituted with C 1-3 alkyl.

In one embodiment, n is 0. In one preferred embodiment, phenethylcarboxamide is substituted in the two position of N in the azetidinyl ring. In one preferred embodiment, phenethylcarboxamide is substituted in the two position of N in the azetidinyl ring with S configuration.

In one embodiment, n is 1. In one preferred embodiment, phenethylcarboxamide is substituted in the two position of N in the pyrrolidinyl ring. In one preferred embodiment, phenethylcarboxamide is substituted in the two position of N in the pyrrolidinyl ring with S configuration.

In one embodiment, n is 2. In one preferred embodiment, phenethylcarboxamide is substituted in the three position of N in the piperidinyl ring. In one preferred embodiment, phenethylcarboxamide is substituted in the three position of N in the piperidinyl ring with R configuration.

In one embodiment, P is CH. In one embodiment, P is N.

In one embodiment, X is N. In one embodiment, X is CH.

In one embodiment, R 2 is C 1-6 alkyl, wherein alkyl group is optionally further substituted with 1-4 halogen. In one preferred embodiment, R 2 is CH 3 . In one preferred embodiment, R 2 is CF 3 .

In one embodiment, R 1 is each independently CN or C 1-6 alkyl, wherein alkyl group is optionally further substituted with 1-4 halogen.

In one preferred embodiment, R 1 is CN. In one preferred embodiment, R 1 is CF 3 . In one preferred embodiment, the CN or CF 3 substitution occurs on the para position of phenethyl ring.

In one embodiment, R 1 is C 1-2 alkoxy. In one preferred embodiment, R 1 is OCH 3 .

In one embodiment, m is 1 or 2. In one preferred embodiment, m is 1.

In one embodiment, R 3 and R 4 are each independently H, OH, F, or NH 2 . In one preferred embodiment, R 3 and R 4 are each independently H or OH. In one preferred embodiment, R 3 and R 4 are each independently H.

In one preferred embodiment, the present invention provides a compound selected from:

1) (S)—N-(4-cyanophenethyl)-1-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 2) (S)-1-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)-phenethyl)pyrrolidine-2-carboxamide; 3) (S)-1-(6-(4-(2-(dimethylamino)ethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)-pyrrolidine-2-carboxamide; 4) (S)-tert-butyl (2-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl) carbamoyl)pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl)carbamate; 5) (S)-1-(6-(4-(2-hydroxyethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)-pyrrolidine-2-carboxamide; 6) (S)-1-(6-(4-(methoxymethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)-pyrrolidine-2-carboxamide; 7) (S)-4-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl) carbamoyl) pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanoic acid; 8) (S)-1-(6-(4-(2-cyanoethyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)-phenethyl)pyrrolidine-2-carboxamide; 9) (S)-1-(6-(4-(2-cyanoethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)-pyrrolidine-2-carboxamide; 10) (S)-tert-butyl ((1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)methyl)carbamate; 11) (S)-tert-butyl (2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)carbamate; 12) (S)—N-(4-cyanophenethyl)-1-(6-(4-((dimethylamino)methyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 13) (S)-tert-butyl ((1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)methyl) (methyl)carbamate; 14) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-(dimethylamino)ethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 15) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-hydroxyethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 16) (S)—N-(4-cyanophenethyl)-1-(6-(4-(3-hydroxypropyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 17) (S)—N-(4-cyanophenethyl)-1-(6-(4-(methoxymethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 18) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-methoxyethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 19) (S)-2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)acetic acid; 20) (S)-3-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)propanoic acid; 21) (S)-4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanoic acid; 22) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 23) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 24) (S)-1-(6-(4-(2-cyanoethyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 25) (S)-1-(6-(4-(2-cyanoethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 26) (S)-4-(1-(6-(2-((2-methoxy-4-(trifluoromethyl)phenethyl) carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)-pyrimidin-4-yl)piperidin-4-yl)butanoic acid; 27) (S)-4-(1-(6-(2-((2,4-dichlorophenethyl)carbamoyl)pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanoic acid; 28) (S)—N-(4-cyanophenethyl)-1-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methylpyrimidin-4-yl)pyrrolidine-2-carboxamide; 29) (S)—N-(4-cyanophenethyl)-1-(4-(4-(hydroxymethyl)piperidin-1-yl)-6-(trifluoromethyl)pyridine-2-yl)pyrrolidine-2-carboxamide; 30) (S)-1-(6-(4-(aminomethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 31) (S)—N-(4-cyanophenethyl)-1-(6-(3-oxopiperazin-1-yl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 32) (S)-1-(6-(4-(2-aminoethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 33) (S)-1-(6-(4-(acetamidomethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 34) (S)—N-(4-cyanophenethyl)-1-(6-(4-((N-methyl acetamido)methyl) piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 35) (S)-ethyl 3-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)propanoate; 36) (S)-2-(3-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)propanamido)ethanesulfonic acid; 37) (S)-2-(4-(1-(6-(2-((2-methoxy-4-(trifluoromethyl)phenethyl)carbamoyl)-pyrrolidin-1-yl)-2-(trifluoromethyl)-pyrimidin-4-yl)piperidin-4-yl) butanamido)ethanesulfonic acid; 38) (S)-2-(4-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl)-carbamoyl)-pyrrolidin-1-yl)-pyrimidin-4-yl)piperidin-4-yl) butanamido)ethanesulfonic acid; 39) (S)-1-(6-(4-(4-oxo-4-((2-sulfamoylethyl)amino)butyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)-pyrrolidine-2-carboxamide; 40) (S)-3-(4-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl) carbamoyl)pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanamido)propane-1-sulfonic acid; 41) (S)-2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-piperidin-4-yl)butanamido)ethanesulfonic acid; 42) (S)—N-(4-cyanophenethyl)-1-(6-(4-(4-oxo-4-((2-sulfamoylethyl)amino) butyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 43) (S)-3-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-piperidin-4-yl)butanamido)propane-1-sulfonic acid; 44) (S)-((4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)methyl)-phosphonic acid; 45) (S)-4-(4-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-5-methoxy-N,N,N-trimethyl-5-oxopentan-1-aminium; 46) (S)-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-methanesulfonic acid; 47) (S)-1-(6-(4-(4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 48) (S)-1-(6-(4-(4-((2-amino-2-oxoethyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 49) (S)-methyl 2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)acetate; 50) (S)-methyl 3-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-propanoate; 51) (S)-methyl 2-amino-6-(4-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)-pyrrolidin-1-yl)-2-(trifluoromethyl)-pyrimidin-4-yl)piperidin-4-yl)butanamido)hexanoate; 52) (S)-2-(4-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-5-guanidinopentanoic acid; 53) (R)-2-(4-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-5-guanidinopentanoic acid; 54) (S)-5-guanidino-2-(4-(1-(2-(trifluoromethyl)-6-((S)-2-((4-(trifluoromethyl)phenethyl)carbamoyl)pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanamido)pentanoic acid; 55) (R)-2-(4-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)succinic acid; 56) (S)-2-(4-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-pentanedioic acid; 57) (S)-2-amino-5-oxo-5-((3-(1-(2-(trifluoromethyl)-6-((S)-2-((4-(trifluoromethyl)phenethyl)carbamoyl)pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)propyl)amino)pentanoic acid; 58) (S)-2-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)ethanesulfonic acid; 59) (S)-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)methanesulfonic acid; 60) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-(3-(2-sulfamoylethyl)ureido)-ethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 61) (S)-3-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)-propanoic acid; 62) (R)-2-(3-(2-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)succinic acid; 63) (S)-2-(3-(2-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)-5-guanidinopentanoic acid; 64) (S)—N-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)-4-(hydroxymethyl)-4-methylpiperidine-1-carboxamide; 65) (S)—N-(2-(1-(6-(2-((4-cyanophenethyl)-carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)-2-(2-aminoethylsulfonamido)acetate methyl ester; 66) (S)-2-(3-(2-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl)-carbamoyl)pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)-ethanesulfonic acid; 67) (S)-2-(3-(3-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl)-carbamoyl)-pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)propyl)ureido)-ethanesulfonic acid; 68) (S)-2-((1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)methoxy)acetic acid; 69) (S)-2-(2-((1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)methoxy)acetamido)-ethanesulfonic acid; 70) (S)-1-(6-(4-(4-((2-aminoethyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)pyrrolidine-2-carboxamide; 71) (S)-1-(6-(4-(4-((2-(methylsulfonamido)ethyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)pyrrolidine-2-carboxamide; 72) (S)-1-(6-(4-(4-((2-aminoethyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 73) (S)—N-(4-cyanophenethyl)-1-(6-(4-(4-((2-(methylsulfonamido)ethyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 74) (S)-4-(N-(2-(4-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl)-carbamoyl)-pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanamido)ethyl)-sulfamoyl)benzoic acid; 75) (S)-1-(6-(4-(4-((2-((9H-purin-6-yl)amino)ethyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)pyrrolidine-2-carboxamide; 76) (2 S)-1-(6-(4-(4-((2-((9-((2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-9H-purin-6-yl)amino)ethyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)-pyrimidin-4-yl)-N-(4-(trifluoromethyl)-phenethyl)-pyrrolidine-2-carboxamide; 77) (2 S)—N-(4-cyanophenethyl)-1-(6-(4-(4-((2-((9-((2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-purin-6-yl)amino)ethyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)-pyrimidin-4-yl)pyrrolidine-2-carboxamide; 78) (S)-2-((2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)ethyl)-amino)pyrimidine-5-carboxylic acid; 79) (S)-methyl-2-((2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-piperidin-4-yl)butanamido)ethyl)amino)-pyrimidine-4-carboxylate; 80) N-(2-(4-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)ethyl)-6-(((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)-pyrimidine-4-carboxamide; 81) (S)-6-((2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)ethyl)amino)-pyrimidine-4-carboxylic acid; 82) (S)-2-((2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)ethyl)amino) pyrimidine-4-carboxylic acid; 83) (S)-2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)acetic acid; 84) (S)-3-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-piperidin-4-yl)butanamido)-propanoic acid; 85) (S)-4-carboxy-4-(4-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-N,N,N-trimethylbutan-1-aminium; 86) (S)-2-amino-6-(4-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-piperidin-4-yl)butanamido)hexanoic acid; 87) (S)—N-(2-(1-(6-(2-((4-cyanophenethyl)-carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)-2-(2-aminoethylsulfonamido)-acetic acid; 88) (S)-2-(4-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanoyl)piperazin-1-yl)acetic acid; 89) (S)—N-(4-cyanophenethyl)-1-(6-(4-(4-((3-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)-3-oxopropyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)-pyrimidin-4-yl)pyrrolidine-2-carboxamide; 90) (S)-1-(6-(4-(4-((2-((6-chloropyrimidin-4-yl)amino)ethyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 91) (S)-1-(6-(4-(4-((2-((6-(bis(2-hydroxyethyl)amino)pyrimidin-4-yl)amino)ethyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 92) (S)-2-(2-((2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)ethyl)amino)-pyrimidine-5-carboxamido)ethanesulfonic acid; 93) (S)-2-(3-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)-propanamido)-ethanesulfonic acid; 94) (S)-2-(2-(4-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl)-carbamoyl)-pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanamido)ethyl-sulfonamido)acetic acid; 95) (S)-2-(2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-ethylsulfonamido)acetic acid; 96) (S)-1-(6-(4-(2-(2-aminoethylsulfonamido)ethyl)piperidin-1-yl)-2-(trifluoromethyl)-pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 97) (S)-2-((2-(N-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)sulfamoyl)ethyl)amino)-pyrimidine-5-carboxylic acid; 98) (S)-(3-(3-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)propyl)ureido)methanesulfonic acid; 99) (S)-2-(3-(3-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)propyl)ureido)-ethanesulfonic acid; 100) (S)—N-(4-cyanophenethyl)-1-(6-(4-(3-(3-(2-sulfamoylethyl)ureido)propyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 101) (S)-2-(3-(3-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)propyl)ureido)acetic acid; 102) ((R)-1-(2-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)-2,5-dioxoimidazolidin-4-yl)methanesulfonic acid; 103) (R)-2-amino-3-((2-(1-(6-((S)-2-((4-cyanophenethyl) carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)amino)-3-oxopropane-1-sulfonic acid; 104) (S)-2-((2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-ethyl) amino)-2-oxoethanesulfonic acid; 105) (R)-2-amino-3-((2-(N-(2-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)-pyrrolidin-1-yl)-2-(trifluoromethyl)-pyrimidin-4-yl)piperidin-4-yl)ethyl)sulfamoyl)ethyl)amino)-3-oxopropane-1-sulfonic acid; 106) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-guanidinoethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 107) (S)-1-(6-(4-(1-amino-1-imino-12-oxo-5,8-dioxa-2,11-diazapentadecan-15-yl)piperidin-1-yl)-2-(trifluoromethyl)-pyrimidin-4-yl)-N-(4-cyanophenethyl)-pyrrolidine-2-carboxamide; 108) (S)—N-(4-cyanophenethyl)-1-(6-(4-(4-((2-guanidinoethyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 109) (S)-6-(4-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-2-guanidinohexanoic acid; 110) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-(2-guanidinoethylsulfonamido) ethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 111) (S)-1-(6-(4-(4-((2-guanidinoethyl)-amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)pyrrolidine-2-carboxamide; 112) (S)-1-(6-(4-(3-guanidinopropyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)-pyrrolidine-2-carboxamide; 113) (S)-2-guanidino-5-oxo-5-((3-(1-(2-(trifluoromethyl)-6-((S)-2-((4-(trifluoromethyl)phenethyl)carbamoyl)pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)propyl)amino)pentanoic acid; 114) (S)-(4-(1-(6-(2-((3,4-dichlorophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)methanesulfonic acid; 115) (S)-(4-(1-(6-(2-((4-chlorophenethyl)-carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-piperidin-4-yl)butanamido)-methanesulfonic acid; 116) (S)-(4-(1-(6-(2-((2,3-dichlorophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-methanesulfonic acid; 117) (S)-4-(1-(2-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)piperidin-4-yl)butanoic acid; 118) (S)-(4-(1-(2-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)piperidin-4-yl)butanamido)methanesulfonic acid; 119) (S)-2-(4-(1-(2-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)piperidin-4-yl)butanamido)ethanesulfonic acid; 120) (S)-2-(4-(1-(2-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)piperidin-4-yl)butanamido)-5-guanidinopentanoic acid; 121) (S)-(3-(3-(1-(2-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)piperidin-4-yl)propyl)ureido)methanesulfonic acid; 122) (S)-2-((S)-2-(4-(1-(2-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)piperidin-4-yl)butanamido)-5-guanidinopentanamido)-5-guanidinopentanoic acid; 123) (R)-2-((R)-2-(4-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-5-guanidino-pentanamido)pentanedioic acid; 124) (2S,4R)—N-(4-cyanophenethyl)-4-hydroxy-1-(6-(4-(2-hydroxyethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 125) (2S,4R)—N-(4-cyanophenethyl)-4-hydroxy-1-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 126) 4-(1-(6-((2S,4R)-4-hydroxy-2-((4-(trifluoromethyl)phenethyl) carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanoic acid; 127) (S)-tert-butyl (2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)-4,4-difluoropyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)carbamate; 128) (2S,4R)-4-hydroxy-1-(6-(4-(4-oxo-4-(((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-amino)butyl)-piperidin-1-yl)-2-(trifluoromethyl)-pyrimidin-4-yl)-N-(4-(trifluoro-methyl)phenethyl)pyrrolidine-2-carboxamide; 129) (S)-1-(6-(4-(2-aminoethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)-4,4-difluoropyrrolidine-2-carboxamide; 130) (S)-2-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)-4,4-difluoropyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido) ethanesulfonic acid; 131) (4R)-4-amino-1-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)pyrrolidine-2-carboxamide; 132) (S)—N-(4-cyanophenethyl)-1-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 133) (S)-1-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)-phenethyl)azetidine-2-carboxamide; 134) (S)—N-(4-cyanophenethyl)-1-(6-(4-((dimethylamino)methyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 135) (S)—N-(4-cyanophenethyl)-1-(6-(4-(methoxymethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 136) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-hydroxyethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 137) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 138) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-methoxyethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 139) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 140) (S)-3-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)propanoic acid; 141) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-(dimethylamino)ethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 142) (S)-1-(6-(4-(2-cyanoethyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)azetidine-2-carboxamide; 143) (S)-1-(6-(4-(2-cyanoethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)azetidine-2-carboxamide; 144) (S)-4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanoic acid; 145) (S)-3-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl) carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)propanoic acid; 146) (S)-4-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl) carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanoic acid; 147) (S)-tert-butyl ((1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)methyl)carbamate; 148) (S)-tert-butyl (2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)carbamate; 149) (S)-tert-butyl (2-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl) carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl)carbamate; 150) (S)-1-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(2-methoxy-4-(trifluoromethyl)phenethyl)azetidine-2-carboxamide; 151) (S)-1-(6-(4-(2-hydroxyethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(2-methoxy-4-(trifluoromethyl)phenethyl)azetidine-2-carboxamide; 152) (S)-3-(1-(6-(2-((2-methoxy-4-(trifluoromethyl)phenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)propanoic acid; 153) (S)-4-(1-(6-(2-((2-methoxy-4-(trifluoromethyl)phenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanoic acid; 154) N-(4-cyanophenethyl)-1-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 155) (S)-(1-(6-(4-aminomethylpiperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)azetidine-2-carboxamide hydrochloride; 156) (S)-1-(6-(4-(2-aminoethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)azetidine-2-carboxamide; 157) (S)-1-(6-(4-(2-aminoethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)-azetidine-2-carboxamide; 158) (S)-3-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)propane-1-sulfonic acid; 159) (S)-2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)ethanesulfonic acid; 160) (S)-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)methanesulfonic acid; 161) (S)-2-(4-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-5-guanidinopentanoic acid; 162) (S)-2-(N-methyl-3-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl) phenethyl)carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)propanamido)ethanesulfonic acid; 163) (S)-(3-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl)-carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)propanamido)-methanesulfonic acid; 164) (S)-2-(3-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl) carbamoyl)-azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)propanamido)ethanesulfonic acid; 165) (S)-(4-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl)-carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanamido)methanesulfonic acid; 166) (S)-di-tert-butyl 2-(4-(1-(2-(trifluoromethyl)-6-((S)-2-((4-(trifluoromethyl) phenethyl)carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanamido)pentanedioate; 167) (R)-di-tert-butyl 2-(4-(1-(2-(trifluoromethyl)-6-((S)-2-((4-(trifluoromethyl) phenethyl)carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanamido)pentanedioate; 168) (S)-5-guanidino-2-(3-(1-(2-(trifluoromethyl)-6-((S)-2-((4-(trifluoromethyl) phenethyl)carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)propanamido)pentanoic acid; 169) (S)-2-(3-(1-(6-(2((2-methoxy-4-(trifluoromethyl)phenethyl)carbamoyl) azetidin-1-yl)-2-trifluoromethyl)-pyrimidin-4-yl)piperidin-4-yl)propanamido)ethanesulfonic acid; 170) (S)—N-(4-cyanophenethyl)-1-(6-(4-(4-oxo-4-(((2R,3S,4S,5S)-2,3,4,5,6-pentahydroxyhexyl)amino)butyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 171) (S)—N-(4-cyanophenethyl)-1-(6-(4-(4-(((R)-2,3-dihydroxypropyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 172) (S)-3-(3-(1-(6-(2((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-trifluoromethyl)pyrimidin-4-yl)propanamido)propane-1-sulfonic acid; 173) (S)-tert-butyl (2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-ethyl)carbamate; 174) (S)-tert-butyl (4-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-butyl)carbamate; 175) (S)-tert-butyl (2-(2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)ethoxy) ethyl)carbamate; 176) (S)-ethyl 3-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)propanoate; 177) (S)-3-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)propanoic acid; 178) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-(3-(2-sulfamoylethyl)ureido) ethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 179) (S)-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)-methanesulfonic acid; 180) (S)-2-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)-ethanesulfonic acid; 181) (S)-tert-butyl (2-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-piperidin-4-yl)ethyl)ureido)ethyl)carbamate; 182) (S)-tert-butyl (2-(2-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)-ethoxy)ethyl)carbamate; 183) (S)-methyl-2-amino-6-(3-(2-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl) azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)hexanoate; 184) (S)-1-(6-(4-(3-(piperidin-4-yl)propyl)piperidin-1-yl)-2-(trifluoromethyl) pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)azetidine-2-carboxamide; 185) (R)-2-amino-3-oxo-3-((2-(1-(2-(trifluoromethyl)-6-((S)-2-((4-(trifluoromethyl)-phenethyl)carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl)amino)-propane-1-sulfonic acid; 186) (S)-2-oxo-2-((2-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl) carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl)amino)-ethanesulfonic acid; 187) (S)-2-oxo-2-(4-(3-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl) carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)propyl)piperidin-1-yl)ethanesulfonic acid; 188) (S)-2-(4-(3-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl) carbamoyl)-azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)propyl)piperidin-1-yl)acetic acid; 189) (S)—N-(4-cyanophenethyl)-1-(6-(4-(4-((2-guanidinoethyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 190) (S)—N-(4-cyanophenethyl)-1-(6-(4-(4-((4-guanidinobutyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 191) (S)—N-(4-cyanophenethyl)-1-(6-(4-(4-((2-(2-guanidinoethoxy)-ethyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 192) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-guanidinoethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 193) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-(3-(2-guanidinoethyl)-ureido)ethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 194) (S)-1-(6-(4-(1-amino-1-imino-9-oxo-5-oxa-2,8,10-triazadodecan-12-yl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)azetidine-2-carboxamide; 195) (S)-1-(6-(4-(3-(1-carbamimidoylpiperidin-4-yl)propyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)-azetidine-2-carboxamide; 196) (S)-methyl-4-(N-(2-(2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)ethoxy)ethyl)-sulfamoyl)benzoate; 197) (S)-4-(N-(2-(2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido) ethoxy) ethyl)sulfamoyl)-benzoic acid; 198) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-(3-(2-(2-(methylsulfonylamino)-ethoxy)ethyl)ureido)ethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 199) (S)-2-(3-(1-(2-(Trifluoromethyl)-6-((S)-2-((4-(trifluoromethyl)phenethyl) carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)propanamido) pentanedioic acid; 200) (R)-2-(4-(1-(2-(trifluoromethyl)-6-((S)-2-((4-(trifluoromethyl)-phenethyl) carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanamido) pentanedioic acid; 201) N-(4-cyanophenethyl)-1-(6-(4-(2-((3-hydroxypropyl)(methyl)amino)ethyl)-piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 202) N-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)-3-hydroxy-N,N-dimethylpropan-1-aminium; 203) (S)-2-((2-((2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)ethanesulfonic acid; 204) (S)-((2-((2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)methanesulfonic acid; 205) (S)-2-((2-((2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)amino)-3,4-dioxocyclobut-1-en-1-yl)(methyl)amino)ethanesulfonic acid; 206) (S)-tert-butyl 3-((2-((2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)propanoate; 207) (S)-3-((2-((2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)propanoic acid; 208) (S)-2-((2-((2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)acetic acid; 209) (R)—N-(4-cyanophenethyl)-1-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidine-3-carboxamide; 210) (R)—N-(4-cyanophenethyl)-1-(6-(4-(2-hydroxyethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidine-3-carboxamide; 211) (R)—N-(4-cyanophenethyl)-1-(6-(4-(methoxymethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidine-3-carboxamide; 212) (R)-1-(6-(4-(2-cyanoethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)piperidine-3-carboxamide; 213) (R)-tert-butyl (2-(1-(6-(3-((4-cyanophenethyl)carbamoyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)carbamate; 214) (R)—N-(4-cyanophenethyl)-1-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidine-3-carboxamide; 215) (R)—N-(4-cyanophenethyl)-1-(6-(4-(2-(2-hydroxy ethoxy)ethyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidine-3-carboxamide; 216) (R)-2-(4-(6-(3-((4-cyanophenethyl)carbamoyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)acetic acid; 217) (R)-1-(6-(4-(2-cyanoethyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)piperidine-3-carboxamide; 218) (R)—N-(4-cyanophenethyl)-1-(6-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidine-3-carboxamide; 219) (R)-1-(6-(4-(2-(1H-imidazol-1-yl)ethyl)piperazin-1-yl)-2-(trifluoromethyl) pyrimidin-4-yl)-N-(4-cyanophenethyl)piperidine-3-carboxamide; 220) (R)-1-(6-(4-(benzo[d][1,3]dioxol-4-ylmethyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)piperidine-3-carboxamide; 221) (R)-1-(6-(4-(2-methoxyethyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)piperidine-3-carboxamide; 222) (R)-1-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)-phenethyl)piperidine-3-carboxamide; 223) (R)-4-(1-(2-(trifluoromethyl)-6-(3-((4-(trifluoromethyl)phenethyl)carbamoyl) piperidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanoic acid; 224) (R)-1-(6-(4-hydroxymethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(2-methoxy-4-(trifluoromethyl)-phenethyl)piperidine-3-carboxamide; 225) (R)-1-(6-(4-(2-hydroxyethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(2-methoxy-4-(trifluoromethyl)-phenethyl)piperidine-3-carboxamide; 226) (R)—N-(4-cyanophenethyl)-1-(6-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidine-3-carboxamide; 227) (R)-2-(4-(1-(2-(trifluoromethyl)-6-(3-((4-(trifluoromethyl)phenethyl) carbamoyl)-piperidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanamido)ethanesulfonic acid; 228) (R)-1-(6-(4-(2-methoxyacetyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)piperidine-3-carboxamide; 229) (R)-1-(6-(4-(2-(dimethylamino)-acetyl)piperazin-1-yl)-2-(trifluoromethyl)-pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)-piperidine-3-carboxamide; 230) (R)-methyl 2-oxo-2-(4-(2-(trifluoromethyl)-6-(3-((4-(trifluoromethyl) phenethyl)-carbamoyl)piperidin-1-yl)pyrimidin-4-yl)piperazin-1-yl)acetate; 231) (R)-2-oxo-2-(4-(2-(trifluoromethyl)-6-(3-((4-(trifluoromethyl)phenethyl)-carbamoyl)piperidin-1-yl)pyrimidin-4-yl)piperazin-1-yl)acetic acid; 232) tert-butyl-((S)-3-hydroxy-1-oxo-1-(4-(2-(trifluoromethyl)-6-((R)-3-((4-(trifluoromethyl)phenethyl)carbamoyl)piperidin-1-yl)pyrimidin-4-yl)piperazin-1-yl)propan-2-yl)carbamate; 233) (R)-1-(6-(4-((S)-2-amino-3-hydroxypropanoyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)piperidine-3-carboxamide; 234) (R)-ethyl 3-(4-(2-(trifluoromethyl)-6-(3-((4-(trifluoromethyl)phenethyl) carbamoyl)-piperidin-1-yl)pyrimidin-4-yl)piperazine-1-carboxamido)propanoate; 235) (R)-3-(4-(2-(trifluoromethyl)-6-(3-((4-(trifluoromethyl)phenethyl)carbamoyl)-piperidin-1-yl)pyrimidin-4-yl)piperazine-1-carboxamido)propanoic acid; 236) (R)-1-(6-(4-(2-aminoethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)piperidine-3-carboxamide; 237) (R)-ethyl 3-(3-(2-(1-(6-(3-((4-cyanophenethyl)carbamoyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)propanoate; 238) (R)-3-(3-(2-(1-(6-(3-((4-cyanophenethyl)carbamoyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)propanoic acid; 239) (R)-1-(6-(4-(2-hydroxyacetyl)piperazin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)piperidine-3-carboxamide; and 240) (R)-1-(6-(4-((2-guanidinoethyl)sulfonyl)piperazin-1-yl)-2-(trifluoromethyl)-pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)piperidine-3-carboxamide, or a pharmaceutically acceptable salt thereof.

In one preferred embodiment, the present invention provides a compound selected from:

1) (S)-2-(3-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)propanamido)-ethanesulfonic acid; 2) (S)-3-(4-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl)-carbamoyl)pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanamido)propane-1-sulfonic acid; 3) (S)-2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-piperidin-4-yl)butanamido)ethanesulfonic acid; 4) (S)-3-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-piperidin-4-yl)butanamido)propane-1-sulfonic acid; 5) (S)-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-methanesulfonic acid; 6) (S)-5-guanidino-2-(4-(1-(2-(trifluoromethyl)-6-((S)-2-((4-(trifluoromethyl) phenethyl)carbamoyl)pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanamido)pentanoic acid; 7) (S)-2-(4-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-pentanedioic acid; 8) (S)-2-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)ethanesulfonic acid; 9) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-(3-(2-sulfamoylethyl)ureido)-ethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 10) (S)-3-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)-propanoic acid; 11) (S)—N-(2-(1-(6-(2-((4-cyanophenethyl)-carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)-2-(2-aminoethylsulfonamido)acetate methyl ester; 12) (S)-2-(2-((2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)ethyl)amino)-pyrimidine-5-carboxamido)ethanesulfonic acid; 13) (S)-2-(2-(4-(1-(2-(trifluoromethyl)-6-(2-((4-(trifluoromethyl)phenethyl)-carbamoyl)-pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)butanamido)ethyl-sulfonamido)acetic acid; 14) (S)-2-(2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)-ethylsulfonamido)acetic acid; 15) (S)-2-((2-(N-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)sulfamoyl)ethyl)-amino)-pyrimidine-5-carboxylic acid; 16) (S)-(3-(3-(1-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)propyl)ureido)-methanesulfonic acid; 17) (R)-2-amino-3-((2-(N-(2-(1-(6-((S)-2-((4-cyanophenethyl)carbamoyl)-pyrrolidin-1-yl)-2-(trifluoromethyl)-pyrimidin-4-yl)piperidin-4-yl)ethyl)sulfamoyl)ethyl)amino)-3-oxopropane-1-sulfonic acid; 18) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-(2-guanidinoethylsulfonamido)ethyl)-piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 19) (S)-2-guanidino-5-oxo-5-((3-(1-(2-(trifluoromethyl)-6-((S)-2-((4-(trifluoromethyl)phenethyl)carbamoyl)pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)propyl)amino)pentanoic acid; 20) (S)-2-(4-(1-(2-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)piperidin-4-yl)butanamido)ethanesulfonic acid; 21) (S)-(3-(4-(2-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)phenyl)propanamido)methanesulfonic acid; 22) (S)-3-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)propane-1-sulfonic acid; 23) (S)-2-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)ethanesulfonic acid; 24) (S)-(4-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)butanamido)methanesulfonic acid; 25) (S)-3-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)propanoic acid; 26) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-(3-(2-sulfamoylethyl)ureido)ethyl)-piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 27) (S)-2-(3-(2-(1-(6-(2-((4-cyanophenethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)piperidin-4-yl)ethyl)ureido)-ethanesulfonic acid; 28) (R)-2-amino-3-oxo-3-((2-(1-(2-(trifluoromethyl)-6-((S)-2-((4-(trifluoromethyl)-phenethyl)carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl)amino)-propane-1-sulfonic acid; 29) (S)—N-(4-cyanophenethyl)-1-(6-(4-(4-((4-guanidinobutyl)amino)-4-oxobutyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 30) (S)—N-(4-cyanophenethyl)-1-(6-(4-(2-guanidino ethyl)piperidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; and 31) (S)-2-(3-(1-(2-(Trifluoromethyl)-6-((S)-2-((4-(trifluoromethyl)phenethyl)-carbamoyl)azetidin-1-yl)pyrimidin-4-yl)piperidin-4-yl)propanamido)-pentanedioic acid,

or pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides a compound of formula (II):

or pharmaceutically acceptable salts thereof, wherein:

each R 1 is independently CN, C 1-6 alkyl or C 1-6 alkoxy, wherein alkyl group is optionally further substituted with 1-4 halogen; m is 0, 1, 2 or 3; R 2 is C 1-6 alkyl or H, wherein alkyl group is optionally further substituted with 1-4 halogen; X is CH or N; A is

In one embodiment, L 3 is absent, and L 1 and L 2 are each independently

wherein N is optionally further mono- or di-substituted with C 1-3 alkyl.

In one preferred embodiment, when L 3 is absent, L 1 and L 2 are each independently

wherein N is optionally further substituted with C 1-3 alkyl.

In one embodiment, L 2 and L 3 are absent, and L 1 is

wherein N is optionally further substituted with C 1-3 alkyl.

In one preferred embodiment, when L 2 and L 3 are absent, L 1 is

wherein N is optionally further substituted with C 1-3 alkyl.

In one embodiment, n 1 , n 2 , n 3 and n 4 are each independently 0, 1, 2, 3 or 4.

In one preferred embodiment, n 1 , n 2 , n 3 and n 4 are each independently 0, 1, 2 or 3.

In one embodiment, each R is independently H, NH 2 , COOH or C 1-6 alkylNHC(NH)NH 2 .

In one preferred embodiment, each R is independently H, NH 2 or COOH.

In one embodiment, T is

CN, OH, NH 2 , CH 3 , CF 3 , H or halogen, wherein N is optionally further mono-, di-, or tri-substituted with C 1-3 alkyl.

In one embodiment, n is 0. In one preferred embodiment, phenethylcarboxamide is substituted in the two position of N in the azetidinyl ring. In one preferred embodiment, phenethylcarboxamide is substituted in the two position of N in the azetidinyl ring with S configuration.

In one embodiment, n is 1. In one preferred embodiment, phenethylcarboxamide is substituted in the two position of N in the pyrrolidinyl ring. In one preferred embodiment, phenethylcarboxamide is substituted in the two position of N in the pyrrolidinyl ring with S configuration.

In one embodiment, n is 2. In one preferred embodiment, phenethylcarboxamide is substituted in the three position of N in the piperidinyl ring. In one preferred embodiment, phenethylcarboxamide is substituted in the three position of N in the piperidinyl ring with R configuration.

In one embodiment, A is

wherein each ring is optionally further substituted with C 1-4 alkyl, C 1-4 alkoxyl or halogen.

In one embodiment, X is CH. In one embodiment, X is N.

In one embodiment, R 2 is C 1-6 alkyl, wherein alkyl group is optionally further substituted with 1-4 halogen. In one preferred embodiment, R 2 is CF 3 .

In one embodiment, R 1 is each independently CN or C 1-6 alkyl, wherein alkyl group is optionally further substituted with 1-4 halogen.

In one preferred embodiment, R 1 is CN. In one preferred embodiment, R 1 is CF 3 . In one preferred embodiment, the CN or CF 3 substitution occurs on the para position of phenethyl.

In one embodiment, R 1 is C 1-2 alkoxy. In one preferred embodiment, R 1 is OCH 3 .

In one embodiment, m is 1 or 2. In one preferred embodiment, m is 1.

In one embodiment, R 3 and R 4 are each independently H, OH, F or NH 2 . In one preferred embodiment, R 3 and R 4 are each independently H or OH. In one preferred embodiment, R 3 and R 4 are each independently H.

In one preferred embodiment, the present invention provides a compound selected from:

1) (S)—N-(4-cyanophenethyl)-1-(6-(5-hexylthiophene-2-yl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 2) (S)-1-(6-(pyridin-4-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)pyrrolidine-2-carboxamide; 3) (S)—N-(4-cyanophenethyl)-1-(6-(pyridin-4-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 4) (S)—N-(4-cyanophenethyl)-1-(6-(pyridin-3-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 5) (S)—N-(4-cyanophenethyl)-1-(6-(p-tolyl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 6) (S)—N-(4-cyanophenethyl)-1-(6-phenyl-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 7) (S)—N-(4-cyanophenethyl)-1-(6-(4-cyanophenyl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 8) (S)—N-(4-cyanophenethyl)-1-(6-(4-(hydroxymethyl)phenyl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 9) (S)—N-(4-cyanophenethyl)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl) phenyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 10) (S)—N-(4-cyanophenethyl)-1-(6-(4-methoxyphenyl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 11) (S)—N-(4-cyanophenethyl)-1-(6-(3,4-dimethoxyphenyl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 12) (S)—N-(4-cyanophenethyl)-1-(6-(4-(trifluoromethoxy)phenyl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 13) (S)—N-(4-cyanophenethyl)-1-(6-(4-ethoxyphenyl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 14) (S)—N-(4-cyanophenethyl)-1-(6-(4-(methylsulfonyl)phenyl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 15) (S)—N-(4-cyanophenethyl)-1-(6-(3-(methylsulfonamido)phenyl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 16) (S)—N-(4-cyanophenethyl)-1-(6-(4-(morpholinosulfonyl)phenyl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 17) (S)—N-(4-cyanophenethyl)-1-(6-(3-fluoropyridin-4-yl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 18) (S)—N-(4-cyanophenethyl)-1-(6-(3,5-dimethylisoxazol-4-yl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 19) (S)-1-(6-(1H-indol-5-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 20) (S)—N-(4-cyanophenethyl)-1-(6-(thiophen-3-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 21) (S)—N-(4-cyanophenethyl)-1-(6-(3-methoxypyridin-4-yl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 22) (S)—N-(4-cyanophenethyl)-1-(6-(2-methoxypyridin-4-yl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 23) (S)-1-(6-(5-chloro-2-methoxy-pyridin-4-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 24) (S)—N-(4-cyanophenethyl)-1-(6-(pyridin-2-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 25) (S)-1-(6-(pyridin-2-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)-pyrrolidine-2-carboxamide; 26) (S)—N-(4-cyanophenethyl)-1-(6-(furan-3-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 27) (S)—N-(4-cyanophenethyl)-1-(6-(thiophen-2-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 28) (S)—N-(4-cyanophenethyl)-1-(6-(5-methylfuran-2-yl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 29) (S)—N-(4-cyanophenethyl)-1-(6-(furan-2-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 30) (S)—N-(4-cyanophenethyl)-1-(6-(5-(morpholinomethyl)thiophen-2-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 31) (S)—N-(4-cyanophenethyl)-1-(6-(1-methyl-1H-indol-5-yl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 32) (S)—N-(4-cyanophenethyl)-1-(6-(5-methylthiophen-2-yl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 33) (S)—N-(4-cyanophenethyl)-1-(6-(4-methylthiophen-2-yl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 34) (S)—N-(4-cyanophenethyl)-1-(6-(3-methylthiophen-2-yl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 35) (S)-1-(6-(benzo[b]thiophen-2-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 36) (S)-benzyl 4-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)phenethylcarbamate; 37) (S)-tert-butyl 4-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)benzylcarbamate; 38) (S)-tert-butyl 4-(4-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)benzyl)piperazine-1-carboxylate; 39) (S)-tert-butyl (4-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)phenyl)(methyl)carbamate; 40) (S)-4-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)thiophene-2-carboxylic acid; 41) (S)—N-(4-cyanophenethyl)-1-(6-(5-(methylcarbamoyl)thiophen-3-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 42) (S)-methyl 5-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)thiophene-2-carboxylate; 43) (S)-5-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)thiophene-2-carboxylic acid; 44) (S)—N-(4-cyanophenethyl)-1-(6-(5-(hydroxymethyl)thiophen-3-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 45) (S)—N-(4-cyanophenethyl)-1-(6-(5-(hydroxymethyl)thiophen-2-yl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 46) (S)-1-(6-(4-(2-aminoethyl)phenyl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 47) (S)-1-(6-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide; 48) (S)—N-(4-cyanophenethyl)-1-(6-(4-(methylamino)phenyl)-2-(trifluoromethyl) pyrimidin-4-yl)pyrrolidine-2-carboxamide; 49) (S)—N-(4-cyanophenethyl)-1-(6-(4-(piperazin-1-ylmethyl)phenyl)-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxamide; 50) (S)-3-(4-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)phenyl)propanoic acid; 51) (S)-2-(3-(4-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)phenyl)propanamido)ethanesulfonic acid; 52) (S)-2-(3-(3-(6-(2-((4-cyanophenethyl)-carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)phenyl)-propanamido)ethanesulfonic acid; 53) (S)-2-(3-(4-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)benzyl)ureido)ethanesulfonic acid; 54) (S)-(3-(4-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)benzyl)ureido)methanesulfonic acid; 55) (S)-3-(3-(4-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)benzyl)ureido)propane-1-sulfonic acid; 56) (S)-2-(3-(4-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)phenethyl)ureido)ethanesulfonic acid; 57) (S)-3-(3-(4-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)phenethyl)ureido)propane-1-sulfonic acid; 58) (S)-3-(3-(4-(6-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)phenyl)-3-methylureido)propanoic acid; 59) (S)—N-(4-cyanophenethyl)-1-(4-(4-(hydroxymethyl)phenyl)-6-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide; 60) (S)-3-(4-(2-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)phenyl)propanoic acid; 61) (S)-(3-(4-(2-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)phenyl)propanamido)methanesulfonic acid; 62) (S)-2-(3-(4-(2-((S)-2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)phenyl)propanamido)-5-guanidinopentanoic acid; 63) (S)-2-((4-(2-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)benzyl)oxy)acetic acid; 64) (S)-(2-((4-(2-(2-((4-cyanophenethyl)carbamoyl)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl)benzyl)oxy)acetamido)methanesulfonic acid; 65) (S)—N-(4-cyanophenethyl)-1-(6-pyridin-4-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 66) (S)—N-(4-cyanophenethyl)-1-(6-(4-(hydroxymethyl)phenyl)-2-(trifluoromethyl) pyrimidin-4-yl)azetidine-2-carboxamide; 67) (S)—N-(4-cyanophenethyl)-1-(6-(pyridin-3-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; 68) (S)—N-(4-cyanophenethyl)-1-(6-(pyridin-2-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide; and 69) N-(4-cyanophenethyl)-1-(6-(pyridin-4-yl)-2-(trifluoromethyl)pyrimidin-4-yl)azetidine-2-carboxamide,

or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain an asymmetric center and may exist as enantiomers. Where the compounds of the present invention possess two or more asymmetric centers, they may additionally exist as diastereomers. When bonds to the chiral carbon are depicted as straight lines in the formulas of the present invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced. The present invention includes all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures, as well as mixtures of diastereomers thereof. Except where otherwise specified, the formulas encompassing compounds of the present invention are shown without a definitive stereochemistry at certain positions. The present invention may be understood to include all stereoisomers of compounds and pharmaceutically acceptable salts thereof. It is generally preferable to administer compounds of the present invention as enantiomerically pure formulations.

Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts. Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent or on a chiral HPLC column. Further, any enantiomer or diastereomer of a compound of the present invention may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

The compounds of the present invention include tautomers of such compounds. Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Exemplary tautomer includes a ketone and its enol form known as keto-enol tautomers.

Accordingly, the compounds within the generic structural formulas, embodiments and specific compounds described and claimed herein are intended to encompass salts, all possible stereoisomers and tautomers.

The compounds of the present invention include all suitable isotopic variations of such compounds. An isotopic variation of a compound is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Exemplary isotope includes isotope of hydrogen, carbon, nitrogen and oxygen such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 35 S, 18 F, 36 Cl, 123 I and the like. Certain isotopic variations of the compounds are useful in drug or substrate tissue distribution studies. Others may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased or decreased in vivo half-life or reduced dosage requirements. Isotopic variations of the compounds of the present invention provided herein are prepared by conventional procedures using appropriate isotopic variations of suitable reagents.

In one aspect, the present invention provides a pharmaceutical composition containing a TGR5 compound described herein, method of preparation and use of same in treating metabolic diseases such as type-2 diabetic mellitus and obesity in a mammal, preferably a human.

In one embodiment, the present invention provides a pharmaceutical composition containing a compound of formula (I) for use in therapy in humans in needs thereof for diabetic diseases. In another embodiment, the present invention provides a pharmaceutical composition containing a compound of formula (II) for use in therapy for diabetic diseases.

The present composition encompasses a TGR5 compound in the form of a vehicle such as a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier comprises agents that aid optimization of solubility, absorption, flavor or texture of the composition. Pharmaceutically acceptable carriers are commonly known to a skilled artisan and include a variety of organic or inorganic carriers including starch, cellulose, gelatin, talc, glycol, polyol, ester, agar, buffering agents, alginic acid and the like that are employed in pharmaceutical formulations. Such carriers include, for solid preparations, diluents, lubricants, binders, and disintegrants, and for liquid preparations, solvents, solubilizing agents, suspending agents, isotonic agents, buffer agents, soothing agents and the like.

Suitable exemplary diluents include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light silica anhydrate and the like. Suitable exemplary lubricants include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Suitable exemplary binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Suitable exemplary disintegrants include starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose, sodium carboxymethylstarch and the like. Suitable exemplary solvents include injectable water, alcohol, propylene glycol, macrogol, sesame oil, corn oil, etc. Suitable exemplary solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, benzylbenzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Suitable exemplary suspending agents include surfactants such as stearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate and the like; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like. Suitable exemplary isotonic agent includes sodium chloride, glycerin, D-mannose and the like. Suitable exemplary buffer agents include buffer solutions of salts, such as phosphate, acetates, carbonates, citrates and the like. Suitable exemplary soothing agents include benzyl alcohol and the like. Suitable exemplary antiseptic substances include para-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Suitable exemplary antioxidants include sulfite salts, ascorbic acid and the like. Suitable exemplary sealers include, but are not limited to HPMC (or hypromellose), HPC, PEG and combinations thereof. In some embodiments, disintegrants are added to the formulation to help the all or part of the dosage form disintegrate after consumption, thereby releasing at least a portion of the active ingredients. Some common disintegrants include several modified cellulose derivatives, such as croscarmellose sodium and other modified starch derivatives such as sodium starch glycolate. It will also be understood by one of ordinary skill in the art that a pharmaceutical composition may contain other suitable ingredients, binders and lubricants that provide optimal dissolution profiles of dosage forms.

When the dosage form of pharmaceutical composition is a capsule, it may contain a liquid carrier. Other materials may be present as coatings or to otherwise modify the physical form of the dosage form. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain sucrose as a sweetening agent and methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. Of course, materials used in preparing any dosage form should be pharmaceutically pure and substantially non-toxic in the amounts employed.

Pharmaceutical additives such as antiseptic substances, antioxidants, coloring agents and sweeteners may also be added if necessary.

The present invention, in various embodiments, provides an oral composition suitable for human administration. The present oral composition encompasses various dosage forms. For example, the oral composition can be a tablet, coated tablet, capsule, caplet, cachet, lozenges, gel capsule, hard gelatin capsule, soft gelatin capsule, troche, dragee, dispersion, powder, granule, pill, liquid, an aqueous or non-aqueous liquid suspension, an oil-in-liquid or oil-in-water emulsion, including sustained release formulations that are known in the art. (See, e.g., Introduction to Pharmaceutical Dosage Forms, 1985, Ansel, H. C., Lea and Febiger, Philadelphia, Pa.; Remington's Pharmaceutical Sciences, 1995, Mack Publ. Co., Easton, Pa.)

These dosage forms can be prepared using standard procedures that are known to the art, including but not limited to encapsulating procedures. In one embodiment, the dosage form provides a low blood concentration of TGR5 agonists (TGR5 compounds) after ingestion but continues to release TGR5 compounds in the gut compartment over time to permit low pharmaceutical exposure (i.e., TGR5 compounds are restricted to the gut compartment). Preferably, the oral compositions (after ingestion) provide a plasma level of TGR5 compounds at <20 ng/mL. More preferably, the present compounds of the invention have <5 ng/mL.

In one embodiment, the present compositions are formulated into a dosage form releasing TGR5 compounds for a period of 1 to 12, typically 3 to 12 hours, more typically 6-12 hours after ingestion. Preferably, the oral pharmaceutical compositions of the present invention may be administered in single or divided doses, from one to four times a day. The oral dosage forms may be conveniently presented in unit dosage forms and prepared by any methods well known in the art of pharmacy. In another embodiment, the present composition contains a predetermined amount of a therapeutic amount of TGR5 compound effective in treating diabetic diseases.

The present formulations can be prepared by any suitable method of pharmacy which includes the step of bringing into association the therapeutic TGR5 compound compositions and a suitable carrier (which can contain one or more accessory ingredients as noted above). In general, the pharmaceutical compositions according to embodiments of the present invention are prepared by uniformly and intimately admixing the TGR5 compounds with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, tablets may be prepared by compressing or molding powders or granules containing the therapeutic TGR5 compounds, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the therapeutic TGR5 compounds in a free-flowing form, including a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active or dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder. The tablets can optionally be coated or scored and can be formulated so as to provide slow or controlled release of the active ingredient TGR5 compounds therein.

When the pharmaceutical compositions are applied to humans, they are desirably administered via the oral route. The therapeutic effective dose of each TGR5 active compounds depends on the age or symptom of the patient to be treated. Generally, the pharmaceutical preparations may contain about 50 mg, 100 mg, 250 mg, 500 mg or 1,000 mg of the TGR5 compounds per unit dosage form and may be administered to humans or animals at a daily dose of 0.1-100 mg per kilogram of body weight. The optimal dose suitable for a particular patient can be conveniently determined (by a physician) without undue experimentation.

The pharmaceutical compositions generally are administered in a therapeutic effective amount for treatment or prophylaxis of diabetic conditions. Initial dosing in human can be accompanied by clinical monitoring of symptoms for the selected condition (e.g., blood sugar (glucose) level or HbA1c test) for administration particularly to mammals, and particularly humans, it is expected that the daily dosage level of the TGR5 compounds may be determined to maintain an optimal blood sugar level or HbA1c level.

It will be appreciated that optimum dosage will be determined by standard methods for each treatment modality and indication, taking into account the indication, its severity, route of administration, complicating conditions and the like. The physician in any event will determine the actual dosage that will be most suitable for an individual and will vary with the age, weight and response of the particular individual. The effectiveness of a selected actual dose can readily be determined, for example, by measuring clinical symptoms or standard diabetic indicia after administration of the selected dose. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this present invention. For conditions or disease states as are treated by the present invention, maintaining consistent daily levels in a subject over an extended period of time, e.g., in a maintenance regime, can be particularly beneficial.

For purposes of the present invention, “treating” or “treatment” in the present context includes alleviating symptoms, enhancing glycemic control or insulin sensitivity, arresting, slowing, retarding or stabilizing progression of a condition or a physiological or morphological marker thereof, or improving clinical outcome, for example as measured by quality of life, incidence or severity of adverse cardiac events, time to end-stage renal disease or survival time.

Without wishing to be bound by a theory, it is discovered that the present tricyclic compounds are good TGR5 agonists and have a low plasma exposure profile (i.e., low C max values). Low plasma exposure refers to maintaining a plasma level of TGR5 compounds (i.e., <200 ng/mL) after administration of the compounds. Preferably, the present compounds of the invention have a C max <20 ng/mL. More preferably, the present compounds of the invention have a C max <5 ng/mL.

The present inventors discovered that when administered via an oral route, the present compounds are restricted to the gut compartment and thus have low bioavailability in the blood stream (i.e., the compounds do not leak into the circulation and the resulting low plasma level). Not wishing to be bound to a theory, it is speculated that one functional group (e.g., (CHR) n1 -L 1 -(CHR) n2 -L 2 -(CHR) n3 -L 3 -(CHR) n4 -T) on the parent molecule may have affected the gut permeability and renders the compounds to be restricted in the gut compartment. It is possible that the functional group acts in concert with other functional groups on the parent molecules to exert this unique effect.

In one aspect, the present invention provides a combination therapy using the compounds as described herein and one or more of an additional therapeutic agent(s). The additional therapeutic agents preferably include medications commonly prescribed for diabetic treatments. Exemplary additional therapeutic agents include, but are not limited to metformin, sulfonylurea (such as gliclazide, glimepiride, and glipizide), nateglinide and repaglinide, dipeptidyl peptidase 4 (DPP-4) (such as linagliptin, saxagliptin, sitagliptin and vildagliptin), thiazolidinediones (such as glitazones or pioglitazone), acarbose, pramlintide, insulin, exenatide, liraglutide, dapagliflozin, canagliflozin and the like.

The combination therapy provides the beneficial effect from the co-action of these therapeutic agents, due to synergistic or additive effects. Therapeutic agents are preferably administered simultaneous, or carried out over a defined time interval (e.g., minutes or hours depending upon the combination selected). In one embodiment, co-administration can be accomplished, for example, by administering to the subject a single dosage form (e.g., capsule) having a fixed ratio of each therapeutic agent. In another embodiment, while TGR5 compound of the present invention is administered by oral route, the second therapeutic agent can be administered by the same route or by different routes (e.g., orally, intravenous injection, intramuscular or nasally). In one embodiment, the combined therapy composition includes an oral TGR5 compound and an injectable insulin. In another embodiment, the combined therapy composition includes an oral TGR5 compound and sitagliptin.

In one aspect, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In one aspect, the present invention relates to a method of treating diseases in a subject by administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof.

The present inventors designed the compounds of the present invention to have favorable PK profile characteristics (e.g., low C max ). Without wishing to be bound by a theory, it is further discovered that the compounds of the present invention, when orally ingested, are not leaking into the blood stream (i.e., low C max ). The low C max is believed to render the present compounds superior properties of reducing side-effects (such as bile retention in gall-bladder). The compounds of the present invention are therefore superior and suitable for treating a TGR5-related metaolic disease, such as pre-diabetes, type-2 diabetes, and obesity. For purposes of this application, TGR5-related metabolic disease may also include fibrosing cholangitis, colitis, pancreatitis, cancer, and the like.

In one embodiment, the subject in need of treatment is a human. The present compounds are suitable for treating a TGR5 related metabolic disease in a human. In one embodiment, the human disorder is pre-diabetes. In a preferred embodiment, the human metabolic disorder is type-2 diabetes. In another preferred embodiment, the human metabolic disorder is obesity. In further embodiments, the TGR5-related metabolic disorder may include diabetes, insulin resistance, and pre-diabetic insulin resistance. In another embodiment, the human metabolic disorder is fibrosing cholangitis. In another embodiment, the human metabolic disorder is an inflammatory disease, preferably colitis. In another embodiment, the human metabolic disorder is a digestive disease, preferably pancreatitis. In another embodiment, the human metabolic disorder is cancer.

Without wishing to be bound by a theory, it is discovered that one functional group (e.g., (CHR) n1 -L 1 -(CHR) n2 -L 2 -(CHR) n3 -L 3 -(CHR) n4 -T) attributes to the non-systemic property of the compounds. The functional group is speculated to render the compound with a low pharmacokinetic profile while surprisingly effective in exerting the glycemic control in diabetic conditions. In accordance with this unexpected finding, the present compounds have practical clinical utility and application in the treatment of TGR5-related metabolic disorders including pre-diabetes, type-2 diabetes, obesity, fibrosing cholangitis, colitis, pancreatitis, cancer, and the like.

While the present invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present invention, which is defined by the scope of the appended claims. Other embodiments, advantages, and modifications are within the scope of the following claims. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the present invention encompassed by the appended claims.

General Synthetic Schemes

Compounds of the present invention were prepared using the synthetic schemes described herein. The general schemes utilize various transformations such as alkylations, reductions, oxidations, displacements, and amide bond formations. During the chemical syntheses, various protecting groups may be employed and subsequently removed in order to generate the compounds of the present invention. Exemplary protecting groups and conditions for their removal are described in Greene's Protecting Groups in Organic Synthesis P. G. M. Nuts, T. W. Greene, Fourth Edition, Wiley, New York, 2006.

Amine protecting groups include, for example, tert-butoxy carbamate, carboxybenzyl group, and 9-fluorenylmethyl carbamate. Deprotection conditions vary depending on the protecting groups. For example, if the amine is protected as a tert-butoxy carbamate, suitable acidic conditions such as a solution of TFA in DCM or a solution of HCl in dioxane can be used to remove the protecting group. Alternatively, if the protecting group is a 9-fluorenylmethyl carbamate, suitable basic conditions such as a solution of piperidine in DMF or a solution of diethylamine in DMF can be used to remove the protecting group. Alternatively, if the amine is protected as a carboxybenzyl group, catalytic hydrogenation can be employed for its deprotection.

Carboxylic acid protecting groups include, for example, tert-butyl, benzyl, ethyl, and methyl ester. Removal of a tert-butyl ester can be completed under acid conditions such as treatment with a solution of TFA in DCM. Alternatively, the removal of a benzyl ester can be completed via hydrogenolysis using, for example, palladium on carbon under a hydrogen atmosphere. In further examples, ethyl and methyl esters can be hydrolyzed to the carboxylic acid under hydrolytic conditions such as LiOH in aqueous THF.

In the general schemes below, the syntheses of compounds sometimes require the formation of an amide bond. Coupling agents such as EDC, DIC, or HATU can be used to form the amide bond generally in a solvent such as DCM or DMF with a suitable base present such as DIEA or triethylamine as required. An additive such as HOBt, HOAt, or DMAP can also be employed during the reaction.

Specific synthetic transformations not covered in the general schemes below are described in detail in the experimental section. It is apparent to those skilled in the art that the order of steps might be adjusted depending on the compound to be produced.

General Scheme 1 depicts three routes to synthesize intermediate VI. As shown in Route 1-1, a suitably protected amino acid derivative III (PG=protecting group) can be coupled with an amine to form amide derivative IV using conditions for amide bond formation known to those skilled in the art and outlined above. Deprotection of the amine protecting group of intermediate IV is carried out by methods known to those skilled in the art and outlined above. The resultant amine V can be converted to Intermediate VI by reaction with a suitable halogen-bearing heterocycle as depicted such as 4,6-dichloro-2-(trifluoromethyl)pyrimidine or 2-chloro-4-iodo-6-(trifluoromethyl)pyridine in the presence of a suitable base such as DIEA or triethylamine. Suitable solvents for this reaction include DMF, DMSO, and dioxane. Depending on the substrates, the reaction can be carried out at room temperature or up to 120° C.

Alternatively, compounds VI can be synthesized via Route 1-2. In this case, an amino acid derivative VII is reacted with a suitable halogen-bearing heterocycle such as 4,6-dichloro-2-(trifluoromethyl)pyrimidine or 2-chloro-4-iodo-6-(trifluoromethyl)pyridine in the presence of a suitable base such as DIEA or triethylamine to yield intermediate VIII. Coupling of a suitable amine to intermediate VIII generates the amide-bearing intermediate VI.

Alternatively, compounds VI can be synthesized via Route 1-3. In this route, ester derivatives IX are reacted with a suitable halogen-bearing heterocycle such as 4,6-dichloro-2-(trifluoromethyl)pyrimidine or 2-chloro-4-iodo-6-(trifluoromethyl)pyridine in the presence of a suitable base such as DIEA or triethylamine. Suitable solvents for this reaction include DMF, DMSO, and dioxane. This reaction yields protected intermediate X. Deprotection of intermediate X to carboxylic acid VIII can be carried out by various methods recognized by those skilled in the art and outlined above. Finally, the carboxylic acid derivative VIII can be converted to intermediate VI via amide formation employing a suitable coupling agent as previously described above.

As depicted in General Scheme 2, treatment of halogen-bearing compound VI with an amine in the presence of a base such as DIEA or triethylamine in a solvent such as DMSO, DMF, NMP, or the like can generate compounds I of the present invention directly. The reaction is generally heated between 80° C. to 120° C. either thermally or in a microwave oven. It is clear to those skilled in the art that protecting groups may need to be removed as described above to generate compounds I. In reactions carried out with a subset of amines, these conditions generate compounds XI, XII, and XIII which can be further reacted as described below to generate compounds of the present invention.

Buchwald/Hartwig conditions can also be employed to convert intermediate VI to compounds of the present invention I. In this case, intermediate VI is generally heated between 80° C. to 120° C. with an amine in the presence of a suitable palladium catalyst such as RuPhos precatalyst, a ligand such as RuPhos, and a suitable base such as cesium carbonate in a solvent such as toluene or the like to generate compounds I. Again, protecting groups may need to be removed as described above to generate compounds I. In reactions carried out with a subset of amines, the Buchwald/Hartwig conditions generate compounds XI, XII, and XIII which can be further reacted as described below to generate compounds of the present invention.

To simplify the remaining schemes, the following is defined:

Some of the compounds produced by the reactions in General Scheme 2 will contain an unprotected carboxylic acid group as depicted in structure XIV. Alternatively, some compounds of the present invention produced by the reactions in General Scheme 2 can harbor a protected carboxylic acid functionality as depicted in compound XI in General Scheme 3. As shown in Route 3-1, removal of the protecting group from XI using methods described previously generates XIV, a carboxylic acid containing compound of the present invention. Various reactions of the carboxylic acid group in XIV are used to generate compounds of the present invention. For instance, as depicted in Route 3-2, carboxylic acid derivative XIV can be coupled with an amine using a suitable coupling agent as described above to generate an amide-bearing compound XV of the present invention.

Alternatively, the carboxylic acid group in XIV can undergo a Curtius rearrangement in the presence of an appropriate amine to generate a urea-bearing compound XVI of the present invention (as depicted in Route 3-3). The carboxylic acid XIV is converted into an isocyanate by treatment with diphenylphosphoryl azide while heating between 80° C. to 100° C. in a suitable solvent such as toluene. Addition of an amine to the reaction yields the urea-bearing compound XVI.

Further compounds of the present invention can be synthesized by reduction of XI when the protecting group, PG 3 , is an appropriate ester such as a methyl ester (Route 3-4). Treatment of XI with a suitable reducing agent such as lithium aluminum hydride or sodium borohydride in a solvent such as ethanol at temperature generally from room temperature to 60° C. produces an alcohol XVII of the present invention.

Some of the compounds produced by the reactions in General Scheme 2 can contain an unprotected amine group as depicted in structure XVIII in General Scheme 4. Additionally, compounds produced by the reactions in General Scheme 2 can harbor a protected amine functionality as depicted in compound XII of General Scheme 4. As shown in Route 4-1, removal of the protecting group yields XVIII, an amine-containing compound of the present invention. Deprotection of the amine protecting group of intermediate XII is carried out by methods known to those skilled in the art and described above.

Various reactions of the amine group in XVIII are used to generate further compounds of the present invention as shown in General Scheme 4. For instance, as depicted in Route 4-2 amine-bearing derivative XVIII can be coupled with a carboxylic acid to generate amide derivative XIX. Coupling agents as described above are employed. Alternatively, amide compounds of the present invention XIX can be synthesized by reaction of an acid chloride with amine XVIII in the presence of a suitable base such as DIEA, triethylamine, or pyridine in a solvent such as DCM.

As shown via Route 4-3, the amine derivative XVIII can also be transformed into a urea-bearing compound XVI of the present invention by conditions known to those skilled in the art. For example, treatment of XVIII with an isocyanate in a suitable solvent such as DCM or DMF will create a urea. Alternatively, treatment of compound XVIII with 1,1′-carbonyldiimidazole in the presence of a suitable base such as DIEA or triethylamine in a solvent such as DCM or DMF followed by heating in the presence of an amine will produce a urea XVI.

Further compounds of the present invention can be synthesized by converting amine-bearing derivative XVIII to a sulfonamide XX by treatment with a sulfonyl chloride in the presence of a base such as triethylamine, DIEA, or pyridine in a solvent such as DCM (Route 4-4).

Furthermore, the amine-bearing derivative XVIII can be transformed into a heterocyclic-bearing compound XXI of the present invention as depicted in Route 4-5. Heterocycles containing a halogen adjacent to nitrogen on the ring are activated to undergo displacement with amines. Therefore, heating such a heterocycle with amine XVIII in the presence of a suitable base such as DIEA or triethylamine in a solvent such as DMSO, DMF, or n-butanol generates heteroaryl-bearing compounds XXI. Heating from 100° C. to 120° C. is generally employed.

As shown in General Scheme 5, the amine-bearing derivative XVIII can be transformed into a guanidine derivative XXII by treatment with 1H-pyrazole-1-carboxamidine hydrochloride in the presence of a suitable base such as DIEA or triethylamine in a solvent such as DMF with heating generally in the range of 80° C. to 120° C. (Route 5-1).

Amine XVIII can alternatively be transformed (Route 5-2) into a hydantoin-bearing compound XXIII of the present invention by treatment with 1,1′-carbonyldiimidazole in the presence of a suitable base such as DIEA or triethylamine in a solvent such as DCM or DMF followed by heating generally in the range of 80° C. to 120° C. in the presence of L-cysteic acid monohydrate.

In addition, as shown in Route 5-3, compound XVIII can be further derivatized by alkylation through the treatment with an alkyl halide in the presence of a suitable base such as potassium carbonate in a solvent such as DMF to create further amine derivatives XXIV of the present invention.

Further compounds of the present invention can be synthesized as depicted in Route 5-4. Treatment with a cyclobutenedione derivative such as 4-diethoxycyclobut-3-ene-1,2-dione with an amine in the presence of a base such as triethylamine or DIEA followed by the addition of compound XVIII generates compounds XXV of the present invention.

As shown in General Scheme 6, a hydroxy-bearing compound XIII can be converted to compounds XXVI of the present invention. The hydroxyl is first activated by treatment with methanesulfonyl chloride, toluenesulfonyl chloride, or the like in the presence of a suitable base such as triethylamine or DIEA in a solvent such as DCM or DMF. The activated intermediate is then treated with a nucleophile (Nu) such as an amine or sulfite ion to generate XXVI. Reactions with an amine are generally carried out in a solvent such as ACN, DMF, or the like at temperatures ranging from room temperature to 100° C. Reactions with sodium sulfite are carried out in a mixture of an organic solvent (such as ACN) and water at temperatures ranging from room temperature to 100° C.

Subsets of compounds synthesized in General Schemes 3, 4, 5, and 6 contain functional groups that allow for further reactions. Additional compounds of the present invention are synthesized by completing further reactions on those subsets of compounds. Therefore, the starting materials in General Schemes 7, 8, and 9 are the products from the procedures carried out in General Schemes 3, 4, 5, and 6.

As stated above, additional compounds of the present invention are synthesized by further reactions on the compounds produced via the procedures outlined in General Schemes 3, 4, 5, and 6. For instance, compounds XXVII of the present invention which contain a suitably protected carboxylic acid could have resulted from the reactions in general schemes 3, 4, 5, and 6. These compounds (XXVII) can be further functionalized as outlined in General Scheme 7 to produce additional compounds of the present invention. As shown in Route 7-1, removal of the protecting group from XXVII employing conditions described previously generates XXVIII, a carboxylic acid containing compound of the present invention.

As shown in Route 7-2, coupling of XXVIII with an amine (under conditions outlined above) produces compounds XXIX of the present invention.

Compounds XXX which contain a suitably protected amine could have resulted from the reactions in general schemes 3, 4, 5, and 6. These compounds (XXX) can be further functionalized as outlined in General Scheme 8 to produce further compounds of the present invention. As shown in Route 8-1, removal of the protecting group produces XXXI, an amine-containing compound of the present invention. Deprotection of the amine protecting group of intermediate XXX is carried out by methods known to those skilled in the art and outlined above.

As shown in Route 8-2, derivative XXXI can be transformed into a guanidine-bearing compound XXXII of the present invention by treatment with 1H-pyrazole-1-carboxamidine hydrochloride in the presence of a suitable base such as DIEA or triethylamine in a solvent such as DMF with heating generally in the range of 80° C. to 120° C.

Further compounds of the present invention can be synthesized by converting amine XXXI to a sulfonamide XXXIII by treatment with a sulfonyl chloride in the presence of a base such as triethylamine, DIEA, or pyridine in a solvent such as DCM (Route 8-3).

As depicted in Route 8-4 and using previously described coupling conditions, amine XXXI can be coupled with a carboxylic acid to generate amide derivative XXXIV. Alternatively, compounds XXXIV can be synthesized by reaction of an acid chloride with amine XXXI in the presence of a suitable base such as DIEA, triethylamine, or pyridine in a solvent such as DCM.

Reactions of the amine group of XXXI with heterocycles generate further compounds of the present invention as shown in General Scheme 9. As mentioned previously, heterocycles containing a halogen adjacent to nitrogen in the ring are activated to undergo displacement with amines. Therefore, heating such a heterocycle with amine XXXI in the presence of a suitable base such as DIEA or triethylamine in a solvent such as DMSO, DMF, or n-butanol generates compounds XXXVI of the present invention (Route 9-1). Heating between 100° C. to 120° C. is generally employed.

As shown in Route 9-2, heating amine XXXI with a suitable heterocycle containing two activated halogens in the presence of a base such as DIEA or triethylamine in a solvent such as DMSO, DMF, or n-butanol yields compounds XXXVII. Heating between 100° C. to 120° C. is generally employed. Amine displacement of the remaining halogen (Route 9-3) generates compounds XXXVIII of the present invention. The conditions employed are similar as described for the first displacement.

Compounds XXXIX of the present invention are synthesized by coupling XXXI with a halogen-bearing heterocycle functionalized with a carboxylic acid (Route 9-4). Standard amide formation conditions outlined above are employed. Displacement of the halogen of the resultant XXXIX with an amine, as shown in Route 9-5 generates compounds XL of the present invention. The reaction is carried out with heating between 100° C. to 120° C. in the presence of a suitable base such as DIEA or triethylamine in a solvent such as DMSO, DMF, or n-butanol.

Under similar conditions, XXXI can be reacted (Route 9-6) with a halogenated heterocyclic harboring a carboxylic acid moiety to generate compounds XLI. The carboxylic acid group can be further reacted by coupling to an amine to generate compounds XLII of the present invention. Coupling agents as described above can be used to complete this reaction.

Additionally, as shown in General Scheme 10, the halogen of compound VI can be reacted to form an aryl or heteroaryl compound II of the present invention by conditions known to those skilled in the art. For example, heating of VI with a aryl or heteroaryl boronic acid or boronic ester in the presence of both a palladium catalyst such as tetrakis(triphenylphosphine) palladium(0), tris(dibenzylideneacetone)dipalladium(0), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II), or the like and a suitable base such as aqueous sodium carbonate or potassium carbonate in a solvent such as dioxane or DMF (Suzuki coupling conditions) will generate compounds II. Alternatively, reactions of VI with aryl or heteroaryl tin derivatives using Stille conditions could also generate compounds II. Alternatively, reactions of IV with aryl or heteroaryl zinc derivatives using Negishi conditions could also be used generate compounds II.

A subset of compounds synthesized in General Scheme 10 contains functional groups that allow for further reactions. For example, structures XLIII and XLIV contain a carboxylic acid (XIV) or amine functionality (XIX) or their respective protected counterparts. These carboxylic acids (XIV) or amines (XIX) can be further reacted using the methods outlined above in General Schemes 3, 4, 5, 7, 8, and 9 to generate further compounds II.

Some other compounds of the present invention in which L 1 , L 2 , and L 3 are present can be synthesized by subjecting the intermediates outlined above to additional reactions following the methods described in the schemes above.

The compounds of the present invention were prepared using the experimental procedures described herein. They can be made by alternate methods which are apparent to a chemist skilled in the art.

ACN=acetonitrile

AIBN=2,2′-azobis(2-methylpropionitrile)

Arg=arginine

Boc=t-butoxycarbonyl

(Boc) 2 O=di-tert-butyl dicarbonate

brine=saturated sodium chloride

t-BuOH=tert-butanol

Cbz=benzyloxycarbonyl

CDI=1,1′-carbonyldiimidazole

Conc.=concentrated

DCE=dichloroethane

DCM=dichloromethane

DIAD=diisopropyl azodicarboxylate

DIBAL=diisobutylaluminum hydride

DIC=diisopropylcarbodiimide

DIEA=diisopropylethylamine

DMAP=4-(dimethylamino)pyridine

DMF=dimethylformamide

DMSO=dimethylsulfoxide

DPPA=diphenylphosphoryl azide

EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

EA=EtOAc=ethyl acetate

Fmoc=9-fluorenylmethoxycarbonyl

Glu=glutamic acid

HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphate

h=hours

HCl=hydrochloric acid

HOAt=1-hydroxy-7-azabenzotriazole

HOBt=N-hydroxybenzotriazole

HPLC=high performance liquid chromatography

LCMS=liquid chromatography-mass spectrometry

LDA=lithium diisopropylamide

min=minutes

MeOH=methanol

MsCl=methanesulfonyl chloride

MS-HPLC=mass-directed reverse phase semi-preparative chromatography

NBS=N-bromosuccinimide

PE=petroleum ether

PDA=photo diode array

PG=protecting group

PMC=2,2,5,7,8-pentamethylchromane-6-sulfonyl

PPh 3 =triphenylphosphine

PS-HOBt=polystyrene bound N-hydroxybenzotriazole

Quant.=quantitative

RuPhos=2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl

RuPhos preCat=chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct

Sat.=saturated

TBAF=tetrabutylammonium fluoride

TBDMSCl=tert-butyldimethylsilyl chloride

TEA=triethylamine

TFA=trifluoroacetic acid

THF=tetrahydrofuran

TMSI=iodotrimethylsilane

XPhos=2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

XPhos G-2=chloro-(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

LC/MS Analysis Methods:

Method A—Compounds were analyzed on an Aquity Ultra Performance Liquid Chromatography employing an Acquity UPLC BEH C18, 1.7 μm, 2.1×50 mm column. Detection was via an Aquity PDA detector and a Waters SQD single quadrupole mass spectrometer. The aqueous acetonitrile based solvent gradient was: 0-0.1 min—Isocratic—10% of acetonitrile (0.01% TFA); 0.1-1.3 min—Linear gradient—10%-90% acetonitrile (0.01% TFA); 1.3-1.8 min—Isocratic—90% acetonitrile (0.01% TFA); 1.8-1.9 min—Linear gradient—90%-10% acetonitrile (0.01% TFA); 1.9-2.0 min—Isocratic—10% acetonitrile (0.01% TFA). Flow rate: 0.6 mL/min.

Method B—Compounds were analyzed on an Aquity Ultra Performance Liquid Chromatography employing a Acquity UPLC BEH C18, 1.7 um, 2.1×50 mm column. Detection was via an Aquity PDA detector and a Waters SQD single quadrupole mass spectrometer. The aqueous acetonitrile based solvent gradient was: 0-0.1 min—Isocratic—20% of acetonitrile (0.01% TFA); 0.1-1.3 min—Linear gradient—20%-95% acetonitrile (0.01% TFA); 1.3-1.8 min—Isocratic—95% acetonitrile (0.01% TFA); 1.8-1.9 min—Linear gradient—95%-20% acetonitrile (0.01% TFA); 1.9-2.0 min—Isocratic—20% acetonitrile (0.01% TFA). Flow rate: 0.6 mL/min.

Method C—Compounds were analyzed on a Waters 2795 AllianceHT Liquid Chromatography employing a Phenomenex Luna C18, 5 μm, 2.1×50 mm column. Detection was via a Waters 996 Photodiode Array detector and a Micromass Quattro Micro triple quadrupole mass spectrometer. The aqueous acetonitrile based solvent gradient was: 0.0-3.0 min—Linear gradient—10%-90% acetonitrile (0.01% TFA); 3.0-3.5 min—Isocratic—90% acetonitrile (0.01% TFA); 3.5-3.6 min—Linear gradient—90%-10% acetonitrile (0.01% TFA); 3.6-5.0 min—Isocratic—10% acetonitrile (0.01% TFA). Flow rate: 0.6 mL/min.

Method D—Compounds were analyzed on an Aquity Ultra Performance Liquid Chromatography employing an Acquity UPLC BEH C18, 1.7 um, 2.1×50 mm column. Detection was via an Aquity PDA detector and a Micromass Quattro Micro triple quadrupole mass spectrometer. The aqueous acetonitrile based solvent gradient was: 0-0.1 min—Isocratic—10% of acetonitrile (0.01% TFA); 0.1-1.3 min—Linear gradient—10%-90% acetonitrile (0.01% TFA); 1.3-1.8 min—Isocratic—90% acetonitrile (0.01% TFA); 1.8-1.9 min—Linear gradient—90%-10% acetonitrile (0.01% TFA); 1.9-2.0 min—Isocratic—10% acetonitrile (0.01% TFA). Flow rate: 0.6 mL/min.

NMR Spectroscopy Method:

1 H NMR Spectroscopy was conducted on a Bruker 400 MHz Avance II FTNMR Spectrometer.

Preparation of Chemical Compounds:

(S)-(9H-fluoren-9-yl)methyl 2-((2,4-dichlorophenethyl)carbamoyl)pyrrolidine-1-carboxylate

To a solution of Fmoc-L-Proline (1.0 g, 3.0 mmol) in DCM (14 mL) were added sequentially 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (682 mg, 3.56 mmol), N-hydroxybenzotriazole (441 mg, 3.26 mmol) and 2-(2,4-dichlorophenyl)ethanamine (0.45 mL, 3.0 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with DCM. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford Intermediate 1A (1.5 g, 99%), which was used in the next step without further purification. LCMS (method A): m/z 509.2 (M+H) + .

(S)—N-(2,4-dichlorophenethyl)pyrrolidine-2-carboxamide

A solution of Intermediate 1A (1.5 g, 3.0 mmol) in 20% piperidine/CHCl 3 (3 mL/12 mL) was stirred at room temperature for one hour. The solution was concentrated in vacuo, and the residue was purified by silica gel chromatography (0-5% MeOH/DCM) to afford Intermediate 1B (355 mg, 42%). LCMS (method A): m/z 287.1 (M+H) + . 1 H NMR (CDCl 3 ) δ 7.68 (br s, 1H), 7.39 (d, 1H), 7.17 (m, 2H), 3.71 (dd, 1H), 3.50 (m, 2H), 3.01-2.91 (m, 3H), 2.82 (m, 1H), 2.15-2.09 (m, 1H), 1.90-1.83 (m, 2H), 1.70-1.65 (m, 2H).

(S)-1-(6-chloro-2-(trifluoromethyl)pyrimidin-4-yl)-N-(2,4-dichlorophenethyl)-pyrrolidine-2-carboxamide

To a solution of Intermediate 1B (40 mg, 0.14 mmol) in DMF (0.3 mL) were added 4,6-dichloro-2-(trifluoromethyl)pyrimidine (30 mg, 0.14 mmol) and diisopropylethylamine (30 μL, 0.17 mmol). The reaction mixture was heated at 90° C. in a microwave for one hour. The reaction mixture was concentrated in vacuo, and the residue was purified by MS-HPLC to afford Intermediate 1 (52 mg, 79%). LCMS (method A): m/z 467.3/469.3 (M+H) + . Using the method outlined above to synthesize Intermediate 1B, the following intermediates were made using the appropriate acids and amines as indicated in Table 1.

(S)-1-(6-chloro-2-(trifluoromethyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid

To a solution of L-Proline (690 mg, 6.0 mmol) in DMF (8.5 mL) were added 4,6-dichloro-2-(trifluoromethyl)pyrimidine (1.43 g, 6.60 mmol) and diisopropylethylamine (1.20 mL, 6.90 mmol). The reaction mixture was stirred at room temperature for one hour. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography (0-5% MeOH/DCM) to afford Intermediate 2A (1.2 g, 65%). LCMS (method A): m/z 296.2 (M+H) + . 1 H NMR (CDCl 3 ) δ 6.52 (s, 1H), 6.74 (dd, 1H), 3.59 (m, 1H), 3.47 (m, 1H), 2.34-2.16 (m, 4H).

(S)-1-(6-chloro-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide

To a solution of Intermediate 2A (148 mg, 0.50 mmol) in DCM (5 mL) were added sequentially 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (115 mg, 0.60 mmol), PS-HOBt resin (1.07 mmol/g) (560 mg, 0.60 mmol), 4-(2-aminoethyl)benzonitrile hydrochloride (96 mg, 0.53 mmol) and diisopropylethylamine (0.22 mL, 1.3 mmol). The reaction mixture was stirred at room temperature overnight. The resin was filtered, and washed with DCM and MeOH. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (0-65% EtOAc/hexanes) to afford Intermediate 2 (116 mg, 55%). LCMS (method A): m/z 424.3 (M+H) + . 1 H NMR (CDCl 3 ) δ 7.53 (d, 2H), 7.23 (d, 2H), 6.75 (br s, 1H), 6.48 (s, 1H), 4.61 (m, 1H), 3.56-3.49 (m, 3H), 3.39 (m, 1H), 2.86 (m, 2H), 2.38 (m, 2H), 2.15 (m, 1H), 1.98 (m, 1H).

Alternatively, Intermediate 2 can be prepared by reacting intermediate 1C with 4,6-dichloro-2-(trifluoromethyl)pyrimidine following the procedure as described for Intermediate 1, step 3.

(S)-1-(6-chloro-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(trifluoromethyl)phenethyl)-pyrrolidine-2-carboxamide

Following the procedure described above for Intermediate 2, starting from intermediate 2A and using 2-(4-(trifluoromethyl)phenyl)ethanamine in step 2, Intermediate 3 was prepared. LCMS (method A): m/z 467.3 (M+H) + . 1 H NMR (CDCl 3 ) δ 7.48 (d, 2H), 7.21 (d, 2H), 6.73 (br s, 1H), 6.45 (s, 1H), 4.61 (m, 1H), 3.59 (m, 1H), 3.49 (m, 2H), 3.32 (m, 1H), 2.85 (m, 2H), 2.37 (m, 2H), 2.14 (m, 1H), 1.97 (m, 1H).

Alternatively, Intermediate 3 can be prepared from intermediate 1D following the procedure as described for Intermediate 1, step 3.

(S)-1-(6-chloro-2-(trifluoromethyl)pyrimidin-4-yl)-N-(3-chloro-4-(trifluoromethyl)-phenethyl)pyrrolidine-2-carboxamide

Following the procedure described above for Intermediate 2, using 2-(3-chloro-4-(trifluoromethyl)phenyl)ethanamine in step 2, Intermediate 4 was prepared. LCMS (method D): m/z 501.0 (M+H) + .

2-(2-methoxy-4-(trifluoromethyl)phenyl)acetamide

2-methoxy-4-trifluoromethyl-phenylacetic acid (1.2 g. 5.0 mmol) and thionyl chloride (2.9 mL, 40 mmol) were heated at reflux for two hours. The reaction was concentrated in vacuo, and azeotroped with anhydrous toluene (3×3 mL). The residue in THF (5 mL) was added to a solution of aqueous ammonium hydroxide (28-30%, 2.8 mL) in anhydrous THF (47 mL) at 0° C. The ice bath was then removed. The reaction was stirred vigorously for 1.5 hours, and was concentrated in vacuo. Water was added to the residue. The mixture was heated at 80° C. for 10 minutes, and then cooled to room temperature. The mixture was filtered to afford Intermediate 5A (1.03 g, 87%). LCMS (Method A): m/z 234.3 (M+H) + .

2-(2-methoxy-4-(trifluoromethyl)phenyl)ethanamine

To Intermediate 5A (1.02 g, 4.37 mmol) in anhydrous THF (12 mL) was added 1M BH 3 .THF (13.1 mL, 13.1 mmol). The solution was heated at reflux for 3.5 hours. The reaction was cooled to room temperature. After H 2 O (1.3 mL) and conc. HCl (5.1 mL) were added, the reaction was stirred for 30 minutes at reflux. The reaction was concentrated in vacuo to reduce the volume to ⅓ of the original amount, and 3N NaOH (12 mL) was added. The aqueous layer was extracted with ethyl ether (3×30 mL). The organic layers were dried (Na 2 SO 4 ), filtered, and concentrated. The residue was purified by silica gel chromatography to afford Intermediate 5B (587 mg, 61%). LCMS (Method A): m/z 220.3 (M+H) + . 1 H NMR (CD 3 OD): δ 7.34-7.32 (d, 1H), 7.20-7.17 (m, 2H), 3.89 (s, 3H), 2.91-2.86 (m, 4H).

(S)-1-(6-chloro-2-(trifluoromethyl)pyrimidin-4-yl)-N-(2-methoxy-4-(trifluoromethyl)phenethyl)pyrrolidine-2-carboxamide

Following the procedure described above for Intermediate 2, using HOBt instead of resin-bound HOBt, Intermediate 2A was coupled with intermediate 5B to afford Intermediate 5. LCMS (method A): m/z 497.5 (M+H) + . Using the method outlined above to synthesize Intermediate 5B, the following intermediates were made using the precursors as indicated in Table 2.

(S)-1-(6-chloropyrimidin-4-yl)-N-(2,4-dichlorophenethyl)pyrrolidine-2-carboxamide

To a solution of Intermediate 1B (110 mg, 0.38 mmol) in DMF (1 mL) were added 4,6-dichloropyrimidine (80 mg, 0.54 mmol) and diisopropylethylamine (130 μL, 0.77 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM, and washed with water and brine. The organic layer was dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to afford Intermediate 6 (129 mg, 84%). LCMS (method A): m/z 399.2 (M+H) + . 1 H NMR (CDCl 3 ) δ 8.25 (s, 1H), 7.30 (t, 1H), 7.09 (m, 2H), 6.86 (br s, 1H), 6.36 (s, 1H), 4.60 (br s, 1H), 3.59-3.44 (m, 3H), 3.30 (br s, 1H), 2.97-2.83 (m, 2H), 2.36 (br, 1H), 2.09-1.96 (m, 3H).

(S)-1-(6-chloro-2-methylpyrimidin-4-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide

Following the procedure described above for intermediate 6, intermediate 1C was reacted with 4,6-dichloro-2-methylpyrimidine by heating in a microwave for one hour at 100° C. to afford intermediate 7. LCMS (method A): m/z 421.5 (M+H) + .

(S)-1-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide

Following the procedure described above for intermediate 6, intermediate 1C was reacted with 2,6-dichloro-4-(trifluoromethyl)pyridine by heating in a microwave for three hours at 100° C. to afford intermediate 8. LCMS (method A): m/z 423.3 (M+H) + .

2-Chloro-4-iodo-6-(trifluoromethyl)pyridine

To a cooled (−100° C.) solution of diisopropylamine (14.5 mL, 104 mmol) in 80 mL of THF under inert atmosphere was added dropwise n-butyllithium (65 mL of a 1.6 M solution in hexanes, 104 mmol) followed by a 10 mL of THF solution of 2-chloro-6-(trifluoromethyl) pyridine (9.5 g, 52 mmol). After two hours, the temperature was raised to −78° C. and a 10 mL solution of iodine in THF (13 g, 52 mmol) was added. After 1 hour, the reaction was poured into water and extracted with DCM. The combined DCM layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 14.9 g of a mixture of 6-chloro-3-iodo-2-(trifluoromethyl)pyridine and 2-chloro-4-iodo-6-(trifluoromethyl)pyridine. This crude material was resubjected to LDA as follows. To a cooled (−78° C.) solution of diisopropylamine (14.5 mL, 104 mmol) in 80 mL of THF under inert atmosphere was added dropwise n-butyllithium (65 mL of a 1.6 M solution in hexanes, 104 mmol) followed by a 30 mL solution of the preceding crude mixture in THF. After three hours, the reaction mixture was poured in water and extracted with DCM. The DCM layers were washed with brine, dried (MgSO 4 ), concentrated in vacuo, and purified via silica gel chromatography (0-20% EtOAc/hexanes) to afford Intermediate 9A as a white solid (6.9 g, 42%). 1 H NMR (CDCl 3 ): δ 7.96 (s, 1H), 7.95 (s, 1H).

(S)-tert-butyl 2-((4-cyanophenethyl)carbamoyl)pyrrolidine-1-carboxylate

To a solution of Boc-L-proline (6.0 g, 28 mmol) in DCM (20 mL) were sequentially added EDC (5.4 g, 28 mmol), HOBt (3.8 g, 28 mmol), triethylamine (7.8 mL, 56 mmol) and 4-(2-aminoethyl)benzonitrile hydrochloride (5.1 g, 28 mmol). After stirring for 48 hours, the reaction mixture was washed with 1N HCl, saturated NaHCO 3 and brine, then dried (MgSO 4 ), and concentrated in vacuo to afford Intermediate 9B (9.17 g, 96%). 1 H NMR (CDCl 3 ): δ 7.55 (d, 2H), 7.28 (d, 2H), 4.20 (bs, 1H), 3.48 (d, 2H), 3.30 (bs, 2H), 2.85 (m, 2H), 2.03 (m, 4H), 1.41 (s, 9H).

(S)—N-(4-cyanophenethyl)pyrrolidine-2-carboxamide hydrochloride

To a solution of Intermediate 9B (9.17 g, 26.7 mmol) in DCM (25 mL) was added a solution of 4N HCl/dioxane (33 mL, 130 mmol). After stirring one hour, the solvent was removed in vacuo to obtain Intermediate 9C which was carried to the next step without purification. LCMS (method A): m/z 244.3 (M+H) + .

(S)—N-(4-cyanophenethyl)-1-(4-iodo-6-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide

To a solution of Intermediate 9C (13 mmol) in dioxane (25 mL) were added Intermediate 9A (4.1 g, 13 mmol) and DIEA (5.8 mL, 33 mmol). After stirring 96 hours at 95° C., the solvent was removed in vacuo, and the residue was redissolved in EtOAc, washed with brine, dried (MgSO 4 ), and concentrated in vacuo. The residue was purified via silica gel chromatography (0-100% EtOAc/hexanes) to afford Intermediate 9 (2.06 g, 30%). LCMS (method A): m/z 515.4 (M+H) + . 1 H NMR (CDCl 3 ): δ 7.37 (d, 2H), 7.23 (s, 1H), 7.07 (d, 2H), 6.91 (s, 1H), 4.46 (d, 1H), 3.40 (m, 3H), 3.22 (m, 1H), 2.74 (m, 2H), 2.11 (m, 1H), 2.03 (m, 2H), 1.08 (m, 1H).

tert-butyl 4-(2-cyanoethyl)piperidine-1-carboxylate

To a stirred solution of 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (1.0 g, 3.9 mmol) in anhydrous THF (10 mL) under nitrogen was added carbonyldiimidazole (631 mg, 3.89 mmol). The reaction was stirred for 90 minutes, cooled to 0° C., and a solution of NH 3 in THF (0.40 M, 15 mL) was added. The ice bath was removed, and the mixture was stirred overnight. THF was removed under reduced pressure. The residue was dissolved in DCM (50 mL), washed with sat. NaHCO 3 (30 mL), and dried over sodium sulfate. The solution was filtered and concentrated in vacuo. This crude material was dissolved in anhydrous THF (20 mL) under nitrogen. Pyridine (0.940 mL, 11.7 mmol) and trifluoroacetic anhydride (3.20 mL, 23.3 mmol) were added dropwise. The mixture was stirred at room temperature overnight. After dilution with ether (100 mL), the mixture was washed with 1N HCl (50 mL), sat. NaHCO 3 (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford Intermediate 10A (434 mg, 47%). 1 H NMR (CDCl 3 ) δ 4.12 (m, 2H), 2.70 (t, 2H), 2.39 (t, 2H), 1.85 (b, 1H), 1.69-1.59 (m, 4H), 1.45 (s, 9H), 1.11 (m, 2H).

3-(piperidin-4-yl)propanenitrile

Intermediate 10A was dissolved in DCM (3 mL), and TFA (1 mL) was added. The mixture was stirred at room temperature for 90 minutes. The solvent was removed under reduced pressure, and the residue was dried in vacuo to afford Intermediate 10 which was used in the next reaction without further purification. 1 H NMR (CDCl 3 ) δ 3.40 (t, 2H), 2.92 (t, 2H), 2.48 (t, 2H), 1.95 (d, 2H), 1.73-1.67 (m, 3H), 1.55-1.44 (m, 2H).

(2S,5S)-tert-butyl 2-hydroxy-5-((4-(trifluoromethyl)phenethyl)carbamoyl)-pyrrolidine-1-carboxylate

Intermediate 11A was prepared from N-Boc-cis-4-hydroxy-L-proline (200 mg, 0.86 mmol) and 4-trifluoromethylphenethylamine (195 mg, 0.860 mmol) following the procedure as described for Intermediate 9, step 2. N,N-Diisopropylethylamine (0.23 mL, 1.3 mmol) was used instead of triethylamine. After work-up, the reaction mixture was purified by silica gel chromatography to afford Intermediate 11A (233 mg, 67%). LCMS (method A): m/z 303.2 (M+H-Boc) + , (M+Na) + 425.3. 1 H NMR (CDCl 3 ): δ 7.57-7.55 (m, 2H), 7.34-7.32 (m, 2H), 7.14 (b, 1H), 5.06-5.03 (m, 1H), 4.39-4.32 (m, 2H), 3.63-3.40 (m, 4H), 2.89 (t, 2H), 2.34-2.28 (m, 1H), 2.14-2.07 (m, 1H), 1.55-1.38 (m, 9H).

(2S,5S)-5-hydroxy-N-(4-(trifluoromethyl)phenethyl) pyrrolidine-2-carboxamide hydrochloride

Following the procedure as described in Intermediate 9, step 3, Intermediate 11A (233 mg, 0.58 mmol) was converted to Intermediate 11 (198 mg, quant.). LCMS (Method C): m/z 303.3 (M+H) + . 1 H NMR (CD 3 OD): δ 8.41 (m, 1H), 7.61-7.59 (m, 2H), 7.45-7.43 (m, 2H), 4.51-4.49 (m, 1H), 4.26-4.22 (m, 1H), 3.66-3.45 (m, 2H), 3.38-3.28 (m, 2H), 2.93 (t, 2H), 2.56-2.49 (m, 1H), 2.06-2.02 (m, 1H). Using the method outlined above to synthesize Intermediate 11, the following intermediates were made using the appropriate acids and amines as indicated in Table 3.

(S)-1-(6-chloro-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)azetidine-2-carboxamide

To a solution of Intermediate 1P (120 mg, 0.54 mmol) in DMF (3.0 mL) were added N,N-diisopropylethylamine (103 μL, 0.590 mmol) and 4,6-dichloro-2-(trifluoromethyl)-pyrimidine (86 μL, 0.57 mmol). The solution was heated in a microwave at 90° C. for one hour, and was then partitioned between DCM and H 2 O. The aqueous layer was extracted with DCM (2×), and the combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to afford Intermediate 12 (191 mg, 86%). LCMS (Method A): m/z 410.2 (M+H) + . 1 H NMR (CDCl 3 ): δ 7.66-7.52 (m, 3H), 7.27-7.25 (m, 2H), 6.35 (s, 1H), 4.94-4.86 (m, 1H), 4.12-4.07 (m, 1H), 4.01-3.95 (m, 1H), 3.61-3.52 (m, 2H), 2.99-2.83 (m, 3H), 2.64-2.55 (m, 1H). Using the method outlined above to synthesize Intermediate 12, the following intermediates were made using the precursors as indicated in Table 4.

tert-butyl 4-(2-((2-tert-butyldimethlsilyl)oxy)ethyl)amino)ethyl)piperidine-1-carboxylate

To a suspension of activated molecular sieves in DMF (2.2 mL) was added CsOH.H 2 O (74 mg, 0.44 mmol), and the mixture was stirred vigorously for 10 minutes. tert-Butyl 4-(2-aminoethyl)piperidine-1-carboxylate (99 μL, 0.44 mmol) was added, and the mixture was stirred for 30 minutes. Then (2-bromoethoxy)(tert-butyl)dimethylsilane (93 μL, 0.53 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was filtered, washed with EtOAc, and partitioned between EtOAc and 1N NaOH. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to afford Intermediate 13 (72.6 mg, 43%). LCMS: m/z 387.6 (M+H) + . 1 H NMR (CDCl 3 ): δ 3.99 (br, 2H), 3.67 (t, 2H), 2.68-2.59 (m, 6H), 1.76-1.54 (m, 5H), 1.10-1.09 (3H), 0.84 (s, 9H), 0.01 (s, 6H).

(R)-1-(6-chloro-2-(trifluoromethyl)pyrimidin-4-yl)-N-(4-cyanophenethyl)piperidine-3-carboxamide

Following the procedure as described for Intermediate 12, Intermediate 1V (85 mg, 0.33 mmol) was converted to Intermediate 14 (57 mg, 39%). LCMS (Method A): m/z 438.3 (M+H) + . 1 H NMR (CDCl 3 ): δ 7.58 (m, 2H), 7.27 (d, 2H), 6.58 (s, 1H), 5.94 (br s, 1H), 4.13 (br s, 1H), 3.63-3.49 (m, 3H), 3.24 (br, 1H), 2.94-2.83 (m, 2H), 2.34 (m, 1H), 2.07-1.70 (m, 3H), 1.55 (m, 2H).

Alternatively, Intermediate 14 can be prepared using a method similar to what was used for Intermediate 2, as shown in the scheme shown below:

Using the method outlined above to synthesize Intermediate 14, the following intermediates were made using the precursors as indicated in Table 5.

4-(6-chloro-2-(trifluoromethyl)pyrimidin-4-yl)morpholine

A mixture of 4,6-Dichloro-2-(trifluoromethyl)pyrimidine (70 μL, 0.46 mmol), morpholine (38 μL, 0.44 mmol) and diisopropylethylamine (80 μL, 0.46 mmol) in DMSO (0.5 mL) was stirred at room temperature for one hour to afford Intermediate 15A. LCMS (method A): m/z 268.1 (M+H) + . The reaction mixture was used directly in the next reaction.

(R)-1-(6morpholino-2-(trifluoromethyl)pyrimidin-4-yl)piperidine-3-carboxylic acid

To a reaction mixture of 15A were (R)-piperidine-3-carboxylic acid (100 mg, 0.77 mmol) and diisopropylethylamine (134 μL, 0.77 mmol), and the reaction was heated at 120° C. in a microwave for four hours. The reaction mixture was purified directly by MS-HPLC to afford Intermediate 15 (69 mg, 42%). LCMS (method A): m/z 361.2 (M+H) + . 1 H NMR (CD 3 OD): δ 5.90 (s, 1H), 4.40 (d, 1H), 4.14 (d, 1H), 3.72 (t, 4H), 3.58 (t, 4H), 3.29-3.09 (m, 2H), 2.50 (m, 1H), 2.09 (m, 1H), 1.77 (m, 2H), 3 (m, 1H). Using the method outlined above to synthesize Intermediate 15, the following intermediate was made from Intermediate 15A and the reagent as indicated in Table 6.

(R)-(9H-fluoren-9-yl)methyl 3-((2-methoxy-4-(trifluoromethyl)phenethyl)-carbamoyl)piperidine-1-carboxylate

Following the procedure as described in Intermediate 1, step 1, (R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-3-carboxylic acid (160 mg, 0.45 mmol) was coupled with Intermediate 5B (110 mg, 0.50 mmol) to afford Intermediate 16A (124 mg, 50%). LCMS (method A): m/z 553.5 (M+H) + .

(R)-(9H-fluoren-9-yl)methyl 3-((2-hydroxy-4-(trifluoromethyl)phenethyl) carbamoyl)piperidine-1-carboxylate

To a solution of Intermediate 16A (145 mg, 0.260 mmol) in DCM (5 mL) at −78° C., BBr 3 (250 μL, 2.6 mol) was added dropwise. The reaction was stirred for one hour at −78° C., and then at room temperature for three hours. The reaction was cooled to 0° C. and quenched with NaHCO 3 . The mixture was extracted with DCM (3×). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated. The residue was purified by silica gel chromatography to afford Intermediate 16B (116 mg, 82%). LCMS (method A): m/z 539.5 (M+H) + .

(R)—N-(2-hydroxy-4-(trifluoromethyl)phenethyl)piperidine-3-carboxamide

Following the procedure as described in Intermediate 1, step 2, Intermediate 16B (152 mg, 0.18 mmol) was converted to Intermediate 16 (65.2 mg, 73%). LCMS (method A): m/z 317.4 (M+H) + . 1 H NMR (CD 3 OD): δ 7.21-7.19 (d, 1H), 7.01-6.99 (m, 2H), 3.42 (t, 2H), 2.97-2.89 (m, 2H), 2.84 (t, 2H), 2.70-2.64 (m, 1H), 2.59-2.52 (m, 1H), 2.32-2.25 (m, 1H), 1.85-1.81 (m, 1H), 1.70-1.44 (m, 3H).

tert-butyl 4-methylphenethylcarbamate

To a solution of 2-(p-tolyl)ethanamine (250 mg, 1.85 mmol) in anhydrous THF (8.5 mL) at 0° C. were added triethylamine (187 mg, 1.85 mmol) and di-tert-butyl dicarbonate (404 mg, 1.85 mmol). The reaction was stirred at 0° C. for 15 minutes, and concentrated in vacuo. The residue was diluted with EtOAc (50 mL), and washed with 0.5 N HCl (20 mL) and H 2 O (20 mL). The organic layer was dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford Intermediate 17A (397 mg, 91%). LCMS (method A): m/z 236.3 (M+H) + .

tert-butyl 4-(bromomethyl)phenethylcarbamate

To a solution of Intermediate 17A (59.3 mg, 2.52 mmol) in DCM (84 mL) were added recrystallized N-bromosuccinimide (417 mg, 2.34 mmol) and AIBN (91 mg, 0.55 mmol). The reaction was heated for 50 minutes at 50° C., and then cooled to room temperature. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to afford Intermediate 17B (120 mg, 15%). 1 H NMR (CDCl 3 ): δ 7.35-7.33 (m, 2H), 7.18-7.16 (m, 2H), 4.53 (b, 1H), 4.49 (s, 2H), 3.40-3.35 (m, 2H), 2.79 (t, 2H), 1.40 (s, 9H).

tert-butyl 4-(fluoromethyl)phenethylcarbamate

To a solution of Intermediate 17B (97 mg, 0.31 mmol) in anhydrous CH 3 CN (4.4 mL) in a pre-dried flask was added AgF (165 mg, 1.30 mmol). The reaction was heated to 65° C. for 2.5 hours. The reaction was cooled to room temperature, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford Intermediate 17C (72 mg, 92%). 1 H NMR (CDCl 3 ): δ 7.34-7.32 (dd, 2H), 7.24-7.22 (m, 2H), 5.41 (s, 1H), 5.29 (s, 1H), 4.52 (b, 1H), 3.41-3.36 (m, 2H), 2.82 (t, 2H), 1.43 (s, 9H).

2-(4-(fluoromethyl)phenyl)ethanamine trifluoroacetate

Following the procedure as described in Intermediate 10, step 2, Intermediate 17C (94 mg, 0.37 mmol) was converted to Intermediate 17 (125 mg, 88%). LCMS (method A): m/z 154.2 (M+H) + . 1 H NMR (CD 3 OD/CDCl 3 ): δ 7.41-7.39 (m, 2H), 7.32-7.30 (m, 2H), 5.36 (s, 2H), 3.19-3.15 (m, 2H), 3.02-2.98 (m, 2H).

4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)benzoic acid

A mixture of 4-(2 aminoethyl)benzoic acid (1.0 g, 5.0 mmol) and NaHCO 3 (1.0 g, 12 mmol) in H 2 O (10 mL) (pre-cooled at 0° C.) was slowly added to a mixture of Fmoc-Cl (1.9 g, 7.4 mmol) in dioxane (20 mL) at 0° C. After 45 minutes at 0° C., the reaction was acidified to pH 1 with 1 N HCl, and extracted with EtOAc (3×75 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford Intermediate 18A (715 mg, 37%). LCMS (method A): m/z 388.4 (M+H) + .

(9H-fluoren-9-yl)methyl 4-(methoxy(methyl)carbamoyl)phenethylcarbamate

To a solution of Intermediate 18A (387 mg, 1.00 mmol) in THF (3 mL) at room temperature were added 2-chloro-4,6-dimethoxy-1,3,5-triazine (210 mg, 1.2 mmol) and N-methylmorpholine (NMM, 0.33 mL, 3.0 mmol). The reaction was stirred for one hour, and N,O-dimethylhydroxylamine. HCl (98 mg, 1.0 mmol) was added. The reaction was stirred overnight at room temperature. The reaction was quenched with H 2 O (4 mL), and extracted with DCM. The combined organic layers were dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford Intermediate 18B (306 mg, 71%). LCMS (method A): m/z 431.4 (M+H) + .

(9H-fluoren-9-yl)methyl 4-formylphenethylcarbamate

To a solution of Intermediate 18B (300 mg, 0.70 mmol) in anhydrous THF (7 mL) at −78° C. was added DIBAL (1M in hexanes, 3.5 mL, 3.5 mmol) dropwise. After one hour the reaction was quenched with saturated citric acid. The cold bath was removed and the reaction was poured into brine (45 mL), and extracted with DCM (2×60 mL). The combined organic layer was dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford Intermediate 18C (195 mg, 75%). LCMS (method A): m/z 372.4 (M+H) + .

(9H-fluoren-9-yl)methyl 4-(difluoromethyl)phenethylcarbamate

To a solution of 4-tert-butyl-2-6-dimethylphenylsulfur trifluoride (298 mg, 1.19 mmol) in anhydrous DCM (1.5 mL) in a polyfluor vessel were added Intermediate 18C (250 mg, 0.68 mmol) and EtOH (16 μL, 0.27 mmol). After stirring 24 hours at room temperature, the reaction was pipetted into aqueous ammonia (28-30%, 3.5 mL) at 0° C. The mixture was stirred for one hour at room temperature. The organic layer was washed with H 2 O, dried (MgSO 4 ), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford Intermediate 18D (124 mg, 74%). LCMS (method A): m/z 394.4 (M+H) + .

2-(4-(difluoromethyl)phenyl)ethanamine

Following the procedure as described in Intermediate 1, step 2, Intermediate 18D (124 mg, 0.320 mmol) was converted to Intermediate 18 (16 mg, 29%). LCMS (method A): m/z 172.3 (M+H) + . 1 H NMR (CD 3 OD): δ 7.49-7.47 (m, 2H), 7.36-7.34 (m, 2H), 6.72 (t, 1H), 2.95-2.92 (m, 2H), 2.86-2.82 (m, 2H).

tert-butyl 3-bromobenzylcarbamate

To a solution of (3-bromophenyl)methanamine hydrochloride (5.0 g, 23 mmol) and di-tert-butyl dicarbonate (5.0 g, 24 mmol) in DCM (50 mL) was added triethylamine (3.2 mL, 23 mmol). The reaction was stirred overnight at room temperature. The mixture was washed with H 2 O, and the organic layer was dried (Na 2 SO 4 ), filtered, and concentrated to afford Intermediate 19A (6.5 g, quant.). 1 H NMR (CDCl 3 ): δ 7.43 (br s, 1H), 7.41-4.38 (m, 1H), 7.21-7.17 (m, 2H), 4.88 (br s, 1H), 4.30-4.29 (m, 2H), 1.47 (s, 9H).

tert-butyl 3-(pyridin-4-yl)benzylcarbamate

Intermediate 19A (504 mg, 1.77 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (726 mg, 3.54 mmol), and sodium carbonate (375 mg, 3.54 mmol) were combined in dioxane (8 mL) and H 2 O (2 mL), and purged with nitrogen for 5 minutes. Pd(dppf)Cl 2 . CH 2 Cl 2 (145 mg, 0.180 mmol) was added, and the reaction was heated to 80° C. for three hours. The reaction was cooled to room temperature, and washed with H 2 O. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to afford Intermediate 19B (388 mg, 77%). LCMS (method A): m/z 285.2. 1 H NMR (CDCl 3 ): δ 8.67-8.66 (dd, 2H), 7.55-7.36 (m, 6H), 4.92-4.91 (br s, 1H), 4.41-4.40 (m, 2H), 1.48 (s, 9H).

(3-(pyridin-4-yl)phenyl)methanamine hydrochloride

Following the procedure described in Intermediate 9, step 3, Intermediate 19B (388 mg, 1.36 mmol) was treated with 4N HCl/dioxane (3.4 mL, 13.6 mmol) to afford Intermediate 19 (360 mg, quant.). LCMS (method A): m/z 185.1 (M+H) + . 1 H NMR (CD 3 OD): δ 8.94-8.92 (m, 2H), 8.48-8.46 (m, 2H), 8.18 (s, 1H), 8.08-8.05 (m, 1H), 7.78-7.71 (m, 2H), 4.29 (s, 2H).

tert-butyl (2-(3-(trifluoromethyl)phenoxy)ethyl)carbamate

To a solution of 3-(trifluoromethyl)phenol (0.15 mL, 1.20 mmol) in CH 3 CN (6.2 mL) were added tert-butyl (2-bromoethyl)carbamate (415 mg, 1.85 mmol) and cesium carbonate (721 mg, 2.21 mmol). The reaction was stirred at room temperature for four hours. The reaction was partitioned between EtOAc and H 2 O, and the aqueous layer was extracted (2×25 mL) with EtOAc. The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford Intermediate 20A (198 mg, 53%). LCMS (method A): m/z 206.2 (M-Boc) + . 1 H NMR (CDCl 3 ): δ 7.41-7.37 (m, 1H), 7.23-7.21 (m, 1H), 7.17 (s, 1H), 7.08-7.05 (m, 1H), 4.96 (b, 1H), 4.06 (t, 2H), 3.58-3.54 (m, 2H), 1.46 (s, 9H).

2-(3-(trifluoromethyl)phenoxy)ethanamine hydrochloride

Following the procedure as described in Intermediate 9, step 3, Intermediate 20A (196 mg, 0.64 mmol) was converted to Intermediate 20 (149 mg, 96%). LCMS (method A): m/z 206.2 (M+H) + . 1 H NMR (CD 3 OD): δ 7.53-7.50 (m, 1H), 7.32-7.26 (m, 3H), 4.29 (t, 2H), 3.39 (t, 2H). Using the method outlined above to synthesize Intermediate 20, the following intermediates were made using starting materials as indicated in Table 7.

Methyl 2-(2-(1,3-dioxoisoindolin-2-yl)ethylsulfonamido)acetate

To a solution of methyl 2-aminoacetate hydrochloride (25 mg, 0.20 mmol) and triethylamine (69 μL, 0.49 mmol) in DCM (1 mL) was added 2-(1,3-dioxoisoindolin-2-yl)ethanesulfonyl chloride (45 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for three hours. The reaction mixture was concentrated in vacuo, and the residual was purified by silica gel chromatography (0-10% MeOH/DCM) to afford Intermediate 21A (37 mg, 70%). LCMS (method A): m/z 327.2 (M+H) + . 1 H NMR (CDCl 3 ) δ 7.87-7.84 (m, 2H), 7.76-7.72 (m, 2H), 5.56 (t, 1H), 4.33 (t, 2H), 4.04 (d, 2H), 3.77 (s, 3H), 3.45 (t, 2H).

Methyl 2-(2-aminoethylsulfonamido)acetate hydrochloride

To a solution of Intermediate 21A (701 mg, 2.15 mmol) in MeOH (4 mL) was added hydrazine monohydrate (104 μL, 2.15 mmol). The reaction mixture was stirred at room temperature overnight. Concentrated hydrochloric acid (1.5 mL) was added, and the white solid was removed by filtration. The filtrate was evaporated to afford Intermediate 21 (720 mg). LCMS (method A): m/z 197.1 (M+H) + . This compound was used directly in the next step without further purification.

4-((tert-butyldimethylsilyl)oxy)but-2-yn-1-ol

To a solution of but-2-yne-1,4-diol (50 g, 580 mmol) in dry DMF (250 mL) were added TBDMSCl (22.0 g, 145 mmol), followed by imidazole (20 g, 290 mmol) in small portions at room temperature under N 2 . The reaction mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (5-20% EtOAc/PE) to afford Intermediate 22A (20 g, 69%). 1 H NMR (CDCl 3 ) δ 4.5-4.3 (m, 4H), 0.9 (s, 9H), 0.2-0.1 (s, 6H).

tert-butyl((4-chlorobut-2-yn-1-yl)oxy)dimethylsilane

To a solution of Intermediate 22A (20 g, 100 mmol) in ether (250 mL) were added CBr 4 (65 g, 200 mmol) and PPh 3 (52 g, 200 mmol) under N 2 . The reaction mixture was stirred at room temperature for four hours. The mixture was filtered, and the solid was washed with ether. The filtrates were concentrated in vacuo to provide a crude oil which was purified by silica gel chromatography (100% PE-5% EtOAc/PE) to afford Intermediate 22B (10 g, 38%). 1 H NMR (CDCl 3 ) δ 4.4-4.3 (s, 2H), 4.0-3.9 (s, 2H), 0.9 (s, 9H), 0.2-0.1 (s, 6H).

tert-butyl 4-((4-((tert-butyldimethylsilyl)oxy)but-2-yn-1-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (18 g, 87 mmol) in DMF (150 mL) was added NaH (3.8 g, 94 mmol, 60%) in small portions at room temperature under N 2 . The mixture was stirred at room temperature for one hour. A solution of Intermediate 22B (19 g, 73 mmol) in DMF (50 mL) was added drop wise at 0° C. The mixture was stirred at room temperature for three hours, and water was added. The mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (2% EtOAc/PE-10% EtOAc/PE) to afford Intermediate 22C (3 g, 11%). LCMS (method A): m/z 406.4 (M+H) + . 1 H NMR (CDCl 3 ) δ 4.4-4.3 (s, 2H), 4.3-4.2 (s, 2H), 3.9-3.6 (m, 3H), 3.2-3.0 (m, 2H), 1.9-1.8 (m, 2H), 1.5-1.4 (s, 9H), 0.9 (s, 9H), 0.2-0.1 (s, 6H).

4-(piperidin-4-yloxy)but-2-yn-1-ol

A solution of Intermediate 22C (6 g, 15.6 mmol) in 6 N HCl/EtOH (80 mL, 1/1) was stirred at room temperature overnight. The organic solvent was removed in vacuo, and the residue was washed with DCM. The aqueous layer was concentrated in vacuo to afford Intermediate 22 (3.1 g, 96%). LCMS (method A): m/z 170.1 (M+H) + . 1 H NMR (D 2 O) δ 4.4-4.2 (d, 4H), 4.0-3.9 (m, 1H), 3.5-3.3 (m 2H), 3.2-3.0 (m, 2H), 2.2-2.0 (m, 2H), 1.9-1.7 (m 2H).

tert-butyl 4-(4-(tert-butoxy)-4-oxobutyl)-3-oxopiperazine-1-carboxylate

Under a N 2 atmosphere, NaH (219 mg, 5.99 mmol, 60% dispersion in mineral oil) was added to a stirring suspension of tert-butyl 3-oxopiperazine-1-carboxylate (1 g, 4.99 mmol) in THF (20 mL) at 0° C. and stirred for five minutes. Ethyl 4-bromobutanoate (1.33 g, 5.99 mmol) was added at 0° C. The reaction was stirred overnight. The reaction was quenched with several drops of methanol, diluted with ethyl acetate, and washed with H 2 O, brine, and dried over magnesium sulfate. The organic layer was concentrated in vacuo which provided the crude material as a clear oil. The crude oil was purified by flash chromatography with ethyl acetate in hexanes as the eluent to afford Intermediate 23A (364 mg, 21%) as a clear oil. LCMS (method A): m/z 343.4 (M+H) + . 1 H NMR (CDCl 3 ): δ 4.06 (s, 2H), 3.63 (t, 2H), 3.42 (t, 2H), 3.36 (t, 2H), 2.26 (t, 2H), 1.84 (quin, 2H), 1.46 (s, 9H), 1.44 (s, 9H).

methyl-4-(2-oxopiperazin-1-yl)butanoate

Following the procedure similar to Intermediate 9, step 3 but using DCM/MeOH (4/1, 10 mL) as solvent, Intermediate 23A (346 mg, 1.01 mmol) was converted to Intermediate 23 (224 mg, 99%) which was used directly without purification. LCMS (method A): m/z 201.2 (M+H) + . 1 H NMR (CDCl 3 ): δ 3.93 (br s, 2H), 3.73 (br s, 2H), 3.68 (s, 3H), 3.56 (br s, 2H), 3.48 (br s, 2H), 2.39 (t, 2H), 1.92-1.89 (m, 2H).