Inhibition of Human Integrin (alpha-4)(beta-7)

Abstract

To provide a compound useful for inhibition of the α4β7 integrin.SOLUTION: The invention provides a compound of the formula (I) in the figure or a salt thereof. In the formula, Ra, Rb and Rc are H, Me, CF3, -(C1-C5)alkylene-N-(Rx)(Ry), or the like; Rx and Ry are H, (C1-C6)-alkyl, or the like, or form a 4-6 membered ring together with N; R1 is methyl, ethyl, or the like; R2 is a substituted phenyl group; R3a and R3b are H, (C1-C5)-alkyl, or the like; and R3c, R3d and R4 are H.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 916,062, filed October 16, 2019.

[0002] Disclosed are novel compounds and related methods useful for the inhibition of α4β7 integrin. The compounds and methods disclosed herein are applicable to the development of medicaments for the treatment of α4β7 integrin-mediated conditions such as inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD).

Background Art

[0003] Integrins are non-covalently associated α / β heterodimeric cell surface receptors that are involved in a number of cell processes. Differential expression of integrins can regulate the adhesive properties of cells, allowing different leukocyte populations to be mobilized to specific organs in response to different inflammatory signals. α4 integrins, including α4β7, play a role in lymphocyte trafficking throughout the gastrointestinal tract. They are expressed on most leukocytes, including B and T lymphocytes, where they mediate cell adhesion through selective binding to their primary ligand, mucosal addressin cell adhesion molecule (MAdCAM). Memory T lymphocytes expressing α4β7 integrin preferentially migrate into the gastrointestinal tract through firm adhesion to mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1).

[0004] Inhibitors of specific integrin-ligand interactions have been used for the treatment of various diseases. For example, monoclonal antibodies that exhibit high binding affinity for α4β7 have shown therapeutic benefits for gastrointestinal autoinflammatory / autoimmune diseases such as Crohn's disease and ulcerative colitis. However, these treatments also have certain undesirable characteristics for patients. Monoclonal antibody α4β7 integrin inhibitors are administered by parenteral administration, have a long half-life that cannot rapidly modify exposure, and have reduced activity due to anti-drug antibody formation. Monoclonal antibody treatment can be difficult to manufacture compared to small molecule treatments. In addition, some treatments that inhibit α4β7 also interfere with the α4β1 integrin-ligand interaction, thereby causing dangerous side effects to patients. Activity at α4β1 integrin is associated with the emergence of progressive multifocal leukoencephalopathy (PML), a life-threatening and progressive brain infection in immunosuppressed patients.

[0005] As an important addition to therapeutic medical products for α4β7 integrin-mediated conditions such as inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD), there remains a medical need for effective and safe oral α4β7 integrin inhibitors.

Summary of the Invention

Means for Solving the Problems

[0006] In certain embodiments, the present invention provides a compound of formula (I):

Chemical formula

Chemical formula

[0007] In some embodiments of the present invention, the compound of formula (I) has only one of R a 、R b and R c being substituted or unsubstituted -(C1-C5) alkylene-N-(R x )(R y ), R1 being (C1-C6) alkyl (e.g., isobutyl), R 3a and R 3bis independently selected from the group consisting of H, (C1-C4)-alkyl (e.g., methyl), halide (e.g., F or Cl), CF3, C(H)F2, and C(F)H2, provided that R 3a and R 3b are both not H, and the compound can be a compound in which R4 is H.

[0008] In some examples, in the compound of formula (I), only one of R a , R b and R c is substituted or unsubstituted -(C1-C5) alkylene-N-(R x )(R y ), and R x and R y are each independently unsubstituted (C1-C6)-alkyl (e.g., methyl), or R x and R y together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclyl ring, R1 is unsubstituted (C1-C6) alkyl (e.g., isobutyl), and R 3a and R 3b are independently selected from the group consisting of H, unsubstituted (C1-C4)-alkyl (e.g., methyl, ethyl, etc.), halide (e.g., F or Cl), CF3, C(H)F2, and C(F)H2, provided that R 3a and R 3b are both not H, and R 3c is selected from the group consisting of H, F, Cl, hydroxyl, substituted or unsubstituted (C1-C4)-alkyl (e.g., methyl), substituted or unsubstituted (C3-C6)-cycloalkyl (e.g., cyclopropyl), (C1-C4)-alkoxy (e.g., methoxy), R 3d is selected from the group consisting of H, halide (e.g., F or Cl), substituted or unsubstituted (C1-C4)-alkyl (e.g., methyl), and hydroxyl, and the compound can be a compound in which R4 is H. In some examples, the compound of formula (I), formula (Ia) and / or formula (Ib) is such that R a , R b and R cwherein only one of them is a substituted or unsubstituted -(C1-C5)alkylene-N-(R x )(R y ), R x and R y are each independently unsubstituted methyl, or R x and R y together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclic ring, R1 is isobutyl, R 3a and R 3b are independently selected from the group consisting of unsubstituted (C1-C4)-alkyl (e.g., methyl), halides (e.g., F or Cl), CF3, C(H)F2 and C(F)H2, R 3c and R 3d are both H, and R4 is H. For example, the compounds of formula (I), formula (Ia) and / or formula (Ib) may be those wherein R1 is isobutyl, R 3a and R 3b are independently selected from the group consisting of unsubstituted (C1-C4)-alkyl (e.g., methyl), halides (e.g., F or Cl), CF3, C(H)F2 and C(F)H2, R 3c and R 3d are both H, R4 is H, and R 5a and R 5e are each a substituted or unsubstituted (C1-C4)-alkyl (e.g., methyl). The compounds of formula (I) are such that only one of R a , R b and R c is a substituted or unsubstituted -(C1-C5)alkylene-N-(R x )(R y ), R x and R y are each independently unsubstituted methyl, or R x and R y together with the N to which they are attached form a 4- to 6-membered heterocyclic ring optionally substituted with a halide (e.g., F), R1 is isobutyl, R 3a and R 3bis independently selected from the group consisting of unsubstituted (C1-C4)-alkyl (e.g., methyl), halide (e.g., F or Cl), CF3, C(H)F2, and C(F)H2, R 3c and R 3d are both H, R4 is H, R 5a and R 5e are each substituted or unsubstituted (C1-C4)-alkyl (e.g., methyl), R 5b , R 5c and R 5d are each independently selected from the group consisting of H, CN, halide (e.g., F, Cl), CF3, C(H)F2, C(F)H2, (C1-C5)-alkyl, hydroxyl, and (C1-C4)-alkoxy. In certain embodiments, the invention relates to a method of treating an autoinflammatory / autoimmune disease, such as Crohn's disease and ulcerative colitis, comprising administering to a subject in need thereof a therapeutically effective amount of any one of the compounds described herein.

[0009] Methods for preparing and isolating the compounds of formula (I), formula (Ia) and / or formula (Ib) are also provided herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0010]

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[0011] In certain embodiments, the present invention relates to compounds that antagonize α4β7 integrin. The compounds are useful for treating diseases that are treatable by inhibition of α4β7 integrin (e.g., Crohn's disease (CD) and ulcerative colitis (UC)).

[0012] Definitions For the sake of brevity, before further description of the present invention, certain terms used in this specification, the examples and the appended claims are gathered herein. These definitions should be read in light of the remainder of the disclosure and understood as would be understood by a person of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

[0013] For the present invention to be more readily understood, certain terms and phrases are defined below and throughout this specification.

[0014] The articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or more than one element.

[0015] The phrase "and / or" as used in this specification and the claims, when used herein, is to be understood to mean "either or both" of the elements so conjoined, i.e., elements that are connected in some cases and disjunctive in other cases. Multiple elements listed together with "and / or" are to be construed in the same fashion, i.e., as "one or more" of the elements so conjoined. Other elements may optionally be present whether related or unrelated to the elements specifically identified by the "and / or" clause, depending on the context. Thus, by way of non-limiting example, reference to "A and / or B" can, when used in conjunction with an open-ended language such as "comprising", in one embodiment, refer to only A (optionally including elements other than B), in another embodiment, refer to only B (optionally including elements other than A), and in yet another embodiment, refer to both A and B (optionally including other elements), etc.

[0016] As used in this specification and the claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted inclusively, i.e., including more than one of a number or list of elements, and optionally, at least one additional item not listed. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one of", or when used in a claim, "consisting of", refer to the inclusion of exactly one of a number or list of elements. In general, the term "or", as used herein, should be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") only when preceded by an exclusive term such as "either", "one of", "only one of", or "exactly one of". "Essentially consists of", when used in a claim, has its ordinary meaning as used in the field of patent law.

[0017] As used in this specification and the claims, the phrase "at least one" in reference to a list of one or more elements means at least one element selected from any one or more of the elements in the list of elements, but does not necessarily include at least one of each and every element specifically listed within the list of elements, and is not to be construed as excluding any combinations of elements in the list of elements. This definition further allows that an element can, in some cases, exist outside of the specifically identified elements within the list of elements to which the phrase "at least one" refers, whether the element is related or unrelated to the specifically identified elements. Thus, by way of non-limiting example, "at least one of A and B" (or equivalently "at least one of A or B", or equivalently "at least one of A and / or B") can, in one embodiment, be at least one A, including, optionally, more than one, where B is absent (and optionally including elements other than B); in another embodiment, be at least one B, including, optionally, more than one, where A is absent (and optionally including elements other than A); and in yet another embodiment, be at least one A, including, optionally, more than one, and at least one B, including, optionally, more than one (and optionally including other elements).

[0018] Moreover, unless clearly indicated to the contrary, in any method claimed in this specification that includes more than one step or act, the order of the method steps or acts is not necessarily limited to the order in which the method steps or acts are recited.

[0019] In the claims, as well as in the above specification, all transitional phrases such as "comprising", "including", "having", "containing", "accompanying", "retaining", "consisting of", etc. are to be understood as open-ended, i.e., meaning including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" are, as explained in the United States Patent and Trademark Office Patent Examination Procedure Manual 2111.03, closed or semi-closed transitional phrases, respectively.

[0020] Certain compounds contained in the compositions of the present invention can exist in special geometric or stereoisomeric forms. In addition, the polymers of the present invention can also be optically active. The present invention contemplates that all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, their racemic mixtures, and other mixtures, fall within the scope of the present invention. Additional asymmetric carbon atoms can be present in substituents, such as alkyl groups. All such isomers, as well as their mixtures, are intended to be included in this invention.

[0021] For example, if a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by induction using a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the thus-formed diastereomers by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomer.

[0022] The structures illustrated in this specification are also meant to include different compounds only in the presence of one or more isotope-enriched atoms. For example, compounds produced by replacement of hydrogen with deuterium or tritium, or replacement of carbon with 13 C or 14 C-enriched carbon are within the scope of this invention.

[0023] Terms such as "α4β7", "a4B7", "a4b7", "alpha-4 beta-7", and "alpha4beta7", when used in this specification, all refer to α4β7.

[0024] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting a subject chemical from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially nonpyrogenic. Some examples of materials that can serve as pharmaceutically acceptable carriers include the following: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and derivatives thereof, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other nontoxic compatible substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the invention are nonpyrogenic, i.e., they do not induce a significant increase in temperature when administered to a patient.

[0025] The term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid addition salts of a compound. These salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free base form separately with a suitable organic or inorganic acid and isolating the thus formed salt. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate, etc. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).

[0026] In other cases, the compounds useful in the methods of the present invention can contain one or more acidic functional groups and can thus form pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salt" in these instances refers to relatively non-toxic inorganic and organic base addition salts of the compound. These salts can likewise be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free acid form separately with a suitable base such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, and aluminum salt, etc. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (See, for example, Berge et al., supra).

[0027] The "therapeutically effective amount" (or "effective amount") of a compound for use in a treatment is the amount of the compound in a preparation which, when administered (to a mammal, preferably a human) as part of a desired dosage regimen, alleviates symptoms, causes remission of a condition or delays the onset of a disease state, for a disorder or condition to be treated or for cosmetic purposes, according to clinically acceptable standards, for example, with a reasonable benefit / risk ratio applicable to any medical treatment.

[0028] The term "preventive or therapeutic" treatment is technically recognized and includes one or more administrations of the subject composition to a host. If it is administered prior to the clinical course of an undesired condition (e.g., a disease or other undesired condition of the host animal), the treatment is preventive (i.e., it protects the host against the onset of the undesired condition), while if it is administered after the manifestation of the undesired condition, the treatment is therapeutic (i.e., it is intended to alleviate, cause remission of or stabilize the existing undesired condition or its side effects).

[0029] The term "patient" refers to a mammal in need of a particular treatment. In certain embodiments, the patient is a primate, dog, cat or horse. In certain embodiments, the patient is a human.

[0030] Aliphatic chains include the classes of alkyl, alkenyl and alkynyl as defined below. Straight-chain aliphatic chains are limited to non-branched carbon chain moieties. As used herein, the term "aliphatic group" refers to straight-chain, branched-chain or cyclic aliphatic hydrocarbon groups, including saturated and unsaturated aliphatic groups, for example, alkyl groups, alkenyl groups or alkynyl groups.

[0031] "Alkyl" refers to a fully saturated cyclic or acyclic branched or unbranched carbon chain moiety having a specified number of carbon atoms or, if not specified, from 1 to a maximum of 30 carbon atoms. For example, alkyl having from 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl, and moieties such as positional isomers of these moieties. Examples of alkyl having from 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, the straight-chain or branched-chain alkyl has 30 or fewer carbon atoms, more preferably 20 or fewer, in its backbone (e.g., C1-C 30 , for branched-chain C3-C 30 ). The alkyl group may be substituted or unsubstituted. As used herein, both "Me" and -CH3 refer to methyl.

[0032] As used herein, the term "alkylene" refers to an alkyl group having a specific number of carbons, e.g., from 2 to 12 carbon atoms, containing two points of attachment to the remainder of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, and the like. The alkylene group may be a cyclic or acyclic branched or unbranched carbon chain moiety and may optionally be substituted with one or more substituents.

[0033] "Cycloalkyl" means a monocyclic or bicyclic, or bridged or spirocyclic, or polycyclic saturated carbon cyclic ring, each having from 3 to 12 carbon atoms. Similarly, preferred cycloalkyls have 3 to 10 carbon atoms in their ring structure, more preferably 3 to 6 carbons in the ring structure. The cycloalkyl group may be substituted or unsubstituted.

[0034] Unless otherwise specified, "lower alkyl", as used herein, is as defined above, but an alkyl group having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, in its skeletal structure, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout the present application, the preferred alkyl group is lower alkyl. In certain embodiments, the substituents designated herein as alkyl are lower alkyl.

[0035] The term "aryl", as used herein, includes substituted or unsubstituted single-ring aromatic groups of 3 to 12 members, where each atom of the ring is carbon (i.e., carbocyclic aryl), or one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, the aryl group includes a ring of 5 to 12 members, more preferably 6 to 10 members. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings, where two or more carbons are common to two adjacent rings, where at least one of the rings is aromatic, for example, the other cyclic ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Examples of carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc. Heteroaryl groups include substituted or unsubstituted aromatic ring structures of 3 to 12 members, more preferably 5 to 12 members, more preferably 5 to 10 members, and this ring structure contains 1 to 4 heteroatoms. Examples of heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, etc. Aryl and heteroaryl can be monocyclic, bicyclic or polycyclic.

[0036] The terms "halo", "halide", or "halogen", as used herein, mean halogen and include, for example, and without limitation, fluoro, chloro, bromo, iodo, etc. in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro, and bromo.

[0037] The term "heterocyclyl" or "heterocyclic group" refers to a ring structure of 3 to 12 members, more preferably a ring of 5 to 12 members, more preferably a ring of 5 to 10 members, which ring structure contains 1 to 4 heteroatoms. The heterocycle may be monocyclic, bicyclic, spirocyclic, or polycyclic. Examples of heterocyclyl groups include thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactone, lactam, for example, azetidinone and pyrrolidinone, sultam, sultone, and the like. The heterocyclic ring can be substituted at one or more positions with substituents such as those described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, and the like.

[0038] The term "carbonyl" is technically recognized and has the formula: [Chem.] comprising a moiety that can be represented by, wherein X' is a bond or represents oxygen or sulfur, and R 15 is hydrogen, alkyl, alkenyl, -(CH2) m -R 10 or a pharmaceutically acceptable salt, and R 16 is hydrogen, alkyl, alkenyl or -(CH2) m -R 10 wherein m and R 10 are as defined above. When X' is oxygen and R 15 or R 16 is not hydrogen, the formula represents an "ester". When X' is oxygen and R 15 is as defined above, the moiety is referred to herein as a carboxyl group, and in particular, when R 15 is hydrogen, the formula represents a "carboxylic acid". When X' is oxygen and R 16 is hydrogen, the formula represents "formate". On the other hand, when X' is a bond and R 15 is not hydrogen, the above formula represents a "ketone" group. When X' is a bond and R 15 is hydrogen, the above formula represents an "aldehyde" group.

[0039] As used herein, the term "substituted" is intended to include all acceptable substituents of an organic compound. In broad aspects, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of the organic compound. Exemplary substituents include, for example, those described hereinabove and selected from one or more substituents such as alkyl, cycloalkyl, heterosilylalkyl, halogen, OH, OMe, C(H)F2, C(F)H2, CF3, C(H)2CF3, SF5, CHFCH2 amine, CH2 amine, and CN. Acceptable substituents for a suitable organic compound are one or more and are the same or different. For the purposes of this invention, a heteroatom, for example, nitrogen, may have a hydrogen substituent of the organic compound described herein and / or any acceptable substituent that satisfies the valence of the heteroatom. The present invention is not intended to be limited in any way by the acceptable substituents of the organic compound. "Substituted" or "substituted with" is understood to include the implicit conditions that such substitution follows the acceptable valences of the substituted atoms and substituents and that the substitution results in a stable compound that does not undergo spontaneous transformation, for example, by rearrangement, cyclization, elimination, etc.

[0040] As used herein, the term "nitro" means -NO2, the term "halogen" designates -F, -Cl, -Br, or -I, the term "hydroxyl" means -OH, and the term "cyano" means -CN.

[0041] As used herein, the definition of each expression, for example, alkyl, m, n, etc., when it appears more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0042] As used herein, the term "prodrug" encompasses compounds that are converted to therapeutically active agents under physiological conditions. A common way to make a prodrug is to include a selected moiety that is hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzyme activity of the host animal.

[0043] For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Edition, 1986 - 87, inside back cover.

[0044] Exemplary compounds In some embodiments, the invention relates to a compound of formula (I), formula (Ia) or formula (Ib):

Chemical formula

Chemical formula

[0045] In some embodiments, the compound of formula (I) is of formula (Ia), formula (Ib), formula (Ic) and / or formula (Id):

Chemical formula

[0046] In some embodiments, the compound of formula (I) is of formula (IIa), formula (IIb) or formula (IIc):

Chemical formula

[0047] In certain embodiments, the present invention relates to any one of the previously described compounds where R1 is unsubstituted (C1-C6)-alkyl. In certain embodiments, the present invention relates to any one of the previously described compounds where R1 is substituted (C1-C6)-alkyl. In certain embodiments, the present invention relates to any one of the previously described compounds where R1 is substituted or unsubstituted (C1-C4)-alkyl. In certain embodiments, R1 is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, sec-butyl, or t-butyl. In certain embodiments, the present invention relates to the case where R1 is [Chemical formula] Relates to any one of the previously described compounds selected from the group consisting of. In certain embodiments, the present invention relates to any one of the previously described compounds wherein R1 is substituted (C1-C4)-alkylene-(C3-C6)-cycloalkyl. In certain embodiments, the present invention relates to any one of the previously described compounds wherein R1 is unsubstituted (C1-C4)-alkylene-(C3-C6)-cycloalkyl. In certain embodiments, R1 is

Chemical formula

Chemical formula

[0048] In certain embodiments, the present invention provides that R 3b is H, provided that R3a and R 3b relates to any one of the previously described compounds, provided that both are not H. In certain embodiments, the present invention relates to R 3b relates to any one of the previously described compounds, wherein R is unsubstituted (C1-C4)-alkyl. In certain embodiments, the present invention relates to R 3b relates to any one of the previously described compounds, wherein R is substituted (C1-C4)-alkyl. In certain embodiments, the substituted (C1-C5)-alkyl is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 3b is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl or t-butyl. In certain embodiments, the present invention relates to R 3b relates to any one of the previously described compounds, wherein R is substituted (C3-C6)-cycloalkyl. In certain embodiments, the present invention relates to R 3b relates to any one of the previously described compounds, wherein R is substituted or unsubstituted (C3-C6)-cycloalkyl. In certain embodiments, the present invention relates to R 3b relates to any one of the previously described compounds, wherein R is cyclopropyl. In certain embodiments, the present invention relates to R 3b relates to any one of the previously described compounds, wherein R is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, the present invention relates to R 3b relates to any one of the previously described compounds, wherein R is CF3. In certain embodiments, the present invention relates to R 3b relates to any one of the previously described compounds, wherein R is C(H)F2. In certain embodiments, the present invention relates to R 3b relates to any one of the previously described compounds, wherein R is C(F)H2. In certain embodiments, the present invention relates to R 3b relates to any one of the previously described compounds, wherein R is substituted-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to R 3bRelates to any one of the previously described compounds, where it is unsubstituted -(C1-C4)-alkoxy. In certain embodiments, the present invention relates to R 3b Relates to any one of the previously described compounds, where it is -OCF3. In certain embodiments, the present invention relates to R 3b Relates to any one of the previously described compounds, where it is substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to R 3b Relates to any one of the previously described compounds, where it is unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe.

[0049] In certain embodiments, R 3a and R 3b are independently selected from the group consisting of H, (C1-C5)-alkyl, halide, CF3, C(H)F2, and C(F)H2, provided that R 3a and R 3b are not both H. For example, R 3a and R 3b can be independently selected from the group consisting of H, methyl, Cl, F, CF3, C(H)F2, and C(F)H2, provided that R 3a and R 3b are not both H.

[0050] In certain embodiments, the present invention relates to R 3c which is selected from the group consisting of H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted cyclopropyl, hydroxyl, methoxy, halide, CF3, C(H)F2, C(F)H2, and -CN, for any one of the previously described compounds. In certain embodiments, the present invention relates to R 3c being H, for any one of the previously described compounds. In certain embodiments, the present invention relates to R 3cRelates to any one of the previously described compounds, wherein R is unsubstituted (C1-C4)-alkyl. In certain embodiments, the present invention provides that R 3c Relates to any one of the previously described compounds, wherein R is substituted (C1-C4)-alkyl. In certain embodiments, the substituted (C1-C5)-alkyl is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 3c Is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl or t-butyl. In certain embodiments, the present invention provides that R 3c Relates to any one of the previously described compounds, wherein R is substituted (C3-C6)-cycloalkyl. In certain embodiments, the present invention provides that R 3c Relates to any one of the previously described compounds, wherein R is substituted or unsubstituted (C3-C6)-cycloalkyl. In certain embodiments, the present invention provides that R 3c Relates to any one of the previously described compounds, wherein R is cyclopropyl. In certain embodiments, the present invention provides that R 3c Relates to any one of the previously described compounds, wherein R is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, the present invention provides that R 3c Relates to any one of the previously described compounds, wherein R is CF3. In certain embodiments, the present invention provides that R 3c Relates to any one of the previously described compounds, wherein R is C(H)F2. In certain embodiments, the present invention provides that R 3c Relates to any one of the previously described compounds, wherein R is C(F)H2. In certain embodiments, the present invention provides that R 3c Relates to any one of the previously described compounds, wherein R is substituted-(C1-C4)-alkoxy. In certain embodiments, the present invention provides that R 3c Relates to any one of the previously described compounds, wherein R is unsubstituted-(C1-C4)-alkoxy. In certain embodiments, the present invention provides that R 3c Relates to any one of the previously described compounds, wherein R is -OCF3. In certain embodiments, the present invention provides that R3c Relates to any one of the previously described compounds, wherein it is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention provides that R 3c Relates to any one of the previously described compounds, wherein it is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe.

[0051] In certain embodiments, the present invention provides that R 3d Relates to any one of the previously described compounds, wherein it is selected from the group consisting of H, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl, halide, methoxy, halide, CF3, C(H)F2, and C(F)H2. In certain embodiments, the present invention provides that R 3d Relates to any one of the previously described compounds, wherein it is H. In certain embodiments, the present invention provides that R 3d Relates to any one of the previously described compounds, wherein it is unsubstituted (C1-C4)-alkyl. In certain embodiments, the present invention provides that R 3d Relates to any one of the previously described compounds, wherein it is substituted (C1-C4)-alkyl. In certain embodiments, the substituted (C1-C5)-alkyl is substituted with a halogen. In certain embodiments, the halogen is F. In certain embodiments, R 3d is methyl. In certain embodiments, the present invention provides that R 3d Relates to any one of the previously described compounds, wherein it is substituted (C3-C6)-cycloalkyl. In certain embodiments, the present invention provides that R 3c Relates to any one of the previously described compounds, wherein it is substituted or unsubstituted (C3-C6)-cycloalkyl. In certain embodiments, the present invention provides that R 3d Relates to any one of the previously described compounds, wherein it is cyclopropyl. In certain embodiments, the present invention provides that R 3dRelates to any one of the previously described compounds, wherein the compound is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, the present invention relates to R 3d Relates to any one of the previously described compounds, wherein R is CF3. In certain embodiments, the present invention relates to R 3d Relates to any one of the previously described compounds, wherein R is C(H)F2. In certain embodiments, the present invention relates to R 3d Relates to any one of the previously described compounds, wherein R is C(F)H2. In certain embodiments, the present invention relates to R 3d Relates to any one of the previously described compounds, wherein R is substituted -(C1-C4)-alkoxy. In certain embodiments, the present invention relates to R 3d Relates to any one of the previously described compounds, wherein R is unsubstituted -(C1-C4)-alkoxy. In certain embodiments, -(C1-C4)-alkoxy is methoxy. In certain embodiments, the present invention relates to R 3d Relates to any one of the previously described compounds, wherein R is -OCF3. In certain embodiments, the present invention relates to R 3d Relates to any one of the previously described compounds, wherein R is substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to R 3d Relates to any one of the previously described compounds, wherein R is unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe.

[0052] In some embodiments, R 3c and R 3d are the same. In some embodiments, R 3c and R 3d are different. In some embodiments, R 3c and R 3d are both H.

[0053] In certain embodiments, the invention relates to any one of the previously described compounds wherein R4 is H. In certain embodiments, the invention relates to any one of the previously described compounds wherein R4 is substituted (C1-C4)-alkyl. In certain embodiments, the invention relates to any one of the previously described compounds wherein R4 is unsubstituted (C1-C4)-alkyl. In certain embodiments, the invention relates to any one of the previously described compounds wherein R4 is methyl, ethyl, n-propyl or i-propyl. In certain embodiments, the invention relates to any one of the previously described compounds wherein R4 is methyl or ethyl.

[0054] In certain embodiments, R 5a is H. In certain embodiments, the invention relates to any one of the previously described compounds wherein R 5a is substituted or unsubstituted (C1-C4)-alkyl. In certain embodiments, the invention relates to any one of the previously described compounds wherein R 5a is unsubstituted (C1-C4)-alkyl. In certain embodiments, the invention relates to any one of the previously described compounds wherein R 5a is substituted (C1-C4)-alkyl. In certain embodiments, substituted (C1-C5)-alkyl is substituted with one or more halogens. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5a is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl or t-butyl. In certain embodiments, the invention relates to any one of the previously described compounds wherein R 5a is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, R 5a is substituted (C3-C6)-cycloalkyl. In certain embodiments, R 5a is unsubstituted (C3-C6)-cycloalkyl. In some embodiments, (C3-C6)-cycloalkyl is cyclopropyl. In certain embodiments, the invention relates to any one of the previously described compounds wherein R5a Relates to any one of the previously described compounds wherein R is CF3. In certain embodiments, the invention provides that R 5a Relates to any one of the previously described compounds wherein R is C(H)F2. In certain embodiments, the invention provides that R 5a Relates to any one of the previously described compounds wherein R is C(F)H2. In certain embodiments, the invention provides that R 5a Relates to any one of the previously described compounds wherein R is (C1-C4)-alkoxy. In some embodiments, the (C1-C4)-alkoxy is methoxy. In certain embodiments, the invention provides that R 5a Relates to any one of the previously described compounds wherein R is methoxy. In certain embodiments, the invention provides that R 5a Relates to any one of the previously described compounds wherein R is hydroxyl. In certain embodiments, the invention provides that R 5a Relates to any one of the previously described compounds wherein R is -OCF3. In certain embodiments, R 5a is CN. In certain embodiments, the invention provides that R 5a Relates to any one of the previously described compounds wherein R is substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the invention provides that R 5a Relates to any one of the previously described compounds wherein R is unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, R 5a is CH2OH.

[0055] In certain embodiments, the invention provides that R 5b Relates to any one of the previously described compounds wherein R is CN. In certain embodiments, the invention provides that R 5b Relates to any one of the previously described compounds wherein R is unsubstituted (C1-C4)-alkyl. In certain embodiments, the invention provides that R 5bRelates to any one of the previously described compounds, where it is a substituted (C1-C4)-alkyl. In certain embodiments, the substituted (C1-C5)-alkyl is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5b is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl or t-butyl. In certain embodiments, the present invention relates to R 5b Relates to any one of the previously described compounds, where it is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, R 5b is a substituted (C3-C6)-cycloalkyl. In certain embodiments, R 5b is an unsubstituted (C3-C6)-cycloalkyl. In certain embodiments, the present invention relates to R 5b Relates to any one of the previously described compounds, where it is CF3. In certain embodiments, the present invention relates to R 5b Relates to any one of the previously described compounds, where it is C(H)F2. In certain embodiments, the present invention relates to R 5b Relates to any one of the previously described compounds, where it is C(F)H2. In certain embodiments, the present invention relates to R 5b Relates to any one of the previously described compounds, where it is a (C1-C4)-alkoxy. In certain embodiments, the present invention relates to R 5b Relates to any one of the previously described compounds, where it is methoxy. In certain embodiments, the present invention relates to R 5b Relates to any one of the previously described compounds, where it is hydroxyl. In certain embodiments, the present invention relates to R 5b Relates to any one of the previously described compounds, where it is -OCF3. In certain embodiments, the present invention relates to R 5b Relates to any one of the previously described compounds, where it is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to R 5bRelates to any one of the previously described compounds, wherein it is unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe.

[0056] In certain embodiments, the present invention relates to R 5c Relates to any one of the previously described compounds, wherein R is CN. In certain embodiments, the present invention relates to R 5c Relates to any one of the previously described compounds, wherein R is unsubstituted (C1-C4)-alkyl. In certain embodiments, the present invention relates to R 5c Relates to any one of the previously described compounds, wherein R is substituted (C1-C4)-alkyl. In certain embodiments, the substituted (C1-C5)-alkyl is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5c is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl or t-butyl. In certain embodiments, the present invention relates to R 5c Relates to any one of the previously described compounds, wherein R is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, R 5c is substituted (C3-C6)-cycloalkyl. In certain embodiments, R 5c is unsubstituted (C3-C6)-cycloalkyl. In certain embodiments, the present invention relates to R 5c Relates to any one of the previously described compounds, wherein R is CF3. In certain embodiments, the present invention relates to R 5c Relates to any one of the previously described compounds, wherein R is C(H)F2. In certain embodiments, the present invention relates to R 5c Relates to any one of the previously described compounds, wherein R is C(F)H2. In certain embodiments, the present invention relates to R 5c Relates to any one of the previously described compounds, wherein R is (C1-C4)-alkoxy. In certain embodiments, the present invention relates to R 5cRelates to any one of the previously described compounds, wherein R is methoxy. In certain embodiments, the present invention provides that R 5c Relates to any one of the previously described compounds, wherein R is hydroxyl. In certain embodiments, the present invention provides that R 5c Relates to any one of the previously described compounds, wherein R is -OCF3. In certain embodiments, the present invention provides that R 5c Relates to any one of the previously described compounds, wherein R is substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention provides that R 5c Relates to any one of the previously described compounds, wherein R is unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe.

[0057] In certain embodiments, the present invention provides that R 5d Relates to any one of the previously described compounds, wherein R is CN. In certain embodiments, the present invention provides that R 5d Relates to any one of the previously described compounds, wherein R is unsubstituted (C1-C4)-alkyl. In certain embodiments, the present invention provides that R 5d Relates to any one of the previously described compounds, wherein R is substituted (C1-C4)-alkyl. In certain embodiments, substituted (C1-C5)-alkyl is substituted with halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5d is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl or t-butyl. In certain embodiments, the present invention provides that R 5d Relates to any one of the previously described compounds, wherein R is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, the present invention provides that R 5d is substituted (C3-C6)-cycloalkyl. In certain embodiments, the present invention provides that R 5d is unsubstituted (C3-C6)-cycloalkyl. In certain embodiments, the present invention provides that R5d Relates to any one of the previously described compounds where it is CF3. In certain embodiments, the present invention relates to R 5d Relates to any one of the previously described compounds where it is C(H)F2. In certain embodiments, the present invention relates to R 5d Relates to any one of the previously described compounds where it is C(F)H2. In certain embodiments, the present invention relates to R 5d Relates to any one of the previously described compounds where it is (C1-C4)-alkoxy. In certain embodiments, the present invention relates to R 5d Relates to any one of the previously described compounds where it is methoxy. In certain embodiments, the present invention relates to R 5d Relates to any one of the previously described compounds where it is hydroxyl. In certain embodiments, the present invention relates to R 5d Relates to any one of the previously described compounds where it is -OCF3. In certain embodiments, the present invention relates to R 5d Relates to any one of the previously described compounds where it is substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to R 5d Relates to any one of the previously described compounds where it is unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe.

[0058] In certain embodiments, the present invention relates to R 5e Relates to any one of the previously described compounds where it is CN. In certain embodiments, the present invention relates to R 5e Relates to any one of the previously described compounds where it is unsubstituted (C1-C4)-alkyl. In certain embodiments, the present invention relates to R 5e Relates to any one of the previously described compounds where it is substituted (C1-C4)-alkyl. In certain embodiments, substituted (C1-C5)-alkyl is substituted with halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5eis methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl or t-butyl. In certain embodiments, the invention relates to R 5e being a halide of any one of the compounds described above. In some embodiments, the halide is Cl or F. In certain embodiments, R 5e is substituted (C3-C6)-cycloalkyl. In certain embodiments, R 5e is unsubstituted (C3-C6)-cycloalkyl. In certain embodiments, the invention relates to R 5e being CF3 of any one of the compounds described above. In certain embodiments, the invention relates to R 5e being C(H)F2 of any one of the compounds described above. In certain embodiments, the invention relates to R 5e being C(F)H2 of any one of the compounds described above. In certain embodiments, the invention relates to R 5e being (C1-C4)-alkoxy of any one of the compounds described above. In certain embodiments, the invention relates to R 5e being methoxy of any one of the compounds described above. In certain embodiments, the invention relates to R 5e being hydroxyl of any one of the compounds described above. In certain embodiments, the invention relates to R 5e being -OCF3 of any one of the compounds described above. In certain embodiments, the invention relates to R 5e being substituted (C1-C4)-alkylene-(C1-C4)-alkoxy of any one of the compounds described above. In certain embodiments, the invention relates to R 5e being unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy of any one of the compounds described above. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe.

[0059] In certain embodiments, R 5bis H. In certain embodiments, the invention relates to R 5b is a substituted or unsubstituted (C1-C4)-alkyl, to any one of the compounds described above. In certain embodiments, the invention relates to R 5b is an unsubstituted (C1-C4)-alkyl, to any one of the compounds described above. In certain embodiments, the invention relates to R 5b is a substituted (C1-C4)-alkyl, to any one of the compounds described above. In certain embodiments, the substituted (C1-C5)-alkyl is substituted with one or more halogens. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5b is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl or t-butyl. In certain embodiments, the invention relates to R 5b is a halide, to any one of the compounds described above. In some embodiments, the halide is Cl or F. In certain embodiments, R 5b is a substituted (C3-C6)-cycloalkyl. In certain embodiments, R 5b is an unsubstituted (C3-C6)-cycloalkyl. In some embodiments, the (C3-C6)-cycloalkyl is cyclopropyl. In certain embodiments, the invention relates to R 5b is CF3, to any one of the compounds described above. In certain embodiments, the invention relates to R 5b is C(H)F2, to any one of the compounds described above. In certain embodiments, the invention relates to R 5b is C(F)H2, to any one of the compounds described above. In certain embodiments, the invention relates to R 5a is a (C1-C4)-alkoxy, to any one of the compounds described above. In some embodiments, the (C1-C4)-alkoxy is methoxy. In certain embodiments, the invention relates to R 5b is methoxy, to any one of the compounds described above. In certain embodiments, the invention relates to R5b Relates to any one of the previously described compounds wherein is hydroxyl. In certain embodiments, the present invention provides that R 5b Relates to any one of the previously described compounds wherein is -OCF3. In certain embodiments, R 5b is CN. In certain embodiments, the present invention provides that R 5b Relates to any one of the previously described compounds wherein is substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention provides that R 5b Relates to any one of the previously described compounds wherein is unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, R 5b is CH2OH.

[0060] In certain embodiments, R 5c is H. In certain embodiments, the present invention provides that R 5c Relates to any one of the previously described compounds wherein is substituted or unsubstituted (C1-C4)-alkyl. In certain embodiments, the present invention provides that R 5a Relates to any one of the previously described compounds wherein is unsubstituted (C1-C4)-alkyl. In certain embodiments, the present invention provides that R 5c Relates to any one of the previously described compounds wherein is substituted (C1-C4)-alkyl. In certain embodiments, substituted (C1-C5)-alkyl is substituted with one or more halogens. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5c is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl or t-butyl. In certain embodiments, the present invention provides that R 5c Relates to any one of the previously described compounds wherein is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, R 5cis a substituted (C3-C6)-cycloalkyl. In certain embodiments, R 5c is an unsubstituted (C3-C6)-cycloalkyl. In some embodiments, the (C3-C6)-cycloalkyl is cyclopropyl. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5c is CF3. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5c is C(H)F2. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5c is C(F)H2. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5c is (C1-C4)-alkoxy. In some embodiments, the (C1-C4)-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5c is methoxy. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5c is hydroxyl. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5c is -OCF3. In certain embodiments, R 5c is CN. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5a is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5c is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, R 5c is CH2OH.

[0061] In certain embodiments, R 5d is H. In certain embodiments, the invention relates to any one of the compounds described above, wherein R5d Relates to any one of the previously described compounds, wherein R is substituted or unsubstituted (C1-C4)-alkyl. In certain embodiments, the present invention provides that R 5d Relates to any one of the previously described compounds, wherein R is unsubstituted (C1-C4)-alkyl. In certain embodiments, the present invention provides that R 5d Relates to any one of the previously described compounds, wherein R is substituted (C1-C4)-alkyl. In certain embodiments, the substituted (C1-C5)-alkyl is substituted with one or more halogens. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5d Is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl or t-butyl. In certain embodiments, the present invention provides that R 5d Relates to any one of the previously described compounds, wherein R is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, R 5d Is substituted (C3-C6)-cycloalkyl. In certain embodiments, R 5d Is unsubstituted (C3-C6)-cycloalkyl. In some embodiments, the (C3-C6)-cycloalkyl is cyclopropyl. In certain embodiments, the present invention provides that R 5d Relates to any one of the previously described compounds, wherein R is CF3. In certain embodiments, the present invention provides that R 5d Relates to any one of the previously described compounds, wherein R is C(H)F2. In certain embodiments, the present invention provides that R 5d Relates to any one of the previously described compounds, wherein R is C(F)H2. In certain embodiments, the present invention provides that R 5d Relates to any one of the previously described compounds, wherein R is (C1-C4)-alkoxy. In some embodiments, the (C1-C4)-alkoxy is methoxy. In certain embodiments, the present invention provides that R 5d Relates to any one of the previously described compounds, wherein R is methoxy. In certain embodiments, the present invention provides that R 5dRelates to any one of the previously described compounds where it is hydroxyl. In certain embodiments, the present invention, R 5d Relates to any one of the previously described compounds where it is -OCF3. In certain embodiments, R 5d is CN. In certain embodiments, the present invention, R 5d Relates to any one of the previously described compounds where it is substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention, R 5d Relates to any one of the previously described compounds where it is unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, the present invention, R 5d is CH2OH.

[0062] In certain embodiments, R 5e is H. In certain embodiments, the present invention, R 5e Relates to any one of the previously described compounds where it is substituted or unsubstituted (C1-C4)-alkyl. In certain embodiments, the present invention, R 5e Relates to any one of the previously described compounds where it is unsubstituted (C1-C4)-alkyl. In certain embodiments, the present invention, R 5e Relates to any one of the previously described compounds where it is substituted (C1-C4)-alkyl. In certain embodiments, substituted (C1-C5)-alkyl is substituted with one or more halogens. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5e is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl or t-butyl. In certain embodiments, the present invention, R 5e Relates to any one of the previously described compounds where it is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, the present invention, R 5eis a substituted (C3-C6)-cycloalkyl. In certain embodiments, R 5e is an unsubstituted (C3-C6)-cycloalkyl. In some embodiments, the (C3-C6)-cycloalkyl is cyclopropyl. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5e is CF3. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5e is C(H)F2. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5e is C(F)H2. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5e is a (C1-C4)-alkoxy. In some embodiments, the (C1-C4)-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5e is methoxy. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5e is hydroxyl. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5e is -OCF3. In certain embodiments, R 5e is CN. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5e is a substituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the invention relates to any one of the compounds described above, wherein R 5e is an unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy is -CH2OMe. In certain embodiments, R 5e is CH2OH.

[0063] In some embodiments, R 5a and R 5e are the same. For example, R5a and R 5e may both be substituted or unsubstituted (C1-C4)-alkyl. In some examples, R 5a and R 5e are both unsubstituted (C1-C4)-alkyl (e.g., methyl). In some examples, R 5a and R 5e are both unsubstituted methyl.

[0064] In some embodiments, R 5b and R 5d are the same. For example, R 5a and R 5e may both be hydrogen.

[0065] In some embodiments, R 5a and R 5e are both substituted, and R 5b and R 5d are both hydrogen. For example, R 5a and R 5e may both be (the same or different) substituted or unsubstituted (C1-C4)-alkyl. In some examples, R 5a and R 5e may both be unsubstituted (C1-C4)-alkyl (e.g., methyl), and R 5b and R 5d are both hydrogen. In some examples, R 5a and R 5e are both unsubstituted methyl, and R 5b and R 5d are both hydrogen. In some embodiments, R 5a and R 5e are independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, (C1-C5)-alkyl, hydroxyl, and (C1-C4)-alkoxy.

[0066] In some embodiments, R 5cis hydrogen, a halide (e.g., F), a substituted or unsubstituted (C1-C4)-alkoxy (e.g., methoxy), or a substituted or unsubstituted (C1-C4)-alkyl (e.g., methyl).

[0067] In some embodiments, R 5a and R 5e are both substituted or unsubstituted (C1-C5)-alkyl, R 5b and R 5d are both hydrogen, and R 5c is hydrogen, a halide (e.g., F), a substituted or unsubstituted (C1-C4)-alkoxy (e.g., methoxy), or a substituted or unsubstituted (C1-C4)-alkyl (e.g., methyl). For example, R 5a and R 5e may both be methyl, R 5b and R 5d are both hydrogen, and R 5c is selected from the group consisting of hydrogen, a halide (e.g., F), a substituted or unsubstituted (C1-C4)-alkoxy (e.g., methoxy), and a substituted or unsubstituted (C1-C4)-alkyl (e.g., methyl). In some examples, R 5a and R 5e may both be methyl, R 5b and R 5d are both hydrogen, and R 5c is selected from the group consisting of hydrogen, F, Cl, methoxy and methyl. In some examples, R 5a , R 5c and R 5e are each methyl, and R 5b and R 5d are both hydrogen. In some embodiments, R 5b , R 5c and R 5d are independently selected from the group consisting of H, CN, a halide, CF3, C(H)F2, C(F)H2, (C1-C5)-alkyl, hydroxyl, and (C1-C4)-alkoxy.

[0068] In certain embodiments, the present invention provides R a, R b and R c relates to any one of the compounds described above, wherein R a , R b and R c at least one of which is a substituted or unsubstituted -(C1-C5) alkylene-N-(R x )(R y ), wherein R x and R y are independently selected from the group consisting of H, substituted or unsubstituted (C1-C6)-alkyl, or substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy, or R x and R y together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclic ring.

[0069] In certain embodiments, the present invention relates to any one of the compounds described above, wherein only one of R a , R b and R c is a substituted or unsubstituted -(C1-C5) alkylene-N-(R x )(R y ), wherein R x and R y are independently selected from the group consisting of H, substituted or unsubstituted (C1-C6)-alkyl, or substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the compounds described above, wherein only one of R a , R b and R c is a substituted or unsubstituted -(C1-C5) alkylene-N-(R x )(R y ), wherein R x and R y are independently selected from the group consisting of substituted or unsubstituted (C1-C6)-alkyl, or substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy. In certain embodiments, the present invention relates to any one of the compounds described above, wherein R a , R b and Rc Only one of which is a substituted or unsubstituted -(C1-C5) alkylene-N-(R x )(R y ), where R x and R y are independently selected from the group consisting of substituted or unsubstituted (C1-C6)-alkyl, and relates to any one of the compounds described above.

[0070] In certain embodiments, the present invention provides that only one of R a , R b and R c is a substituted or unsubstituted -(C1-C5) alkylene-N-(R x )(R y ), where R x and R y together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclyl ring, and relates to any one of the compounds described above. In certain embodiments, the present invention provides that only one of R a , R b and R c is a substituted or unsubstituted -(C1-C5) alkylene-N-(R x )(R y ), where R x and R y together with the N to which they are attached form a 4- to 6-membered heterocyclyl ring optionally substituted with one or more halides (e.g., F, Cl), and relates to any one of the compounds described above.

[0071] In some embodiments, R a , R b and R c are independently selected from the group consisting of H, substituted or unsubstituted (C1-C5)-alkyl, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)-alkoxy, -OCF3, and at least one of R a , R b and R c is ---(C1-C3) alkylene-N-(R x )(R yand wherein R x and R y are each independently selected from the group consisting of H and (C1-C6)-alkyl, or R x and R y together with the N to which they are attached form a 4- to 6-membered heterocyclyl ring optionally substituted with one or more halides (e.g., F or Cl).

[0072] In some embodiments, R a , R b and R c are each independently selected from the group consisting of H, substituted or unsubstituted (C1-C5)-alkyl, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)-alkoxy, -OCF3, and at least one of R a , R b and R c is -(C1-C3)alkylene-N-(R x )(R y ), where R x and R y are each independently selected from the group consisting of (C1-C6)-alkyl (e.g., methyl), or R x and R y together with the N to which they are attached form a 4- to 6-membered heterocyclyl ring optionally substituted with one or more halides (e.g., F or Cl).

[0073] In certain embodiments, the invention relates to any one of the compounds described above, wherein only one of R a , R b and R c is selected from the group consisting of

Chemical formula

Chemical formula

[0074] In certain embodiments, the present invention relates to R a wherein R is selected from the group consisting of H, substituted or unsubstituted (C1-C5)-alkyl, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)-alkoxy, and -OCF3, and relates to any one of the compounds described above. In certain embodiments, the present invention relates to R a wherein R is selected from the group consisting of H, substituted or unsubstituted (C1-C5)-alkyl, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)-alkoxy, and -OCF3, and one of R b and R c is substituted or unsubstituted -(C1-C5)alkylene-N-(R x )(R y ), where R x and R y are independently selected from the group consisting of H, substituted or unsubstituted (C1-C6)-alkyl, or substituted or unsubstituted (C1-C4)alkylene-(C1-C4)-alkoxy, or R x and R y together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclic ring, and relates to any one of the compounds described above.

[0075] In certain embodiments, the present invention relates to any one of the compounds described above, wherein R a is H. In certain embodiments, the present invention relates to any one of the compounds described above, wherein R a is Me. In certain embodiments, the present invention relates to any one of the compounds described above, wherein R a is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, the present invention relates to any one of the compounds described above, wherein R a is CF3. In certain embodiments, the present invention relates to any one of the compounds described above, wherein R a is C(H)F2. In certain embodiments, the present invention relates to R aRelates to any one of the previously described compounds, wherein it is C(F)H2. In certain embodiments, the present invention provides that R a Relates to any one of the previously described compounds, wherein it is substituted (C1-C4)-alkoxy. In certain embodiments, the present invention provides that R a Relates to any one of the previously described compounds, wherein it is unsubstituted (C1-C4)-alkoxy. In some embodiments, the (C1-C4)-alkoxy is methoxy. In certain embodiments, the present invention provides that R a Relates to any one of the previously described compounds, wherein it is -OCF3. In certain embodiments, the present invention provides that R a Relates to any one of the previously described compounds, wherein it is substituted -(C1-C5)alkylene-N-(R x )(R y ). In certain embodiments, the present invention provides that R a Relates to any one of the previously described compounds, wherein it is unsubstituted -(C1-C5)alkylene-N-(R x )(R y ). In some embodiments, the -(C1-C5)alkylene of -(C1-C5)alkylene-N-(R x )(R y ) is substituted with one or more halides or -(C1-C4)alkyl. In certain embodiments, the present invention provides that --(C1-C5)alkylene-N-(R x )(R y ) is --(C1-C4)alkylene-N-(R x )(R y ), and relates to any one of the previously described compounds.

[0076] In some embodiments, R a is substituted (C1-C5)-alkyl, substituted (C1-C4)-alkoxy, or substituted -(C1-C5)alkylene-N-(R x )(R y ), where substituted means substituted with a halide or (C1-C4)-alkoxy. In some embodiments, R ais a substituted (C1-C5)-alkyl, substituted (C1-C4)-alkoxy, or substituted-(C1-C5)alkylene-N-(R x )(R y ) where substituted means substituted with F or methoxy.

[0077] In some embodiments, R a is

Chemical formula

Chemical formula

[0078] In certain embodiments, the present invention relates to a compound wherein R a is selected from the group consisting of H, substituted or unsubstituted (C1-C5)-alkyl, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C4)-alkoxy, and -OCF, and R b is a substituted or unsubstituted-(C1-C5)alkylene-N-(R x )(R y ) where R x and R y are independently selected from the group consisting of H, substituted or unsubstituted (C1-C6)-alkyl, or substituted or unsubstituted (C1-C4)alkylene-(C1-C4)-alkoxy, or R x and R y together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered heterocyclic ring, relating to any one of the compounds described above.

[0079] In certain embodiments, the present invention relates to any one of the compounds described above wherein R b is H. In certain embodiments, the present invention relates to R brelates to any one of the previously described compounds, where Me is R b relates to any one of the previously described compounds, where R is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, the present invention relates to R b relates to any one of the previously described compounds, where R is CF3. In certain embodiments, the present invention relates to R b relates to any one of the previously described compounds, where R is C(H)F2. In certain embodiments, the present invention relates to R b relates to any one of the previously described compounds, where R is C(F)H2. In certain embodiments, the present invention relates to R b relates to any one of the previously described compounds, where R is a substituted (C1-C4)-alkoxy. In certain embodiments, the present invention relates to R b relates to any one of the previously described compounds, where R is an unsubstituted (C1-C4)-alkoxy. In some embodiments, the (C1-C4)-alkoxy is methoxy. In certain embodiments, the present invention relates to R b relates to any one of the previously described compounds, where R is -OCF3. In certain embodiments, the present invention relates to R b relates to any one of the previously described compounds, where R is a substituted -(C1-C5)alkylene-N-(R x )(R y ). In certain embodiments, the present invention relates to R b relates to any one of the previously described compounds, where R is an unsubstituted -(C1-C5)alkylene-N-(R x )(R y ). In some embodiments, the -(C1-C5)alkylene-N-(R x )(R y ) of -(C1-C5)alkylene is substituted with one or more halides or -(C1-C4)alkyl. In certain embodiments, the present invention relates to --(C1-C5)alkylene-N-(R x )(R y ) being --(C1-C4)alkylene-N-(R x )(R yrelates to any one of the previously described compounds, which is as follows.

[0080] In some embodiments, R b is substituted (C1-C5)-alkyl, substituted (C1-C4)-alkoxy, or substituted-(C1-C5) alkylene-N-(R x )(R y ), where being substituted means being substituted with a halide or (C1-C4)-alkoxy. In some embodiments, R b is substituted (C1-C5)-alkyl, substituted (C1-C4)-alkoxy, or substituted-(C1-C5) alkylene-N-(R x )(R y ), where being substituted means being substituted with F or methoxy.

[0081] In some embodiments, R b is

Chemical formula

Chemical formula

[0082] In certain embodiments, the present invention relates to any one of the previously described compounds wherein R c is H. In certain embodiments, the present invention relates to any one of the previously described compounds wherein R c is Me. In certain embodiments, the present invention relates to any one of the previously described compounds wherein R c is a halide. In some embodiments, the halide is Cl or F. In certain embodiments, the present invention relates to any one of the previously described compounds wherein R c is CF3. In certain embodiments, the present invention relates to any one of the previously described compounds wherein R cRelates to any one of the previously described compounds wherein C(H)F2. In certain embodiments, the present invention provides for R c Relates to any one of the previously described compounds wherein C(F)H2. In certain embodiments, the present invention provides for R c Relates to any one of the previously described compounds wherein R is substituted (C1-C4)-alkoxy. In some embodiments, the (C1-C4)-alkoxy is methoxy. In certain embodiments, the present invention provides for R c Relates to any one of the previously described compounds wherein R is unsubstituted (C1-C4)-alkoxy. In certain embodiments, the present invention provides for R c Relates to any one of the previously described compounds wherein R is -OCF3. In certain embodiments, the present invention provides for R c Relates to any one of the previously described compounds wherein R is substituted -(C1-C5)alkylene-N-(R x )(R y ). In certain embodiments, the present invention provides for R c Relates to any one of the previously described compounds wherein R is unsubstituted -(C1-C5)alkylene-N-(R x )(R y ). In some embodiments, the -(C1-C5)alkylene of -(C1-C5)alkylene-N-(R x )(R y ) is substituted with one or more halides or -(C1-C4)alkyl. In certain embodiments, the present invention provides for --(C1-C5)alkylene-N-(R x )(R y ) being --(C1-C4)alkylene-N-(R x )(R y ) and relates to any one of the previously described compounds.

[0083] In some embodiments, R c is substituted (C1-C5)-alkyl, substituted (C1-C4)-alkoxy, or substituted -(C1-C5)alkylene-N-(R x )(R y) and wherein the substituent is a halide or (C1-C4)-alkoxy substituted. In some embodiments, R c is a substituted (C1-C5)-alkyl, substituted (C1-C4)-alkoxy, or substituted -(C1-C5)alkylene-N-(R x )(R y ), where the substituent is F or methoxy substituted.

[0084] In some embodiments, R c is

Chemical formula

Chemical formula

[0085] In some embodiments, at least one of R a , R b and R c is H.

[0086] In some embodiments, at least one of R a , R b and R c is a charged amine, and at least one of R a , R b and R c is H.

[0087] In certain embodiments, the invention relates to any one of the compounds described above, wherein R x is H. In certain embodiments, the invention relates to any one of the compounds described above, wherein R x is a substituted (C1-C6)-alkyl. In certain embodiments, the invention relates to any one of the compounds described above, wherein R x is an unsubstituted (C1-C6)-alkyl. In certain embodiments, the invention relates to any one of the compounds described above, wherein Rx Relates to any one of the previously described compounds, wherein the substituent is (C1-C4)-alkyl. In some embodiments, the (C1-C6)-alkyl is substituted with OMe, CN, or a halide. In certain embodiments, the present invention provides that R x Relates to any one of the previously described compounds, wherein the substituent is unsubstituted (C1-C4)-alkyl. In certain embodiments, the present invention provides that R x Relates to any one of the previously described compounds, wherein the substituent is (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy is -(CH2)2OMe. In certain embodiments, the present invention provides that R x Relates to any one of the previously described compounds, wherein the substituent is Me.

[0088] In certain embodiments, the present invention provides that R y Relates to any one of the previously described compounds, wherein the substituent is H. In certain embodiments, the present invention provides that R y Relates to any one of the previously described compounds, wherein the substituent is substituted (C1-C6)-alkyl. In certain embodiments, the present invention provides that R y Relates to any one of the previously described compounds, wherein the substituent is unsubstituted (C1-C6)-alkyl. In certain embodiments, the present invention provides that R y Relates to any one of the previously described compounds, wherein the substituent is substituted (C1-C4)-alkyl. In some embodiments, the (C1-C6)-alkyl is substituted with OMe, CN, or a halide. In certain embodiments, the present invention provides that R y Relates to any one of the previously described compounds, wherein the substituent is unsubstituted (C1-C4)-alkyl. In certain embodiments, the present invention provides that R y Relates to any one of the previously described compounds, wherein the substituent is (C1-C4)-alkylene-(C1-C4)-alkoxy. In some embodiments, the (C1-C4)-alkylene-(C1-C4)-alkoxy is -(CH2)2OMe. In certain embodiments, the present invention provides that R yrelates to any one of the previously described compounds, where Me is Me.

[0089] In certain embodiments, the present invention provides that R x is Me and R y is Me, and relates to any one of the previously described compounds.

[0090] In certain embodiments, the present invention provides that R x and R y together with the N to which they are attached form a substituted or unsubstituted 4- to 6-membered ring, and relates to any one of the previously described compounds. In some embodiments, the 4- to 6-membered ring is a substituted or unsubstituted heterocycloalkyl. In some embodiments, the substituted 4- to 6-membered heterocycloalkyl is substituted with a halide of (C1-C6) alkyl. In some embodiments, the 4- to 6-membered ring is a substituted or unsubstituted heteroaryl. In some embodiments, the substituted 4- to 6-membered heteroaryl is substituted with a halide of (C1-C6) alkyl. In some embodiments, the 4- to 6-membered ring is

Chemical formula

[0091] In certain embodiments, the present invention relates to a compound of formula (Ia) or (Ib):

Chemical formula

[0092] In certain embodiments, the present invention relates to any of the compounds illustrated in FIG. 1.

[0093] In certain embodiments, the present invention relates to compounds selected from the group consisting of: (3S)-3-(4,5-difluoro-2',6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid; (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid; (3S)-3-(2-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid; (3S)-3-(4,4'-Difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(5-Chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoic acid; (3S)-3-(4,4'-Difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoic acid; (3S)-3-(4-Fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; and (3S)-3-(4-Fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid or a pharmaceutically acceptable salt thereof.

[0094] In certain embodiments, the invention relates to a compound selected from the group consisting of:

Chemical formula

[0095] In certain embodiments, the invention relates to a compound selected from the group consisting of: (S)-3-(4,5-Difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoic acid; (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid; (S)-3-((S)-2-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid; (S)-3-(4,4'-Difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (S)-3-(5-Chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoic acid; (S)-3-(4,4'-Difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamido)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid; (S)-3-(4-Fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; and (S)-3-(4-Fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; or a pharmaceutically acceptable salt thereof.

[0096] In certain embodiments, the present invention relates to a compound selected from the group consisting of:

Chemical formula

[0097] Exemplary pharmaceutical compositions The compounds of formula (I) can be formulated into various pharmaceutical compositions. The compounds of formula (I) (including the compounds of formula (Ia) and formula (Ib) as provided herein), as well as their pharmaceutically acceptable salts, can be pharmaceutical active ingredients (APIs) that are combined with one or more other components to form drug substance pharmaceutical compositions. The drug substance (DS) pharmaceutical compositions can include an API (i.e., a compound of formula (I) or its pharmaceutically acceptable salt) and one or more pharmaceutically acceptable carriers, diluents, and / or excipients. The carrier, diluent, or excipient can be selected to be compatible with the other components of the formulation and to be suitably safe and effective for the intended treatment. The desired weight concentration of the compound of formula (I) as the pharmaceutical active ingredient (API) can be combined with other inactive components for forming the drug substance (DS) in the formulation batch. The pharmaceutically acceptable compositions can be formulated for administration by a suitable route, for example, oral delivery in unit dosage forms (including as capsules or tablets). Such compositions can be prepared by associating the pharmaceutical active ingredient (API) comprising the compound of formula (I) with a carrier or excipient.

[0098] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as a pharmaceutical active ingredient (API).

[0099] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (Ia) or a pharmaceutically acceptable salt thereof as a pharmaceutical active ingredient (API).

[0100] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (Ib) or a pharmaceutically acceptable salt thereof as a pharmaceutical active ingredient (API).

[0101] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (3S)-3-(4,5-difluoro-2',6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid or a pharmaceutically acceptable salt thereof.

[0102] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

[0103] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

[0104] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

[0105] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid or a pharmaceutically acceptable salt thereof.

[0106] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid or a pharmaceutically acceptable salt thereof.

[0107] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

[0108] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid or a pharmaceutically acceptable salt thereof.

[0109] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamide)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

[0110] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (3S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid or a pharmaceutically acceptable salt thereof.

[0111] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (3S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid or a pharmaceutically acceptable salt thereof.

[0112] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid or a pharmaceutically acceptable salt thereof.

[0113] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

[0114] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

[0115] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

[0116] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid or a pharmaceutically acceptable salt thereof.

[0117] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid or a pharmaceutically acceptable salt thereof.

[0118] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

[0119] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid or a pharmaceutically acceptable salt thereof.

[0120] In certain embodiments, the present invention provides a pharmaceutical composition comprising, as a pharmaceutical active ingredient (API), the compound (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamide)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

[0121] In certain embodiments, the present invention provides a pharmaceutical composition comprising the compound (S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid or a pharmaceutically acceptable salt thereof as a pharmaceutical active ingredient (API).

[0122] In certain embodiments, the present invention provides a pharmaceutical composition comprising the compound (S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid or a pharmaceutically acceptable salt thereof as a pharmaceutical active ingredient (API).

[0123] In certain embodiments, the present invention relates to a pharmaceutical composition comprising a compound selected from the group consisting of:

Chemical formula

[0124] Pharmaceutically acceptable compositions containing the compound of formula (I) can be prepared by various procedures. For example, the compound of formula (I) can be formulated with suitable excipients, diluents or carriers and formed into tablets or capsules and other suitable dosage forms.

[0125] The pharmaceutical composition can be provided in unit dosage form containing a predetermined amount of the API comprising a compound of formula (I) per unit dosage. Such units can contain the desired amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, depending on the condition being treated, the route of administration, and the age, weight and condition of the patient. Such unit dosages can thus be administered at the desired dosage intervals. The concentration of the active compound in the pharmaceutical composition depends on various applicable parameters and considerations, such as the rate of absorption, inactivation and excretion of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage values also vary with the severity of the condition to be alleviated. For any particular subject, the specific dosage regimen should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and it is further understood that the concentration ranges described herein are for illustration only and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered in a single dose or divided into a number of smaller doses and administered at varying time intervals.

[0126] In certain embodiments, the mode of administration of the active compound is oral. Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. A pharmaceutical composition containing a compound of formula (I) formulated for oral delivery can be prepared in unit dosage form, e.g., capsules, at the desired dosage strength of the compound of formula (I). For oral administration in liquid form, the oral drug components can be combined with any oral non-toxic pharmaceutically acceptable inert carrier, e.g., ethanol, glycerol, water, etc. For oral administration in the form of tablets or capsules, the compound of formula (I) can be combined with an oral non-toxic pharmaceutically acceptable inert carrier. Other examples of excipients, diluents, and carriers suitable for such formulations include the following: fillers and extenders, e.g., starch and sugars; and binders, e.g., cellulose derivatives. Further, if desired or necessary, suitable binders, lubricants, disintegrants, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, natural sugars, natural or synthetic gums, etc. Lubricants and / or glidants can be used in these dosage forms.

[0127] Tablets, pills, capsules, troches, and the like can contain any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth gum or gelatin; excipients such as starch or lactose, disintegrants such as alginic acid, Primogel or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate or orange flavor. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. In addition, the unit dosage form can contain various other materials that modify the physical form of the dosage unit, such as a sugar coating, or other enteric agents.

[0128] The compounds can be administered as ingredients in elixirs, suspensions, syrups, wafers, and the like. Syrups can contain, in addition to the active compound(s), sucrose or a sweetening agent as a sweetening agent, and certain preservatives, dyes and colorants and flavors.

[0129] The compounds can be formulated as solutions suitable for parenteral administration by, for example, intramuscular, subcutaneous or intravenous routes. For example, the compounds of formula (I) can be dissolved in a suitable buffer. A pharmaceutical composition containing the desired concentration of the compound of formula (I) can be formulated as an injectable drug solution (useful, for example, in preclinical animal studies).

[0130] Exemplary methods Compounds that inhibit α4β7 are useful in the development of medicaments for treating patients with ulcerative colitis and Crohn's disease. Patients with ulcerative colitis (UC) and Crohn's disease (CD) suffer from autoimmune inflammation in the gastrointestinal tract, and for many of these patients, CD4 +Memory T cells drive disease progression and relapse through their ability to secrete pro-inflammatory effector cytokines in the gut and affect surrounding immune cells and tissues. The progression and relapse of these disease states are thought to involve the extravasation of T cells that leave the blood and invade tissues in the gut, leading to the inflammatory conditions found in UC and CD via integrin-related mechanisms. Inhibition of α4β7 disrupts this mechanism and can thereby prevent the localization of T cells to tissues and effectively treat and prevent diseases such as UC and CD. T cell homing to the gut requires the surface expression of integrin α4β7 and chemokine receptor CCR9. CCR9 is utilized by cells to migrate in response to the gradient of CCL25 expressed in the small intestine, while α4β7 is the tethering molecule that binds the ligand, mucosal addressin cell adhesion molecule 1 (MAdCAM-1). Integrin α4β7 binds MAdCAM-1 with high affinity and facilitates cell rolling and firm adhesion, followed by extravasation into tissues.

[0131] The pharmaceutical composition can comprise a compound capable of inhibiting α4β7 integrin on inflammatory cells so as to inhibit or prevent the adhesion of these cells to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and the invasion of these cells into the intestinal lamina propria and gut-associated lymphoid tissue.

[0132] The compounds of formula (I) were evaluated using a fluorescence polarization (FP) assay. The FP assay is used to evaluate the potency of a compound on a purified protein. The FP assay consists of measuring the headpiece that binds to a purified integrin αβ heterodimer ectodomain or a surrogate or truncated ligand. The results of the FP assay for exemplary compounds of formula (I) are provided herein.

[0133] The compounds of formula (I) were further evaluated using a ligand binding assay (LBA) to examine the compound potency of free ligands that bind to receptors expressed on cells. The MAdCAM ligand binding assay measures the binding of fluorescently labeled MAdCAM-1-Fc to RPMI 8866 cells in the presence of Mn++ using flow cytometry. This assay determines the binding of compounds to the native full-length receptors on the cell surface. One advantage of the MAdCAM ligand binding assay is its ability to quantify and discriminate the activity of potent compounds that exceed the functional sensitivity limit of the FP assay [about 10 nM for Mn]. Ligand binding assays (LBAs) are used to examine compound potency and the selectivity of free ligands that bind to receptors expressed on cells.

[0134] In some embodiments, the compounds of the invention can be selected from one or more of the following numbered embodiments: 1. Formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0135] In some embodiments, the compounds of the present invention have the formula (I):

Chemical formula

Chemical formula

[0136] In some embodiments, the compound of the present invention has the formula (Ia):

Chemical formula

Chemical formula

[0137] In some embodiments, the compounds of the present invention have the formula (Ic)

Chemical formula

[0138] In some embodiments, the compound of the present invention is the compound (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-3-methyl-5-((S)-2-methylpiperidin-1-yl)phenyl)propanoic acid [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0139] In certain embodiments, the invention relates to any one of the methods described above, wherein the subject is a mammal. In certain embodiments, the invention relates to any one of the methods described above, wherein the subject is a human. [Examples]

[0140] The invention will now be generally described, which will be more readily understood by reference to the following examples, which are given solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0141] Examples 1-4 illustrate the synthesis of certain compounds presented in Figure 1, including compounds of formula (Ia) and formula (Ib). The compounds in Figure 1 can be prepared as a mixture of diastereomeric compounds having the (3S) configuration (i.e., at the stereocenter that is beta to the carboxylic acid moiety) as disclosed in Examples 1-4, and as a mixture of diastereomers at the chiral center covalently bonded to the pyridone ring nitrogen atom of formula (I) (such as that shown in formula (Ib)).

[0142] In Figure 1, the compounds having greater activity in the fluorescence polarization (FP) assay of Example 5 are shown with the stereochemistry of formula (Ia). Example 5 describes the fluorescence polarization (FP) assay. Example 6 describes the ligand binding (LB) assay. Example 7 describes the cell adhesion (CA) assay.

[0143] Further Embodiments In some embodiments, the compound can be selected from one or more of the enumerated embodiments provided below:

[0144] Embodiment 1. Formula (I): [Chemical formula] [In the formula, R a , R b and R c are independently selected from the group consisting of H, Me, halide, CF3, C(H)F2, C(F)H2 and -(C1-C5)alkylene-N-(R x )(R y ), provided that at least one of R a , R b and R c is -(C1-C5)alkylene-N-(R x )(R y ), and R x and R y are independently selected from the group consisting of H and substituted or unsubstituted (C1-C6)-alkyl, or R x and R y together with the N to which it is attached form a 4- to 6-membered ring, R1 is substituted or unsubstituted (C1-C6)-alkyl, substituted or unsubstituted (C1-C4)-alkylene-(C3-C6)-cycloalkyl, or substituted or unsubstituted (C1-C4)-alkylene(C1-C4)-alkoxy, R2 is [Chemical formula] and R 3a and R 3b are independently selected from the group consisting of H, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, -OH, -CN, halide, CF3, C(H)F2, C(F)H 2、 -(C1-C4)-alkoxy, -OCF3 and substituted or unsubstituted (C1-C4)-alkylene-(C1-C4)-alkoxy, provided that both R 3a and R 3b are not both H, and R3c and R 3d is H, R4 is H or a substituted or unsubstituted (C1-C4)-alkyl, R 5a and R 5e are independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted (C1-C5)-alkyl, hydroxyl and (C1-C4)-alkoxy, R 5b , R 5c and R 5d are independently selected from the group consisting of H, CN, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, substituted or unsubstituted (C3-C6)-cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, hydroxyl and (C1-C4)-alkoxy] of the compound, or a pharmaceutically acceptable salt thereof.

[0145] Embodiment 2. The compound of Embodiment 1, wherein R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or t-butyl.

[0146] Embodiment 3. The compound of Embodiment 2, wherein R1 is isobutyl.

[0147] Embodiment 4. R1 is

Chemical formula

[0148] Embodiment 5. R1 is

Chemical formula

[0149] Embodiment 6. R 3a and R 3bis a compound of any one of Embodiments 1 to 5 independently selected from the group consisting of a halide, a substituted or unsubstituted (C1-C5)-alkyl, a substituted or unsubstituted (C3-C6)-cycloalkyl, a substituted or unsubstituted (C1-C4)-alkoxy, CF3, C(H)F2, and C(F)H2.

[0150] Embodiment 7. R 3a and R 3b is a compound of Embodiment 6 independently selected from the group consisting of a halide and a (C1-C4)-alkyl.

[0151] Embodiment 8. The compound of Embodiment 7, wherein the halide is Cl or F.

[0152] Embodiment 9. The compound of Embodiment 7 or 8, wherein the (C1-C4)-alkyl is methyl.

[0153] Embodiment 10. R 3a is methyl and R 3b is F, which is a compound of any one of Embodiments 1 to 7.

[0154] Embodiment 11. R 3a is F and R 3b is methyl, which is a compound of any one of Embodiments 1 to 7.

[0155] Embodiment 12. The compound of any one of Embodiments 1 to 11, wherein R4 is H.

[0156] Embodiment 13. The compound of any one of Embodiments 1 to 11, wherein R4 is methyl, ethyl, n-propyl, or isopropyl.

[0157] Embodiment 14. R 5a and R 5e are a compound of any one of Embodiments 1 to 13 independently selected from the group consisting of a halide, CF3, C(H)F2, C(F)H2, and a substituted or unsubstituted (C1-C4)-alkyl.

[0158] Embodiment 15. R 5a A compound according to any one of Embodiments 1 to 14, wherein R is a halide.

[0159] Embodiment 16. R 5a A compound according to Embodiment 15, wherein R is F or Cl.

[0160] Embodiment 17. R 5a A compound according to any one of Embodiments 1 to 14, wherein R is CF3.

[0161] Embodiment 18. R 5a A compound according to any one of Embodiments 1 to 14, wherein R is C(H)F2.

[0162] Embodiment 19. R 5a A compound according to any one of Embodiments 1 to 14, wherein R is C(F)H2.

[0163] Embodiment 20. R 5a A compound according to any one of Embodiments 1 to 14, wherein R is unsubstituted (C1-C4)-alkyl.

[0164] Embodiment 21. R 5a A compound according to Embodiment 20, wherein R is methyl.

[0165] Embodiment 22. R 5a A compound according to any one of Embodiments 1 to 14, wherein R is substituted (C1-C5)-alkyl substituted with at least one halide.

[0166] Embodiment 23. R 5a A compound according to any one of Embodiments 1 to 14, wherein R is unsubstituted (C1-C4)-alkoxy.

[0167] Embodiment 24. R 5a A compound according to Embodiment 23, wherein R is OMe.

[0168] Embodiment 25. R 5e A compound according to any one of Embodiments 1 to 24, wherein R is a halide.

[0169] Embodiment 26. R 5e is F or Cl, the compound of Embodiment 25.

[0170] Embodiment 27. R 5e is CF3, the compound of any one of Embodiments 1 to 24.

[0171] Embodiment 28. R 5e is C(H)F2, the compound of any one of Embodiments 1 to 24.

[0172] Embodiment 29. R 5e is C(F)H2, the compound of any one of Embodiments 1 to 24.

[0173] Embodiment 30. R 5e is unsubstituted (C1-C4)-alkyl, the compound of any one of Embodiments 1 to 24.

[0174] Embodiment 31. R 5e is methyl, the compound of Embodiment 30.

[0175] Embodiment 32. R 5e is substituted (C1-C5)-alkyl substituted with at least one halide, the compound of any one of Embodiments 1 to 24.

[0176] Embodiment 33. R 5e is unsubstituted (C1-C4)-alkoxy, the compound of any one of Embodiments 1 to 24.

[0177] Embodiment 34. R 5e is OMe, the compound of Embodiment 33.

[0178] Embodiment 35. R 5b , R 5c and R 5dThe compound of any one of Embodiments 1 to 34, independently selected from the group consisting of H, halide, CF3, C(H)F2, C(F)H2, substituted or unsubstituted (C1-C5)-alkyl, and substituted or unsubstituted (C1-C4)-alkoxy.

[0179] Embodiment 36. R 5b The compound of any one of Embodiments 1 to 35, wherein R is H.

[0180] Embodiment 37. R 5b The compound of any one of Embodiments 1 to 35, wherein R is a halide.

[0181] Embodiment 38. R 5b The compound of Embodiment 37, wherein R is Cl or F.

[0182] Embodiment 39. R 5b The compound of any one of Embodiments 1 to 35, wherein R is CF3.

[0183] Embodiment 40. R 5b The compound of any one of Embodiments 1 to 35, wherein R is C(H)F2.

[0184] Embodiment 41. R 5b The compound of any one of Embodiments 1 to 35, wherein R is C(F)H2.

[0185] Embodiment 42. R 5b The compound of any one of Embodiments 1 to 35, wherein R is unsubstituted (C1-C4)-alkyl.

[0186] Embodiment 43. R 5b The compound of Embodiment 37, wherein R is methyl.

[0187] Embodiment 44. R 5b The compound of any one of Embodiments 1 to 35, wherein R is unsubstituted (C1-C4)-alkoxy.

[0188] Embodiment 45. R 5bThe compound of Embodiment 44, where it is OMe.

[0189] Embodiment 46. R 5b The compound of any one of Embodiments 1 to 35, where it is unsubstituted (C3-C6)-cycloalkyl.

[0190] Embodiment 47. R 5b The compound of Embodiment 46, where it is cyclopropyl.

[0191] Embodiment 48. R 5c The compound of any one of Embodiments 1 to 47, where it is H.

[0192] Embodiment 49. R 5c The compound of any one of Embodiments 1 to 47, where it is a halide.

[0193] Embodiment 50. R 5c The compound of Embodiment 49, where it is Cl or F.

[0194] Embodiment 51. R 5c The compound of any one of Embodiments 1 to 47, where it is CF3.

[0195] Embodiment 52. R 5c The compound of any one of Embodiments 1 to 47, where it is C(H)F2.

[0196] Embodiment 53. R 5c The compound of any one of Embodiments 1 to 47, where it is C(F)H2.

[0197] Embodiment 54. R 5c The compound of any one of Embodiments 1 to 47, where it is unsubstituted (C1-C4)-alkyl.

[0198] Embodiment 55. R 5c The compound of Embodiment 54, where it is methyl.

[0199] Embodiment 56. R 5cThe compound of any one of embodiments 1-47, wherein is unsubstituted (C1-C4)-alkoxy.

[0200] Embodiment 57. R 5c 57. The compound of embodiment 56, wherein is OMe.

[0201] Embodiment 58. R 5c The compound of any one of embodiments 1-47, wherein is unsubstituted (C3-C6)-cycloalkyl.

[0202] Embodiment 59. R 5b 59. The compound of embodiment 58, wherein is cyclopropyl.

[0203] Embodiment 60. R 5d The compound of any one of embodiments 1-59, wherein is H.

[0204] Embodiment 61. R 5d The compound of any one of embodiments 1-59, wherein is a halide.

[0205] Embodiment 62. R 5d The compound of embodiment 61, wherein is Cl or F.

[0206] Embodiment 63. R 5d The compound of any one of embodiments 1-59, wherein is CF3.

[0207] Embodiment 64. R 5d The compound of any one of embodiments 1-59, wherein is C(H)F2.

[0208] Embodiment 65. R 5d The compound of any one of embodiments 1-59, wherein is C(F)H2.

[0209] Embodiment 66. R 5d The compound of any one of embodiments 1-59, wherein is unsubstituted (C1-C4)-alkyl.

[0210] Embodiment 67. R5d The compound of Embodiment 66, where [the relevant group] is methyl.

[0211] Embodiment 68. R 5d The compound of any one of Embodiments 1 to 67, where [the relevant group] is unsubstituted (C1 - C4)-alkoxy.

[0212] Embodiment 69. R 5d The compound of Embodiment 68, where [the relevant group] is OMe.

[0213] Embodiment 70. R 5d The compound of any one of Embodiments 1 to 67, where [the relevant group] is unsubstituted (C3 - C6)-cycloalkyl.

[0214] Embodiment 71. R 5d The compound of Embodiment 70, where [the relevant group] is cyclopropyl.

[0215] Embodiment 72. R 5b and R 5d The compound of any one of Embodiments 1 to 35, where [the relevant group] and [another relevant group] are each H.

[0216] Embodiment 73. R a The compound of any one of Embodiments 1 to 72, where [the relevant group] is H.

[0217] Embodiment 74. R a The compound of any one of Embodiments 1 to 72, where [the relevant group] is Me.

[0218] Embodiment 75. R a The compound of any one of Embodiments 1 to 72, where [the relevant group] is a halide.

[0219] Embodiment 76. R a The compound of Embodiment 75, where [the relevant group] is Cl or F.

[0220] Embodiment 77. R a The compound of any one of Embodiments 1 to 72, where [the relevant group] is CF3.

[0221] Embodiment 78. Ra A compound according to any one of Embodiments 1 to 72, wherein R is C(H)F2.

[0222] Embodiment 79. R a A compound according to any one of Embodiments 1 to 72, wherein R is C(F)H2.

[0223] Embodiment 80. R a A compound according to any one of Embodiments 1 to 72, wherein R is unsubstituted -(C1-C3)alkylene-N-(R x )(R y ).

[0224] Embodiment 81. R a A compound according to any one of Embodiments 1 to 72, wherein R is substituted -(C1-C3)alkylene-N-(R x )(R y ) substituted with F or OMe.

[0225] Embodiment 82. R b A compound according to any one of Embodiments 1 to 81, wherein R is H.

[0226] Embodiment 83. R b A compound according to any one of Embodiments 1 to 81, wherein R is Me.

[0227] Embodiment 84. R b A compound according to any one of Embodiments 1 to 81, wherein R is a halide.

[0228] Embodiment 85. R b A compound according to Embodiment 84, wherein R is Cl or F.

[0229] Embodiment 86. R b A compound according to any one of Embodiments 1 to 81, wherein R is CF3.

[0230] Embodiment 87. R b A compound according to any one of Embodiments 1 to 81, wherein R is C(H)F2.

[0231] Embodiment 88. R b is C(F)H2, a compound of any one of Embodiments 1 to 81.

[0232] Embodiment 89. R b is unsubstituted-(C1-C3)alkylene-N-(R x )(R y ) and is a compound of any one of Embodiments 1 to 81.

[0233] Embodiment 90. R b is substituted-(C1-C3)alkylene-N-(R x )(R y ) substituted with F or OMe and is a compound of any one of Embodiments 1 to 81.

[0234] Embodiment 91. R c is H, a compound of any one of Embodiments 1 to 90.

[0235] Embodiment 92. R c is Me, a compound of any one of Embodiments 1 to 90.

[0236] Embodiment 93. R c is a halide, a compound of any one of Embodiments 1 to 90.

[0237] Embodiment 94. R c is Cl or F, a compound of Embodiment 93.

[0238] Embodiment 95. R c is CF3, a compound of any one of Embodiments 1 to 90.

[0239] Embodiment 96. R c is C(H)F2, a compound of any one of Embodiments 1 to 90.

[0240] Embodiment 97. R c is C(F)H2, a compound of any one of Embodiments 1 to 90.

[0241] Embodiment 98. R c is unsubstituted -(C1-C3) alkylene -N-(R x )(R y ), a compound of any one of Embodiments 1 to 90.

[0242] Embodiment 99. R c is substituted -(C1-C3) alkylene -N-(R x )(R y ) substituted with F or OMe, a compound of any one of Embodiments 1 to 90.

[0243] Embodiment 100. R x is H, a compound of any one of Embodiments 1 to 99.

[0244] Embodiment 101. R x is unsubstituted (C1-C6)-alkyl, a compound of any one of Embodiments 1 to 99.

[0245] Embodiment 102. R y is H, a compound of any one of Embodiments 1 to 100.

[0246] Embodiment 103. R y is unsubstituted (C1-C6)-alkyl, a compound of any one of Embodiments 1 to 100.

[0247] Embodiment 104. R x and R y together with the N to which they are attached form an unsubstituted 4- to 6-membered ring, a compound of any one of Embodiments 1 to 72, 80 to 81, 89 to 90, and 98 to 99.

[0248] Embodiment 105. R x and R y together with the N to which they are attached form a substituted 4- to 6-membered ring substituted with at least one halide, substituted or unsubstituted (C1-C4) alkyl, or OMe, a compound of any one of Embodiments 1 to 72, 80 to 81, 89 to 90, and 98 to 99.

[0249] Embodiment 106. The compound of Embodiment 104 or 105, wherein the 4- to 6-membered ring is 3- to 6-membered hetero cycloalkyl.

[0250] Embodiment 107. The compound of Embodiment 104 or 105, wherein the 4- to 6-membered ring is 4- to 5-membered hetero cycloalkyl.

[0251] Embodiment 108. Formula (Ia):

Chemical formula

[0252] Embodiment 109. The compound of Embodiment 108, wherein R 5a and R 5e are independently unsubstituted (C1-C4) alkyl.

[0253] Embodiment 110. The compound of Embodiment 108 or 109, wherein R b is unsubstituted -(C1-C3) alkylene-N(R x )(R y ).

[0254] Embodiment 111. R aThe compound of Embodiment 1 or 108, wherein R is selected from the group consisting of H, C(H)F2, CF3, and Me.

[0255] Embodiment 112. R b is

Chemical formula

[0256] Embodiment 113. R b is

Chemical formula

[0257] Embodiment 114. R c is H or F, the compound of Embodiment 1 or 108.

[0258] Embodiment 115. R1 is

Chemical formula

[0259] Embodiment 116. R 5a is CF3, the compound of any one of Embodiments 108 - 115.

[0260] Embodiment 117. R 5a is C(H)F2, the compound of any one of Embodiments 108 - 115.

[0261] Embodiment 118. R 5a is C(F)H2, the compound of any one of Embodiments 108 - 115.

[0262] Embodiment 119. R 5a is methyl, the compound of any one of Embodiments 108 - 115.

[0263] Embodiment 120. R 5a A compound according to any one of Embodiments 108 to 115, wherein R is OMe.

[0264] Embodiment 121. R 5a A compound according to any one of Embodiments 108 to 115, wherein R is F or Cl.

[0265] Embodiment 122. R 5b A compound according to any one of Embodiments 108 to 121, wherein R is H.

[0266] Embodiment 123. R 5b A compound according to any one of Embodiments 108 to 121, wherein R is CF3.

[0267] Embodiment 124. R 5b A compound according to any one of Embodiments 108 to 121, wherein R is C(H)F2.

[0268] Embodiment 125. R 5b A compound according to any one of Embodiments 108 to 121, wherein R is C(F)H2.

[0269] Embodiment 126. R 5b A compound according to any one of Embodiments 108 to 121, wherein R is methyl.

[0270] Embodiment 127. R 5b A compound according to any one of Embodiments 108 to 121, wherein R is OMe.

[0271] Embodiment 128. R 5b A compound according to any one of Embodiments 108 to 121, wherein R is F or Cl.

[0272] Embodiment 129. R 5c A compound according to any one of Embodiments 108 to 128, wherein R is H.

[0273] Embodiment 130. R 5cA compound of any one of Embodiments 108 to 128, wherein it is CF3.

[0274] Embodiment 131. R 5c A compound of any one of Embodiments 108 to 128, wherein it is C(H)F2.

[0275] Embodiment 132. R 5c A compound of any one of Embodiments 108 to 128, wherein it is C(F)H2.

[0276] Embodiment 133. R 5c A compound of any one of Embodiments 108 to 128, wherein it is methyl.

[0277] Embodiment 134. R 5c A compound of any one of Embodiments 108 to 128, wherein it is OMe.

[0278] Embodiment 135. R 5c A compound of any one of Embodiments 108 to 128, wherein it is F or Cl.

[0279] Embodiment 136. R 5d A compound of any one of Embodiments 108 to 135, wherein it is H.

[0280] Embodiment 137. R 5d A compound of any one of Embodiments 108 to 135, wherein it is CF3.

[0281] Embodiment 138. R 5d A compound of any one of Embodiments 108 to 135, wherein it is C(H)F2.

[0282] Embodiment 139. R 5d A compound of any one of Embodiments 108 to 135, wherein it is C(F)H2.

[0283] Embodiment 140. R 5d A compound of any one of Embodiments 108 to 135, wherein it is methyl.

[0284] Embodiment 141. R 5d is OMe, a compound of any one of Embodiments 108 to 135.

[0285] Embodiment 142. R 5d is F or Cl, a compound of any one of Embodiments 108 to 135.

[0286] Embodiment 143. R 5e is CF3, a compound of any one of Embodiments 108 to 142.

[0287] Embodiment 144. R 5e is C(H)F2, a compound of any one of Embodiments 108 to 142.

[0288] Embodiment 145. R 5e is C(F)H2, a compound of any one of Embodiments 108 to 142.

[0289] Embodiment 146. R 5e is methyl, a compound of any one of Embodiments 108 to 142.

[0290] Embodiment 147. R 5e is OMe, a compound of any one of Embodiments 108 to 142.

[0291] Embodiment 148. R 5e is F or Cl, a compound of any one of Embodiments 108 to 142.

[0292] Embodiment 149. R 5b , R 5c and R 5d at least one of which is H, a compound of any one of Embodiments 1 and 108 to 121.

[0293] Embodiment 150. R 5b , R 5c and R 5d at least two of which are H, a compound of any one of Embodiments 1 and 108 to 121.

[0294] Embodiment 151. R 5b , R 5c and R 5d is H, a compound of any one of Embodiments 1 and 108 - 121.

[0295] Embodiment 152. R 3a is H, a compound of any one of Embodiments 1 and 108 - 151.

[0296] Embodiment 153. R 3a is methyl, a compound of any one of Embodiments 1 and 108 - 151.

[0297] Embodiment 154. R 3a is a halide, a compound of any one of Embodiments 1 and 108 - 151.

[0298] Embodiment 155. R 3a is CF3, a compound of any one of Embodiments 1 and 108 - 151.

[0299] Embodiment 156. R 3a is C(H)F2, a compound of any one of Embodiments 1 and 108 - 151.

[0300] Embodiment 157. R 3a is C(F)H 2. and is a compound of any one of Embodiments 1 and 108 - 151.

[0301] Embodiment 158. R 3a is OMe, a compound of any one of Embodiments 1 and 108 - 151.

[0302] Embodiment 159. R 3b is H, a compound of any one of Embodiments 1 and 108 - 158.

[0303] Embodiment 160. R 3bThe compound of any one of Embodiments 1 and 108 to 158, wherein R is methyl.

[0304] Embodiment 161. R 3b The compound of any one of Embodiments 1 and 108 to 158, wherein R is a halide.

[0305] Embodiment 162. R 3b The compound of any one of Embodiments 1 and 108 to 158, wherein R is CF3.

[0306] Embodiment 163. R 3b The compound of any one of Embodiments 1 and 108 to 158, wherein R is C(H)F2.

[0307] Embodiment 164. R 3b The compound of any one of Embodiments 1 and 108 to 158, wherein R is C(F)H2.

[0308] Embodiment 165. R 3b The compound of any one of Embodiments 1 and 108 to 158, wherein R is OMe.

[0309] Embodiment 166. R 3b The compound of any one of Embodiments 1 and 108 to 158, wherein R is OCF3.

[0310] Embodiment 167. R 3b The compound of any one of Embodiments 1 and 108 to 158, wherein R is cyclopropyl.

[0311] Embodiment 168. R 3a is methyl and R 3b is F, the compound of any one of Embodiments 108 to 151.

[0312] Embodiment 169. R 3a is F and R 3b is methyl, the compound of any one of Embodiments 108 to 151.

[0313] The compound of Embodiment 1 selected from any one of the compounds of FIG. 1 or their enantiomers.

[0314] Embodiment 171. Formula (Ic):

Chemical formula

[0315] Embodiment 172. (3S)-3-(4,5-Difluoro-2',6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; (3S)-3-(2-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid; (3S)-3-(2-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid; (3S)-3-(2-(5-(2-(Azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid; (3S)-3-(4,4'-Difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(5-Chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoic acid; (3S)-3-(4,4'-Difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoic acid; (3S)-3-(4-Fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(4-Fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; and (3S)-3-(5-Chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0316] Embodiment 173. The compound:

Chemical formula

[0317] Embodiment 174. The compound:

Chemical formula

[0318] Embodiment 175. The compound:

Chemical formula

[0319] Embodiment 176. The compound:

Chemical formula

[0320] Embodiment 177. Compound:

Chemical formula

[0321] Embodiment 178. Compound:

Chemical formula

[0322] Embodiment 179. Compound:

Chemical formula

[0323] Embodiment 180. Compound:

Chemical formula

[0324] Embodiment 181. Compound:

Chemical formula

[0325] Embodiment 182. Compound:

Chemical formula

[0326] Embodiment 183. Compound: [Chemical formula] The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0327] Embodiment 184. Compound: [Chemical formula] The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0328] Embodiment 185. (3S)-3-(4,5-difluoro-2',6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof, which is the compound of Embodiment 1.

[0329] Embodiment 186. (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, which is the compound of Embodiment 1.

[0330] Embodiment 187. (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, which is the compound of Embodiment 1.

[0331] The compound of Embodiment 1, which is (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0332] The compound of Embodiment 1, which is (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0333] The compound of Embodiment 1, which is (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0334] The compound of Embodiment 1, which is (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0335] The compound of Embodiment 1, which is (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0336] Embodiment 193. The compound of Embodiment 1, which is (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamide)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0337] Embodiment 194. The compound of Embodiment 1, which is (3S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0338] Embodiment 195. The compound of Embodiment 1, which is (3S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0339] Embodiment 196. The compound of Embodiment 1, which is (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0340] The compound of Embodiment 1, which is (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0341] The compound of Embodiment 1, which is (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0342] The compound of Embodiment 1, which is (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0343] The compound of Embodiment 1, which is (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0344] The compound of Embodiment 1, which is (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0345] Embodiment 202. The compound of Embodiment 1, which is (S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0346] Embodiment 203. The compound of Embodiment 1, which is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0347] Embodiment 204. The compound of Embodiment 1, which is (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0348] Embodiment 205. The compound of Embodiment 1, which is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamide)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0349] Embodiment 206. The compound of Embodiment 1, which is (S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0350] Embodiment 207. The compound of Embodiment 1, which is (S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0351] Embodiment 208. The compound of Embodiment 1, which is (S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

[0352] Embodiment 209. A pharmaceutical composition comprising a compound of any one of Embodiments 1 to 208 and a pharmaceutically acceptable excipient.

[0353] Embodiment 210. A method for inhibiting α4β7 integrin in a cell, comprising contacting the cell with a compound of any one of Embodiments 1 to 208 under conditions effective to reduce the adhesion of the cell to MAdCAM-1.

[0354] A method for reducing the adhesion of cells containing α4β7 integrin to MAdCAM-1, which comprises contacting the cells with a compound according to any one of Embodiments 1 to 208 under conditions effective for reducing the adhesion of the cells to MAdCAM-1.

[0355] Embodiment 212. A method for treating inflammatory bowel disease, ulcerative colitis or Crohn's disease, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of Embodiments 1 to 208.

[0356] [Example 1] General scheme for the synthesis of α4β7 inhibitors Synthesis of β-amino acids The synthesis of β-amino acids can be achieved using well-known procedures described in the literature, for example, "Enantioselective Synthesis of β-Amino Acids", 2nd Edition, Editors: Eusebio Juaristi, Vadim A. Soloshonok, First published: January 27, 2005, John Wiley & Sons, Inc., Ellman et al., Acc. Chem. Res. 2002, 35, pp. 984-995; Franklin A. Davis and Bang-Chi Chen, Chem. Soc. Rev., 1998, 27, pp. 13-18; Jacobsen, M. F., Skrydstrup, T., J. Org. Chem. 2003, 68, p. 7122; Tang, T. P., Ellman, J. A., J. Org. Chem. 2002, 67, p. 7819; and Tang, T. P., Ellman, J. A., J. Org. Chem. 1999, 64, p. 12, but not limited thereto.

[0357] Reductive amination

[0358] [Chemical formula] Procedure A: A mixture of amine (1 equiv), aldehyde (1.2 equiv) in DCM (1 - 2 mL / mmol amine) was stirred at room temperature for 30 minutes. Then, NaBH(OAc)3 (1.5 equiv) was added portionwise and stirred overnight at room temperature. The solvent was concentrated in vacuo and the residue was purified by silica gel chromatography to afford the desired amine. Procedure B: A mixture of aldehyde (1 equiv), amine (1.05 - 2 equiv) in DCE (3 - 4 mL / mmol aldehyde) was stirred at room temperature for 10 - 30 minutes. Then, NaBH(OAc)3 (3 - 4 equiv) was added portionwise and stirred at room temperature for 1 - 16 hours until completion by LC / MS. The solvent was concentrated in vacuo and the residue was purified by silica gel chromatography to afford the desired amine. Procedure C: A mixture of aldehyde (1 equiv), AcOH (1.2 equiv), amine (1.05 - 2 equiv) in DCM (2 - 3 mL / mmol aldehyde) and MeOH (0.5 mL / mmol aldehyde) was stirred at room temperature for 15 - 30 minutes. Then, NaBH(OAc)3 (2 equiv) was added portionwise and stirred at room temperature for 1 - 16 hours until completion by LC / MS. The solvent was concentrated in vacuo and the residue was purified by silica gel chromatography to afford the desired amine.

[0359] Alkylation

[0360]

Chem.

[0361]

Chem.

[0362] Phenol Deprotection

[0363]

Chem.

[0364] Wittig Reaction

[0365]

Chem.

[0366] From enol ether to aldehyde

[0367]

Chem.

[0368] Stille reaction

[0369]

Chem.

[0370] From alkene to aldehyde

[0371]

Chem.

[0372] From ester to acid

[0373]

Chem.

[0374] Amine protection

[0375]

Chem.

[0376] Preparation of Arylborane

[0377]

Chemical Structure

[0378] Suzuki Coupling “Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds”, N. Miyaura, A. Suzuki Chem. Rev. 1995, 957, 2457 - 2483.

[0379]

Chemical Structure

[0380]

Chem.

[0381]

Chem.

[0382] Boc Deprotection

[0383]

Chem.

[0384]

Chem.

[0385] Amide bond formation “Peptide Coupling Reagents, More than a Letter Soup”, A. El-Faham, F. Albericio Chem. Rev. 2011, 111, 11, pp. 6557 - 6602; “Amide bond formation and peptide coupling”, C. A. G. N. Montalbetti, V. Falque Tetrahedron 2005, 61, 10827 - 10852.

[0386]

Chem.

[0387] Ester hydrolysis

[0388]

Chem.

[0389] Analysis method LCMS analysis method The final compound was analyzed using LC / MS conditions with a UV detector monitoring at 214 nm and 254 nm and a mass spectrometry scan in the ESI+ ionization mode from 110 to 800 amu. LC / MS A: Column: XBridge C18, 4.6×50 mm, 3.5 μm; Mobile phase: A water (10 mM ammonium bicarbonate), B CH3CN, Gradient: 5% - 95% B at 1.4 minutes, then held for 1.6 minutes, Flow rate: 1.8 mL / min, Oven temperature 50 °C. LC / MS B: Column: SunFire C18, 4.6×50 mm, 3.5 μm, Mobile phase: A water (0.01% TFA), B CH3CN, Gradient: 5% - 95% B at 1.5 minutes, then held for 1.5 minutes, Flow rate: 2.0 mL / min, Oven temperature 50 °C. LC / MS C: Column: XBridge C18, 4.6×50 mm, 3.5 μm, Mobile phase: A water (10 mM ammonium bicarbonate), B CH3CN, Gradient: 5% - 95% B at 1.5 minutes, then held for 1.5 minutes, Flow rate: 1.8 mL / min, Oven temperature 50 °C. LC / MS D: Column: Poroshell 120 EC-C138, 4.6×30 mm, 2.7 μm, Mobile phase: A water (0.01% TFA), B CH3CN (0.01% TFA), Gradient: 5% - 95% B at 1.2 minutes, then held for 1.8 minutes, Flow rate: 2.2 mL / min, Oven temperature 50 °C.

[0390] [Example 2] Preparation of intermediate Preparation of Ethyl (S)-3-(5-Bromo-2-fluoro-3-methylphenyl)-3-((tert-butoxycarbonyl)amino)propanoate

[0391] Step 1: 5-Bromo-2-fluoro-3-methylbenzaldehyde

[0392]

Chem.

[0393] Step 2: (R,E)-N-(5-Bromo-2-fluoro-3-methylbenzylidene)-2-methylpropane-2-sulfinamide

[0394]

Chem.

[0395] Step 3: Ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate Ethyl 2-bromoacetate +

[0396]

Chemical Structure

[0397] Step 4: Ethyl (S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate

[0398] [Chemical formula] A solution of ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate (8.0 g, 19.6 mmol, 1.00 equiv) in DCM (20 mL) was added with HCl-dioxane (4 M, 20 mL, 80.0 mmol, 4.08 equiv), and the mixture was stirred at room temperature for 4 h. LCMS indicated that the reaction was complete. The mixture was filtered and concentrated in vacuo to obtain the crude product ethyl (S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate as a yellow oil (8.0 g), which was used in the next step without further purification. Yield 100% (ESI 304.2 [M+H] + ).

[0399] Step 5: Ethyl (S)-ethyl 3-(5-bromo-2-fluoro-3-methylphenyl)-3-(tert-butoxycarbonylamino)propanoate

[0400]

Chemical Structure

[0401] Preparation of Ethyl (S)-3-((tert-Butoxycarbonyl)amino)-3-(2-Fluoro-3-Methyl-5-(4,4,5,5-Tetramethyl-1,3,2-Dioxaborolan-2-Yl)phenyl)Propanoate

[0402]

Chem.

[0403] Preparation of Ethyl (S)-3-Amino-3-(2',4-Difluoro-5,6'-Dimethyl-[1,1'-Biphenyl]-3-Yl)Propanoate

[0404] Step 1: Ethyl (S)-3-((tert-Butoxycarbonyl)amino)-3-(2',4-Difluoro-5,6'-Dimethyl-[1,1'-Biphenyl]-3-Yl)Propanoate

[0405]

Chem.

[0406] Step 2: Ethyl (S)-3-amino-3-(2',4-difluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0407] [Chemical Structure] To a stirred solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4-difluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (210 mg, 0.48 mmol, 1.0 equiv) in DCM (2 mL) was added HCl-dioxane (4 M, 3.0 mL, 6.0 mmol, 12.5 equiv). The mixture was stirred at room temperature for 2 h. LCMS indicated that the reaction was complete. The mixture was concentrated in vacuo to afford ethyl (S)-3-amino-3-(2',4-difluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate as a colorless oil (160 mg). Yield 99% (ESI 334.1 [M+H] + ).

[0408] Preparation of Ethyl (S)-3-amino-3-(2'-cyano-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate Hydrochloride

[0409] Step 1: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-cyano-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0410] [Chemical formula] To a solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (350 mg, 0.77 mmol, 1.0 equiv) in dioxane (10 mL) were added 2-bromo-3-methylbenzonitrile (226 mg, 1.16 mmol, 1.5 equiv), Pd(dppf)Cl2 (56 mg, 0.077 mmol), K2CO3 (193 mg, 1.4 mmol, 1.8 equiv) and water (2 mL). The reaction mixture was stirred at 110 °C for 3 h under a nitrogen atmosphere. Water (20 mL) was added and the solution was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4、 It was filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 4:1) to give ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-cyano-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate as a colorless oil (260 mg). Yield 76% (ESI 341.1 [M+H-100] + )

[0411] Step 2: Ethyl (S)-3-amino-3-(2'-cyano-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0412]

Chemical formula

[0413] Preparation of ethyl (S)-3-amino-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0414] Step 1: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0415] [Chemical formula] Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (1.0 g, 2.22 mmol, 1.00 equiv), 2-bromo-1-chloro-3-methylbenzene (543 mg, 2.66 mmol, 1.20 equiv), K2CO3 (613 mg, 4.44 mmol, 2.0 equiv) and Pd(dppf)Cl2 (81 mg, 0.11 mmol, 0.05 equiv) in a mixture of dioxane (10 mL) and H2O (2 mL) was stirred at 110 °C for 2 h under a nitrogen atmosphere. Water (30 mL) was added and the solution was extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 2:1) to give ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate as a colorless oil (800 mg). Yield 80% (ESI 450.18 [M+H] + ).

[0416] Step 2: Ethyl (S)-3-amino-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0417] [Chemical formula] A mixture of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (300 mg, 0.67 mmol, 1.00 equiv) in DCM (9 mL) was added to HCl-dioxane (4 M, 9.0 mL, 36.0 mmol, 53.73 equiv), and the mixture was stirred at room temperature for 1 h. LCMS indicated that the reaction was complete. The mixture was concentrated in vacuo to give ethyl (S)-3-amino-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate as a white solid (200 mg), which was used directly in the next reaction without further purification. Yield 86% (ESI 350.1 [M+H] + ).

[0418] Preparation of ethyl (S)-3-amino-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0419] Step 1: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0420] [Chemical formula] (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (500 mg, 1.12 mmol, 1.00 equiv), cyclopropylboronic acid (116 mg, 1.35 mmol, 1.20 equiv), K3PO4 (475 mg, 2.24 mmol, 2.00 equiv), PCy3 (31 mg, 0.11 mmol, 0.10 equiv) and Pd(OAc)2 (11 mg, 0.11 mmol, 0.10 equiv) in dioxane (10 mL) and H2O (2 mL) were stirred at 110 °C for 36 h under a nitrogen atmosphere. Water (30 mL) was added and the solution was extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 2:1) to give (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate as a colorless oil (400 mg). Yield 79% (ESI 456.2 [M+H] + )

[0421] Step 2: (S)-Ethyl 3-amino-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0422] [Chemical formula] A mixture of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (400 mg, 0.88 mmol, 1.0 equiv) in DCM (9 mL) was added to HCl-dioxane (4 M, 9.0 mL, 36.0 mmol, 40.9 equiv), and the mixture was stirred at room temperature for 1 hour. LCMS indicated that the reaction was complete. The mixture was concentrated in vacuo to give ethyl (S)-3-amino-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate as a white solid (300 mg), which was used directly in the next reaction without further purification. Yield 96% (ESI 356.2 [M+H] + ).

[0423] Preparation of ethyl (S)-3-amino-3-(4-fluoro-4'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0424] Step 1: Ethyl (S)-3-amino-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0425] [Chemical formula] To a solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (350 mg, 0.77 mmol, 1.0 equiv) in dioxane (10 mL) were added 1-ethyl-2-iodo-3-methylbenzene (286 mg, 1.16 mmol, 1.5 equiv), Pd(dppf)Cl2 (56 mg, 0.077 mmol, 0.1 equiv), K2CO3 (193 mg, 1.4 mmol, 1.8 equiv) and water (2 mL). The reaction mixture was stirred at 110 °C for 3 h under a nitrogen atmosphere. Water (10 mL) was added and the solution was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (60 mL) and dried over anhydrous Na2SO4 、 filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 4:1) to give ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate as a colorless oil (240 mg). Yield 70% (ESI 344.2 [M+H-100] + ).

[0426] Step 2: Ethyl (S)-3-amino-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0427] [Chemical formula] To a stirred solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (210 mg, 0.47 mmol, 1.0 equiv) in DCM (2 mL) was added HCl-dioxane (4 M, 3.0 mL, 6.0 mmol, 12.8 equiv). The mixture was stirred at room temperature for 1 h. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo to afford ethyl (S)-3-amino-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride as a colorless oil (170 mg). Yield 94% (ESI 344.1 [M+H] + ).

[0428] Preparation of (S)-ethyl 3-amino-3-(4-fluoro-2'-methoxy-5,6'-dimethylbiphenyl-3-yl)propanoate

[0429] Step 1: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoate

[0430] [Chemical formula] (S)-Ethyl 3-(tert-butoxycarbonylamino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (1 g, 2.22 mmol, 1.0 equiv), 2-bromo-1-methoxy-3-methylbenzene (666 mg, 3.33 mmol, 1.5 equiv), K2CO3 (919 mg, 6.66 mmol, 3.0 equiv) and Pd(dppf)Cl2 (162 mg, 0.222 mmol, 0.1 equiv) in a mixture of dioxane (15 mL) and H2O (1.5 mL) was stirred at 100 °C for 3 h under a nitrogen atmosphere. LCMS indicated that the reaction was complete. The reaction mixture was cooled to room temperature. Water (50 mL) was added and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 2:1) to give (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-2'-methoxy-5,6'-dimethylbiphenyl-3-yl)propanoate as a yellow oil (0.96 g). Yield 97% (ESI 346.1 [M+H] + ).

[0431] Step 2: (S)-Ethyl 3-amino-3-(4-fluoro-2'-methoxy-5,6'-dimethylbiphenyl-3-yl)propanoate

[0432] [Chemical Structure] (S)-Ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-2'-methoxy-5,6'-dimethylbiphenyl-3-yl)propanoate (0.96 g, 2.15 mmol, 1.0 equiv) was added to a stirred solution in DCM (7 mL) with HCl-dioxane (4 M, 2.15 mL, 4 equiv), and the mixture was stirred at 25 °C for 2 h. LCMS indicated the completion of the reaction. The mixture was concentrated in vacuo, and the residue was purified by reverse-phase HPLC on a C18 / 40 g column (A: water, 10 mM NH4HCO3, B: MeOH, 0–100%) to give (S)-ethyl 3-amino-3-(4-fluoro-2'-methoxy-5,6'-dimethylbiphenyl-3-yl)propanoate as a yellow oil (0.6 g). Yield 81% (ESI 346.1 [M+H] + ).

[0433] Preparation of (S)-ethyl 3-amino-3-(4-fluoro-2'-methoxy-5-methyl-6'-(trifluoromethyl)biphenyl-3-yl)propanoate

[0434] Step 1: 1-Methoxy-2-nitro-3-(trifluoromethyl)benzene

[0435] [Chemical formula] To a mixture of 2-nitro-3-(trifluoromethyl)phenol (1.5 g, 7.25 mmol, 1.0 equiv) in acetone (20 mL) were added K2CO3 (3 g, 21.75 mmol, 3 equiv) and CH3I (5.15 g, 36.25 mmol, 5 equiv), and the mixture was stirred at room temperature for 16 h. LCMS indicated the completion of the reaction. The reaction mixture was filtered and washed with EtOAc (20 mL). The filtrate was concentrated in vacuo, and the residue was purified by a silica gel column (petroleum ether:EtOAc 2:1) to give 1-methoxy-2-nitro-3-(trifluoromethyl)benzene as a white solid (1.3 g). Yield 81%.

[0436] Step 2: 2-Methoxy-6-(trifluoromethyl)aniline

[0437]

Chem.

[0438] Step 3: 2-Bromo-1-methoxy-3-(trifluoromethyl)benzene

[0439]

Chem.

[0440] Step 4: (S)-Ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-2'-methoxy-5-methyl-6'-(trifluoromethyl)biphenyl-3-yl)propanoate

[0441]

Chem.

[0442] Step 5: (S)-ethyl 3-amino-3-(4-fluoro-2'-methoxy-5-methyl-6'-(trifluoromethyl)biphenyl-3-yl)propanoate

[0443]

Chemical formula

[0444] Preparation of (S)-ethyl 3-amino-3-(2',6'-dichloro-4-fluoro-5-methylbiphenyl-3-yl)propanoate

[0445] Step 1: (S)-Ethyl 3-(tert-butoxycarbonylamino)-3-(2',6'-dichloro-4-fluoro-5-methylbiphenyl-3-yl)propanoate

[0446]

Chemical formula

[0447] Step 2: (S)-Methyl 3-amino-3-(2',6'-dichloro-4-fluoro-5-methylbiphenyl-3-yl)propanoate

[0448]

Chem.

[0449] Preparation of Ethyl (S)-3-Amino-3-(2',4-Difluoro-4',5,6'-Trimethyl-[1,1'-Biphenyl]-3-Yl)Propanoate

[0450] Step 1: 2-Fluoro-4,6-Dimethylaniline

[0451]

Chem.

[0452] Step 2: 2-Bromo-1-Fluoro-3,5-Dimethylbenzene

[0453]

Chem.

[0454] Step 3: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4-difluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0455]

Chem.

[0456] Step 4: (S)-Ethyl 3-amino-3-(2',4-difluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0457] [Chemical formula] A stirred solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4-difluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (720 mg, 1.29 mmol, 1.0 equiv) in DCM (2 mL) was treated with HCl-dioxane (4 M, 2.0 mL, 4.0 mmol, 3.1 equiv) and stirred at room temperature for 1 h. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo to afford ethyl (S)-3-amino-3-(2',4-difluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate as a yellow oil (450 mg). Yield 93% (ESI 348.1 [M+H] + ).

[0458] Preparation of (S)-ethyl 3-amino-3-(2',6'-dichloro-4-fluoro-4',5-dimethylbiphenyl-3-yl)propanoate

[0459] Step 1: 1,3-Dichloro-2-iodo-5-methylbenzene

[0460]

Chemical formula

[0461] Step 2: (S)-Ethyl 3-(tert-butoxycarbonylamino)-3-(2',6'-dichloro-4-fluoro-4',5-dimethylbiphenyl-3-yl)propanoate

[0462]

Chem.

[0463] Step 3: (S)-Ethyl 3-amino-3-(2',6'-dichloro-4-fluoro-4',5-dimethylbiphenyl-3-yl)propanoate

[0464]

Chem.

[0465] Preparation of ethyl (S)-3-amino-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0466] Step 1: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0467]

Chemical Structure

[0468] Step 2: (S)-Ethyl 3-amino-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0469] [Chemical formula] To a stirred solution of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (4.0 g, 9.2 mmol, 1.00 equiv) in DCM (6 mL) was added HCl-dioxane (4 M, 4 mL, 16.0 mmol, 1.7 equiv). The mixture was stirred at room temperature for 30 min. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18 / 120 g column (A: water, 10 mM NH4HCO3, B: MeOH, 0 - 100%) to give ethyl (S)-3-amino-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (2.0 g) as a colorless oil. Yield 61% (ESI 330.1 [M+H] + ).

[0470] Preparation of ethyl (S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0471] Step 1: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0472] [Chemical formula] (S)-Ethyl 3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate (6.0 g, 14.7 mmol, 1.00 equiv), (4-fluoro-2,6-dimethylphenyl)boronic acid (3.7 g, 22.1 mmol, 1.5 equiv), K2CO3 (6.1 g, 44.1 mmol, 3.0 equiv) and Pd(dppf)Cl2 (1.1 g, 1.47 mmol, 0.01 equiv) in a mixture of dioxane (50 mL) and H2O (5 mL) was stirred at 110 °C for 1 h under a nitrogen atmosphere. LCMS indicated that the reaction was complete. The mixture was cooled to room temperature. Water (50 mL) was added and the solution was extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (30 mL) and dried over anhydrous Na2SO4 、 filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 1:1) to give (S)-ethyl 3-(((R)-tert-butylsulfinyl)amino)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate as a yellow oil (5.5 g). Yield 83% (ESI 452.0 (M+H) + ).

[0473] Step 2: (S)-Ethyl 3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0474] [Chemical formula] A solution of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (5.5 g, 12.2 mmol, 1.00 equiv) in DCM (6 mL) was added to HCl-dioxane (4 M, 6 mL, 24.0 mmol, 1.97 equiv), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, and the residue was purified by reverse-phase HPLC on a C18 / 120 g column (A: water / 0.01% TFA, B: MeOH, 0 - 100%) to give ethyl (S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate as a yellow solid (4.0 g). Yield 95% (ESI 348.1 (M+H) + ).

[0475] Preparation of ethyl (S)-3-amino-3-(4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0476] Step 1: 2-(4-chloro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0477] [Chemical formula] To a solution of 2-bromo-5-chloro-1,3-dimethylbenzene (4.0 g, 18.2 mmol, 1.0 equiv) in anhydrous THF (40 mL) was added n-BuLi (2 N, 11.0 mL, 22.0 mmol, 1.2 equiv) at -78 °C under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 40 minutes, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.1 g, 27.5 mmol, 1.5 equiv) in anhydrous THF (40 mL) was added, and the mixture was stirred at -78 °C for 3 hours. After completion, saturated NH4Cl solution (aqueous) (100 mL) was added. The mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel (petroleum ether:EtOAc 2:1) to obtain the desired 2-(4-chloro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a white solid (4.4 g). Yield 90%.

[0478] Step 2: Ethyl (S)-3-amino-3-(4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0479] [Chemical formula] A mixture of ethyl (S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate (500 mg, 1.7 mmol, 1.0 equiv), 2-(4-chloro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (544 mg, 2.04 mmol, 1.2 equiv), Pd(dppf)Cl2 (62 mg, 0.085 mmol, 0.05 equiv), and K2CO3 (704 mg, 5.1 mmol, 3.0 equiv) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 110 °C for 2 hours under a nitrogen atmosphere. Water (20 mL) was added, and the solution was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 、It was filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 1:2) to give ethyl (S)-3-amino-3-(4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate as a colorless oil (250 mg). Yield 41% (ESI 364.2 [M+H] + ).

[0480] Preparation of ethyl (S)-3-amino-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoate

[0481] Step 1: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoate

[0482] [Chemical formula] (S)-Ethyl 3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate (3.8 g, 9.3 mmol, 1.0 equiv), mesitylboronic acid (3.05 g, 18.6 mmol, 2.0 equiv), K2CO3 (3.85 g, 27.9 mmol, 3.0 equiv) and Pd(dppf)Cl2 (340 mg, 0.465 mmol, 0.05 equiv) in a mixture of dioxane (30 mL) and H2O (5 mL) were stirred at 110 °C for 2 h under a nitrogen atmosphere. LCMS indicated that the reaction was complete. The reaction mixture was cooled to room temperature. Water (80 mL) was added and the mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 1:1) to give (S)-ethyl 3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoate as a yellow oil (3.1 g). Yield 75% (ESI 448.2 [M+H] + ).

[0483] Step 2: (S)-Ethyl 3-amino-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoate

[0484] [Chemical formula] A stirred solution of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoate (3.1 g, 6.94 mmol, 1.0 equiv) in DCM (7 mL) was treated with HCl-dioxane (4 M, 6.8 mL, 3.9 equiv) and stirred at 25 °C for 2 h. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18 / 40 g column (A: water, 10 mM NH4HCO3, B: MeOH, 0 - 100%) to afford (S)-ethyl 3-amino-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoate as a yellow oil (1.6 g). Yield 67% (ESI 344.2 [M+H] + ).

[0485] [Example] Preparation of Ethyl (S)-3-Amino-3-(4-fluoro-2',5,6'-trimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate Hydrochloride

[0486] Step 1: 2,6-Dimethyl-4-(trifluoromethyl)aniline

[0487] [Chemical formula] 2,6-Dibromo-4-(trifluoromethyl)aniline (638 mg, 2.00 mmol, 1.0 equiv), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (3.5 M in THF, 3.43 mL, 12.00 mmol, 6.0 equiv), K2CO3 (1.10 g, 7.96 mmol, 3.98 equiv) and Pd(dppf)Cl2 (245 mg, 0.30 mmol, 0.15 equiv) in dioxane (6 mL) and water (1 mL) were stirred at 90 °C for 8 h under a nitrogen atmosphere. The mixture was filtered through a pad of celite, washed with ethyl acetate (100 mL), and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 20:1) to afford 2,6-dimethyl-4-(trifluoromethyl)aniline as a colorless oil (1.63 g). Yield 48% (ESI 190.1 (M+H) + ).

[0488] Step 2: 2-Bromo-1,3-dimethyl-5-(trifluoromethyl)benzene

[0489] [Chemical formula] A mixture of 2,6-dimethyl-4-(trifluoromethyl)aniline (793 mg, 4.19 mmol, 1.0 equiv), tert-butyl nitrite (0.94 mL, 7.84 mmol, 1.9 equiv) and copper(I) bromide (794 mg, 5.53 mmol, 1.3 equiv) in anhydrous acetonitrile (16 mL) was stirred at 60 °C for 2 h under a nitrogen atmosphere. LCMS indicated that the reaction was complete. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 6:1) to afford 2-bromo-1,3-dimethyl-5-(trifluoromethyl)benzene as a colorless oil (975 mg). Yield 46%. 1 H NMR (400 MHz, DMSO-d6) δ: 7.55 (s, 2H), 2.42 (s, 6H).

[0490] Step 3: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2',5,6'-trimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate

[0491]

Chem.

[0492] Step 5: Ethyl (S)-3-amino-3-(4-fluoro-2',5,6'-trimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0493]

Chem.

[0494] Preparation of ethyl (S)-3-amino-3-(4'-cyclopropyl-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0495] Step 1: 4-Cyclopropyl-2,6-dimethylaniline

[0496] [Chemical formula] To a mixture of 4-bromo-2,6-dimethylaniline (2.0 g, 10.0 mmol, 1.0 equiv) and cyclopropylboronic acid (1.03 g, 12.0 mmol, 1.2 equiv) in toluene (15 mL) under a nitrogen atmosphere was added a solution of K3PO4 (4.2 g, 20.0 mmol, 2.0 equiv) in H2O (3 mL), tricyclohexylphosphine (280.0 mg, 1.0 mmol, 0.1 equiv) and Pd(OAc)2 (224.0 mg, 1.0 mmol, 0.1 equiv). The mixture was stirred at 100 °C for 4 h under a nitrogen atmosphere. Water (30 mL) was added and the solution was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4 、It was filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 2:1) to give 4-cyclopropyl-2,6-dimethylaniline (0.8 g), which was used in the next step without further purification. Yield 93% (ESI 162.2 [M+H] + ).

[0497] Step 2: 2-Bromo-5-cyclopropyl-1,3-dimethylbenzene

[0498]

Chem.

[0499] Step 3: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-cyclopropyl-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0500]

Chem.

[0501]

[0502]

Chemical formula

[0503] Preparation of ethyl (S)-3-amino-3-(4-fluoro-4'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0504] Step 1: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-4'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0505] [Chemical formula] To a solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (350 mg, 0.77 mmol, 1.0 equiv) in dioxane (10 mL) were added 2-bromo-5-methoxy-1,3-dimethylbenzene (166 mg, 0.77 mmol, 1.0 equiv), Pd(dppf)Cl2 (56 mg, 0.077 mmol, 0.1 equiv), K2CO3 (213 mg, 1.54 mmol, 2.0 equiv) and water (2 mL). The reaction mixture was stirred at 110 °C for 3 h under a nitrogen atmosphere. Water (10 mL) was added and the solution was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na2SO4 、 filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 7:1) to give ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-4'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate as a colorless oil (230 mg). Yield 65% (ESI 360.2 [M+H-100] + ).

[0506] Step 2: Ethyl (S)-3-amino-3-(4-fluoro-4'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0507]

Chemical Structure

[0508] Preparation of ethyl (S)-3-amino-3-(4'-cyano-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0509] Step 1: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-cyano-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0510] [Chemical formula] (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (450 mg, 1 mmol, 1.0 equiv), 4-bromo-3,5-dimethylbenzonitrile (316 mg, 1.5 mmol, 1.5 equiv), Pd(dppf)Cl2 (37 mg, 0.05 mmol, 0.05 equiv) and K2CO3 (414 mg, 3 mmol, 3.0 equiv) in a mixture of 1,4-dioxane (8 mL) and water (2 mL) was stirred at 110 °C for 2 h under a nitrogen atmosphere. Water (10 mL) was added and the solution was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4 、 filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 1:1) to give (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(4'-cyano-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate as a colorless oil (320 mg). Yield 70% (ESI 455.2 [M+H] + ).

[0511] Step 2: (S)-Ethyl 3-amino-3-(4'-cyano-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0512]

Chemical Structure

[0513] Preparation of ethyl (S)-3-amino-3-(4'-((dimethylamino)methyl)-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0514] Step 1: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-4'-formyl-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0515] [Chemical formula] Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (465 mg, 1.03 mmol, 1.1 equiv), 4-bromo-3,5-dimethylbenzaldehyde (200 mg, 0.93 mmol, 1.0 equiv), K2CO3 (259 mg, 1.87 mmol, 2.0 equiv) and a mixture of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (68 mg, 0.09 mmol, 0.1 equiv) in dioxane (10 mL) and H2O (1 mL) were stirred at 80 °C for 3 h under a nitrogen atmosphere. LCMS indicated that the reaction was complete. The mixture was cooled to room temperature. Water (50 mL) was added and the solution was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 1:3) to give ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-4'-formyl-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate as a yellow oil (300 mg). Yield 64% (ESI 358.1 [M+H-100] + ).

[0516] Step 2: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-((dimethylamino)methyl)-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0517] [Chemical Structure] (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-4'-formyl-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (1.3 g, 2.8 mmol, 1.0 equiv) and dimethylamine hydrochloride (233 mg, 2.9 mmol, 1.05 equiv) in DCE (10 mL) were stirred at room temperature for 30 min. Sodium triacetoxyborohydride (1.2 g, 5.6 mmol, 2.0 equiv) was added and the mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM:MeOH 9:1) to give (S)-ethyl 3-((tert-butoxycarbonyl)amino)-3-(4'-((dimethylamino)methyl)-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate as a yellow oil (800 mg). Yield 58.7% (ESI 487.2 (M+H) + )

[0518] Step 3: (S)-Ethyl 3-amino-3-(4'-((dimethylamino)methyl)-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0519] [Chemical formula] A stirred solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-((dimethylamino)methyl)-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (800 mg, 1.64 mmol, 1.0 equiv) in DCM (10 mL) was treated with HCl-dioxane (4 M, 3 mL, 12.0 mmol) and stirred at room temperature for 1 h. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo and the residue was purified by reverse phase on a C18 / 40 g column (A: water, 10 mM NH4HCO3, B: MeOH, 0 - 100%) to afford ethyl (S)-3-amino-3-(4'-((dimethylamino)methyl)-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate as a white solid (600 mg). Yield 94% (ESI 387.2 (M+H) + ).

[0520] Preparation of ethyl (S)-3-amino-3-(4-fluoro-4'-((3-fluoroazetidin-1-yl)methyl)-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0521] Step 1: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-4'-((3-fluoroazetidin-1-yl)methyl)-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0522] [Chemical formula] (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-4'-formyl-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (1.3 g, 2.8 mmol, 1.0 equiv) and 3-fluoroazetidine hydrochloride (233 mg, 2.9 mmol, 1.05 equiv) in DCM (10 mL) were stirred at room temperature for 30 min. Sodium triacetoxyborohydride (1.2 g, 5.6 mmol, 2.0 equiv) was added and the mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM:MeOH 9:1) to give (S)-ethyl 3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-4'-((3-fluorocyclobutyl)methyl)-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate as a yellow oil (800 mg). Yield 54.7% (ESI 517.2 [M+H] + ).

[0523] Step 2: (S)-Ethyl 3-amino-3-(4-fluoro-4'-((3-fluoroazetidin-1-yl)methyl)-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0524] [Chemical Structure] A solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-4'-((3-fluoroazetidin-1-yl)methyl)-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (800 mg, 1.5 mmol, 1.0 equiv) in DCM (10 mL) was added to HCl-dioxane (4 M, 10.0 mL, 40.0 mmol, 26.7 equiv), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, and the residue was purified by reverse-phase HPLC on a C18 / 120 g column (A: water / 0.01% TFA, B: MeOH, 0 - 100%) to give ethyl (S)-3-amino-3-(4-fluoro-4'-((3-fluoroazetidin-1-yl)methyl)-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate as a white solid (500 mg). Yield 78% (ESI 417.1 [M+H] + ).

[0525] Preparation of ethyl (S)-3-amino-3-(2'-cyclopropyl-4-fluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0526] Step 1: 2-bromo-1-chloro-3,5-dimethylbenzene

[0527] [Chemical formula] To a mixture of 2-chloro-4,6-dimethylaniline (3.0 g, 19.3 mmol, 1.00 equiv) and CuBr2 (21.5 g, 96.5 mmol, 5.00 equiv) in ACN (50 mL) was added t-BuONO (5.96 g, 58.9 mmol, 3.00 equiv), and the mixture was stirred at 60 °C for 2 h under a nitrogen atmosphere. The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (petroleum ether 100%) to give the compound 2-bromo-1-chloro-3,5-dimethylbenzene as a colorless oil (2.8 g). Yield: 67% (ESI 220 [M+H]+).

[0528] Step 2: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0529]

Chemical formula

[0530] Step 3: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0531]

Chemical formula

[0532] Step 4: Ethyl (S)-3-amino-3-(2'-cyclopropyl-4-fluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0533]

Chemical formula

[0534] Preparation of ethyl (S)-3-amino-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0535] Step 1: 2-Bromo-6-fluoro-3-methylbenzaldehyde

[0536] [Chemical formula] To a mixture of 2-bromo-4-fluoro-1-methylbenzene (5.0 g, 26.5 mmol, 1.00 equiv) in anhydrous THF (50 mL) under a nitrogen atmosphere, lithium diisopropylamide (2.0 M, 14.6 mL, 29.2 mmol, 1.10 equiv) was added at -78 °C, and the mixture was stirred at -78 °C for 1 hour. DMF (3.87 g, 53 mmol, 2.00 equiv) was added to the reaction mixture at -78 °C, and the mixture was stirred at -78 °C for 0.5 hour, then slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched with water (20 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product 2-bromo-6-fluoro-3-methylbenzaldehyde as a brown liquid (4.2 g). Yield 73%. 1 1H NMR (400 MHz, MeOD) δ 10.02 (s, 1H), 7.45 - 7.17 (m, 1H), 7.05 - 7.00 (m, 1H), 2.26 (s, 3H).

[0537] Step 2: (2-Bromo-6-fluoro-3-methylphenyl)methanol

[0538]

Chemical formula

[0539] Step 3: (2-Bromo-3-(bromomethyl)-4-fluoro-1-methylbenzene

[0540] [Chemical formula] To a mixture of (2-bromo-6-fluoro-3-methylphenyl)methanol (3.2 g, 14.6 mmol, 1.00 equivalent) in THF (50 mL) under a nitrogen atmosphere, PBr3 (3 mL, 29.2 mmol, 2.00 equivalents) was added at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column (petroleum ether:EtOAc 99:1) to obtain 2-bromo-3-(bromomethyl)-4-fluoro-1-methylbenzene as a white solid (3.58 g). Yield 90%. 1 1H NMR (400 MHz, MeOD) δ 7.33 - 7.30 (m, 1H), 7.09 - 7.04 (m, 1H), 4.72 (d, J = 2.0 Hz, 2H), 2.40 (s, 3H).

[0541] Step 4: 2-Bromo-4-fluoro-1,3-dimethylbenzene

[0542] [Chemical formula] To a mixture of 2-bromo-3-(bromomethyl)-4-fluoro-1-methylbenzene (2.0 g, 7.09 mmol, 1.00 equivalent) in DMF (20 mL), NaBH4 (0.536 g, 14.18 mmol, 2.00 equivalents) and AgNO3 (2.4 g, 14.18 mmol, 2.00 equivalents) were added at room temperature. The reaction was stirred at room temperature for 0.5 hour. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 、 filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM 100%) to obtain 2-bromo-4-fluoro-1,3-dimethylbenzene as a colorless oil (1.00 g). Yield 69%. 11H NMR (400 MHz, CDCl3) δ 7.09 - 7.01 (m, 1H), 6.90 (t, J = 8.7 Hz, 1H), 2.37 (s, 3H), 2.34 (d, J = 2.4 Hz, 3H).

[0543] Step 5: Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0544]

Chemical formula

[0545] Step 6: Ethyl (S)-3-amino-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride

[0546] [Chemical formula] To a mixture of the product ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (1.2 g, 2.68 mmol, 1.00 equiv) in 1,4-dioxane (6 mL) was added HCl-dioxane (4 M 4.0 mL, 16.0 mmol, 5.97 equiv). The mixture was stirred at room temperature for 1 h. LCMS indicated that the reaction was complete. The mixture was concentrated in vacuo to give ethyl (S)-3-amino-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate hydrochloride (1.0 g, crude), which was used directly in the next reaction without further purification. (ESI 348.2 [M+H] + ).

[0547] Preparation of (S)-ethyl 3-amino-3-(4-fluoro-3'-methoxy-2',5,6'-trimethylbiphenyl-3-yl)propanoate

[0548] Step 1: 1-Bromo-2,4-dimethyl-3-nitrobenzene

[0549] [Chemical formula] To a mixture of 1,3-dimethyl-2-nitrobenzene (10 g, 66 mmol, 1.0 equiv) in DCM (100 mL) were added FeBr3 (390 mg, 211.32 mmol, 0.02 equiv) and Fe (1.12 g, 20 mmol, 0.3 equiv). Br2 (11.6 g, 72.6 mmol, 1.1 equiv) was added dropwise, and the mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column (petroleum ether) to give 1-bromo-2,4-dimethyl-3-nitrobenzene as a white solid (10 g). Yield 66%.

[0550] Step 2: 1-Methoxy-2,4-dimethyl-3-nitrobenzene

[0551]

Chemical formula

[0552] Step 3: 3-Methoxy-2,6-dimethylaniline

[0553]

Chemical formula

[0554] Step 4: 2-Bromo-4-methoxy-1,3-dimethylbenzene

[0555]

Chem.

[0556] Step 5: (S)-Ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethylbiphenyl-3-yl)propanoate

[0557]

Chem.

[0558] Step 6: (S)-ethyl 3-amino-3-(4-fluoro-3'-methoxy-2',5,6'-trimethylbiphenyl-3-yl)propanoate

[0559] [Chemical formula] (S)-Ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethylbiphenyl-3-yl)propanoate (1 g, 2.18 mmol, 1.00 equiv) in DCM (8 mL) was stirred, and HCl-dioxane (4 M, 2.18 mL, 8.72 mmol, 4 equiv) was added. The mixture was stirred at room temperature for 2 h. LCMS indicated the completion of the reaction. The mixture was concentrated in vacuo, and the residue was purified by reverse-phase HPLC on a C18 / 80 g column (A: water, 10 mM NH4HCO3, B: MeOH, 0 - 100%) to give (S)-ethyl 3-amino-3-(4-fluoro-3'-methoxy-2',5,6'-trimethylbiphenyl-3-yl)propanoate (600 mg) as a colorless oil. Yield 77% (ESI 360.1 [M+H] + ).

[0560] Preparation of Ethyl (S)-3-amino-3-(6'-cyano-4-fluoro-2',3',5-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0561] Step 1: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6'-cyano-4-fluoro-2',3',5-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0562]

Chemical Structure

[0563] Step 2: Ethyl (S)-3-amino-3-(6'-cyano-4-fluoro-2',3',5-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0564] [Chemical formula] A stirred solution of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6'-cyano-4-fluoro-2',3',5-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (500 mg, 1.1 mmol, 1.0 equiv) in DCM (10 mL) was treated with HCl-dioxane (4 M, 10 mL, 40.0 mmol, 36.4 equiv). The mixture was stirred at room temperature for 1 h. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18 / 40 g column (A: water, 10 mM NH4HCO3, B: MeOH, 0 - 100%) to afford ethyl (S)-3-amino-3-(6'-cyano-4-fluoro-2',3',5-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (200 mg) as a colorless oil. Yield 51.8% (ESI 355.2 [M+H] + ).

[0565] Preparation of (S)-ethyl 3-amino-3-(3',4-difluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoate

[0566] Step 1: (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(3',4-difluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoate

[0567] [Chemical Structure] (S)-Ethyl 3-(tert-butoxycarbonylamino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (500 mg, 1.14 mmol, 1 equiv) and 2-bromo-4-fluoro-1,3,5-trimethylbenzene (309 mg, 1.43 mmol, 1.2 equiv) in dioxane (10 mL) were added to a solution of K2CO3 (314.6 mg, 2.28 mmol, 2 equiv) in H2O (2 mL) and Pd(dppf)Cl2 (80 mg, 0.11 mmol, 0.1 equiv). The mixture was heated at 110 °C for 2 h under a nitrogen atmosphere. Water (20 mL) was added and the solution was extracted with EtOAc (20 mL × 3). The combined organic layers were concentrated in vacuo and the residue was purified by silica gel column (petroleum ether:EtOAc 1:1) to give methyl (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(3',4-difluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoate as a colorless oil (500 mg). Yield 97.8% (ESI 461.5 [M+H] + ).

[0568] Step 2: (S)-Ethyl 3-amino-3-(3',4-difluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoate

[0569]

Chem.

[0570] Preparation of ethyl (S)-3-(5-bromo-3-chloro-2-fluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate

[0571] Step 1: (R,E)-N-(5-bromo-3-chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide

[0572] [Chemical formula] (R,E)-N-(5-Bromo-3-chloro-2-fluorobenzylidene)-2-methylpropan-2-sulfinamide was obtained as a yellow oil (14.0 g) in 98% yield (ESI 341.9 (M+H) + ) by purifying the residue on a silica gel column (petroleum ether: EtOAc 4:1).

[0573] Step 2: Ethyl (S)-3-(5-bromo-3-chloro-2-fluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate

[0574] [Chemical formula] To a mixture of Zn (13.0 g, 205.5 mmol, 5.00 equiv) in anhydrous THF (200 mL) under a nitrogen atmosphere, chlorotrimethylsilane (888 mg, 8.22 mmol, 0.2 equiv) was added dropwise at room temperature, and the mixture was stirred at 50 °C for 1 hour under a nitrogen atmosphere. The mixture was cooled to 20 - 30 °C. Ethyl 2-bromoacetate (17.1 g, 102.7 mmol, 2.50 equiv) was added dropwise at room temperature under a nitrogen atmosphere, and the mixture was stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature. A solution of (R,E)-N-(5-bromo-3-chloro-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (14.0 g, 41.1 mmol, 1.00 equiv) in anhydrous THF (20 mL) was added dropwise to the mixture at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. LCMS indicated that the reaction was complete. Water (100 mL) and EtOAc (100 mL) were added to the mixture, and the mixture was stirred at room temperature for 5 minutes. The mixture was filtered. The filtrate was extracted with EtOAc (100 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 4:1) to obtain ethyl (S)-3-(5-bromo-3-chloro-2-fluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate as a yellow oil (12.0 g). Yield 73% (ESI 429.9 (M+H) + ).

[0575] Preparation of Ethyl (S)-3-Amino-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0576] Step 1: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0577]

Chemical Structure

[0578] Step 2: (S)-Ethyl 3-amino-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0579] [Chemical formula] To a mixture of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (3.0 g, 43.66 mmol, 1.0 equiv) in DCM (20 mL) was added HCl-dioxane (4 M, 20 mL, 80 mmol, 1.8 equiv). The mixture was stirred at room temperature for 1 h. LCMS indicated the completion of the reaction. The mixture was concentrated in vacuo and the residue was purified by reverse-phase HPLC on a C18 / 120 g column (A: water, 10 mM NH4HCO3, B: MeOH, 0 - 100%) to give ethyl (S)-3-amino-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate as a white solid (1.8 g). Yield 78% (ESI 350.0 [M+H] + ).

[0580] Preparation of ethyl (S)-3-amino-3-(5-chloro-4,4'-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0581] Step 1: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-chloro-4,4'-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0582] [Chemical formula] (S)-Ethyl 3-(5-bromo-3-chloro-2-fluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate (2.0 g, 4.66 mmol, 1.0 equiv) and (4-fluoro-2,6-dimethylphenyl)boronic acid (940 mg, 5.59 mmol, 1.2 equiv) in a mixture of dioxane (20 mL) was added a solution of K2CO3 (1.3 g, 9.32 mmol, 2.0 equiv) in H2O (2 mL) and Pd(dppf)Cl2 (341 mg, 0.47 mmol, 0.1 equiv). The mixture was heated at 110 °C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 1:1) to give (S)-ethyl 3-(((R)-tert-butylsulfinyl)amino)-3-(5-chloro-4,4'-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate as a colorless oil (1.2 g). Yield 54% (ESI 472.1 [M+H] + ).

[0583] Step 2: (S)-Ethyl 3-amino-3-(5-chloro-4,4'-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0584] [Chemical formula] A mixture of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-chloro-4,4'-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (1.2 g, 2.54 mmol, 1.0 equiv) in DCM (6 mL) was added to HCl-dioxane (4 M, 3 mL, 12 mmol, 4.7 equiv). The mixture was stirred at room temperature for 1 h. LCMS indicated that the reaction was complete. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18 / 80 g column (A: water, 0.01% TFA, B: MeOH, 0 - 100%) to give ethyl (S)-3-amino-3-(5-chloro-4,4'-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate as a white solid (900 mg). Yield 96% (ESI 368.1[M+H] + )。

[0585] Preparation of ethyl (S)-3-amino-3-(5-chloro-4-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0586] Step 1: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-chloro-4-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0587]

Chemical Structure

[0588] Step 2: (S)-Ethyl 3-amino-3-(5-chloro-4-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0589] [Chemical formula] A mixture of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-chloro-4-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (1.9 g, 4.06 mmol, 1.0 equiv) in DCM (20 mL) was added to HCl-dioxane (4 M, 3 mL, 12 mmol, 3.0 equiv). The mixture was stirred at room temperature for 1 h. LCMS indicated that the reaction was complete. The mixture was concentrated in vacuo and the residue was purified by reverse-phase HPLC on a C18 / 120 g column (A: water, 10 mM NH4HCO3, B: MeOH, 0 - 100%) to give ethyl (S)-3-amino-3-(5-chloro-4-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate as a white solid (1.3 g). Yield 88% (ESI 364.1 (M+H) + ).

[0590] Preparation of ethyl (S)-3-(5-bromo-2,3-difluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate

[0591] Step 1: (R,E)-N-(5-bromo-2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide

[0592] [Chemical formula] A mixture of 5-bromo-2,3-difluorobenzaldehyde (4.5 g, 20.36 mmol, 1.0 equiv) and (R)-2-methylpropan-2-sulfinamide (2.7 g, 22.40 mmol, 1.1 equiv) in anhydrous THF (50 mL) was added dropwise with Ti(OEt)4 (9.3 g, 40.72 mmol, 2.0 equiv) at room temperature while maintaining the temperature below 30 °C under a nitrogen atmosphere. The reaction mixture was warmed to 35 °C and stirred for 1 h. LCMS indicated that the reaction was complete. Water (50 mL) and EtOAc (50 mL) were added to the mixture, and the mixture was stirred at room temperature for 10 min. The mixture was filtered and washed with EtOAc (50 mL). The filtrate was separated. The organic layer was washed with water (70 mL) and brine (70 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 4:1) to give (R,E)-N-(5-bromo-2,3-difluorobenzylidene)-2-methylpropan-2-sulfinamide as a yellow oil (6.0 g). Yield 91% (ESI 325.9 (M+H) + ).

[0593] Step 2: Ethyl (S)-3-(5-bromo-2,3-difluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate

[0594]

Chem.

[0595] Preparation of Ethyl (S)-3-Amino-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0596] Step 1: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0597] [Chemical Structure Diagram] (S)-Ethyl 3-(5-bromo-2,3-difluorophenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate (1.0 g, 2.4 mmol, 1.00 equiv), K2CO3 (664 mg, 4.8 mmol, 2.0 equiv), Pd(dppf)Cl2 (175 mg, 0.24 mmol, 0.1 equiv) and (2,6-dimethylphenyl)boronic acid (720 mg, 4.8 mmol, 2.00 equiv) in dioxane (12 mL) and H2O (1.2 mL) were stirred at 110 °C for 2 h under a nitrogen atmosphere. LCMS indicated that the reaction was complete. The reaction mixture was poured into 50 mL of water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether:EtOAc 2:1) to give (S)-ethyl 3-(((R)-tert-butylsulfinyl)amino)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate as a yellow oil (900 mg). Yield 85% (ESI 438.1 (M+H) + )

[0598] Step 2: (S)-Ethyl 3-amino-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0599] [Chemical formula] To a mixture of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (900 mg, 2.06 mmol, 1.0 equiv) in DCM (4 mL) was added HCl-dioxane (4 M, 2 mL, 8.0 mmol, 3.88 equiv). The mixture was stirred at room temperature for 1 h. LCMS indicated the completion of the reaction. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18 / 40 g column (A: water / 0.01% TFA, B: MeOH, 0 - 100%) to give ethyl (S)-3-amino-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate as a pale yellow solid (800 mg). Yield 90% (ESI 334.1 [M+H] + ).

[0600] Preparation of ethyl (S)-3-amino-3-(4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0601] Step 1: Ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0602]

Chemical formula

[0603] Step 2: (S)-Ethyl 3-amino-3-(4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0604] [Chemical formula] A mixture of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate (1.0 g, 2.2 mmol, 1.0 equiv) in DCM (4 mL) was added to HCl-dioxane (4 M, 2 mL, 4.0 mmol, 1.8 equiv). The mixture was stirred at room temperature for 1 h. LCMS indicated that the reaction was complete. The mixture was concentrated in vacuo and the residue was purified by reverse-phase HPLC on a C18 / 80 g column (A: water, 10 mM NH4HCO3, B: MeOH, 0 - 100%) to give ethyl (S)-3-amino-3-(4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate as a white solid (750 mg). Yield 97% (ESI 352.1 [M+H] + ).

[0605] Preparation of ethyl (S)-3-amino-3-(4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0606] Scheme:

[0607]

Chem.

[0608]

Chem.

[0609] Step 2: (S)-Ethyl 3-amino-3-(4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate

[0610] [Chemical formula] To a mixture of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (1.4 g, 3.1 mmol, 1.0 equiv) in DCM (20 mL) was added HCl-dioxane (4 M, 2 mL, 8.0 mmol, 2.58 equiv). The mixture was stirred at room temperature for 1 h. LCMS indicated that the reaction was complete. The mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18 / 120 g column (A: water / 0.01% TFA, B: MeOH, 0 - 100%) to give ethyl (S)-3-amino-3-(4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate as a pale yellow solid (1.0 g). Yield 93% (ESI 348.1 (M+H) + ).

[0611] Preparation of ethyl (S)-3-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate

[0612] Step 1: 5-Bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde

[0613]

Chemical formula

[0614] Step 2: (R,E)-N-(5-Bromo-2-fluoro-3-(trifluoromethyl)benzylidene)-2-methylpropan-2-sulfinamide

[0615] [Chemical formula] To a mixture of 5-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (8.0 g, 29.50 mmol, 1.00 equiv) and (R)-2-methylpropan-2-sulfinamide (3.9 g, 32.45 mmol, 1.1 equiv) in anhydrous THF (100 mL) under a nitrogen atmosphere, Ti(OEt)4 (13.0 g, 59.00 mmol, 2.00 equiv) was added dropwise at room temperature while maintaining the temperature below 30 °C. The reaction mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. LCMS indicated the completion of the reaction. Water (100 mL) and EtOAc (100 mL) were added to the mixture and stirred at room temperature for 5 min. The mixture was filtered and washed with EtOAc (50 mL). The filtrate was separated. The organic layer was washed with water (50 mL) and brine (50 mL), dehydrated over anhydrous Na2SO 4, 4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 5:1) to give (R,E)-N-(5-bromo-2-fluoro-3-(trifluoromethyl)benzylidene)-2-methylpropan-2-sulfinamide as a yellow oil (8.0 g). Yield 72% (ESI 373.9 (M+H) + ).

[0616] Step 3: Ethyl (S)-3-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate

[0617]

Chem.

Claims

1. A compound selected from the group consisting of: a. (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; b. (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoic acid; c. (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid; d. (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid; e. (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; f. (S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid; g. (S)-3-((S)-2-(5-(2-(Dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoic acid; h. (S)-3-(4,4'-Difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; i. (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamido)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid; j. (S)-3-(4-Fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; and k. (S)-3-(4-Fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; or a pharmaceutically acceptable salt thereof, for treating an α 4 β 7 integrin-mediated condition, a medicament for treating an wherein the α4β7 integrin-mediated condition is a gastrointestinal autoinflammatory or autoimmune disease Pharmaceutical.

2. The pharmaceutical according to claim 1, wherein the compound is (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid, or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical according to claim 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical according to claim 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical according to claim 1, wherein the compound is (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical according to claim 1, wherein the compound is (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical according to claim 1, wherein the compound is (S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical according to claim 1, wherein the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical according to claim 1, wherein the compound is (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical according to claim 1, wherein the compound is (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamide)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical according to claim 1, wherein the compound is (S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical according to claim 1, wherein the compound is (S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)propanoic acid, or a pharmaceutically acceptable salt thereof.

13. A compound selected from the group consisting of: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, and one or more other components, an α 4 β 7 A composition for treating an integrin-mediated condition, comprising wherein the α4β7 integrin-mediated condition is a gastrointestinal autoinflammatory or autoimmune disease Composition.

14. The compound is [Chemical Formula 2] or a pharmaceutically acceptable salt thereof, the composition according to claim 13.

15. The compound is 【Chemical Formula 3】 The composition according to claim 13, which is or a pharmaceutically acceptable salt thereof.

16. The compound is 【Chemical 4】 The composition according to claim 13, which is or a pharmaceutically acceptable salt thereof.

17. The compound is 【Chemical Formula 5】 The composition according to claim 13, which is or a pharmaceutically acceptable salt thereof.

18. The compound is 【Chemical Formula 6】 The composition according to claim 13, which is or a pharmaceutically acceptable salt thereof.

19. The compound is 【Chemical Formula 7】 The composition according to claim 13, which is or a pharmaceutically acceptable salt thereof.

20. The compound is 【Chemical 8】 The composition according to claim 13, which is or a pharmaceutically acceptable salt thereof.

21. The compound is 【Chemical Formula 9】 The composition according to claim 13, which is or a pharmaceutically acceptable salt thereof.

22. The compound is 【Chemical Formula 10】 The composition according to claim 13, which is or a pharmaceutically acceptable salt thereof.

23. The compound is 【Chemical 11】 The composition according to claim 13, which is or a pharmaceutically acceptable salt thereof.

24. The compound is 【Chemical Formula 12】 The composition according to claim 13, which is or a pharmaceutically acceptable salt thereof.

25. Said α 4 β 7 The pharmaceutical according to any one of claims 1 to 12, wherein the integrin-mediated state is selected from inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD).

26. said α 4 β 7 The medicament according to claim 25, wherein the integrin-mediated state is inflammatory bowel disease (IBD).

27. the aforementioned α 4 β 7 The medicament according to claim 25, wherein the integrin-mediated state is ulcerative colitis (UC).

28. Said α 4 β 7 The medicament according to claim 25, wherein the integrin-mediated condition is Crohn's disease (CD).

29. The composition according to any one of claims 13 to 24, wherein the one or more other components are pharmaceutically acceptable excipients.

30. said α 4 β 7 The composition according to any one of claims 13 to 24 and 29, wherein the integrin-mediated state is selected from inflammatory bowel disease (IBD), ulcerative colitis (UC), and Crohn's disease (CD).

31. Said α 4 β 7 The composition according to claim 30, wherein the integrin-mediated state is inflammatory bowel disease (IBD).

32. Said α 4 β 7 The composition according to claim 30, wherein the integrin-mediated state is ulcerative colitis (UC).

33. said α 4 β 7 The composition according to claim 30, wherein the integrin-mediated condition is Crohn's disease (CD).

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